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Gut Microbiome–Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders
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ACS Chemical Neuroscience

Cite this: ACS Chem. Neurosci. 2023, 14, 10, 1717–1763
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https://doi.org/10.1021/acschemneuro.3c00127
Published May 8, 2023

Copyright © 2023 The Authors. Published by American Chemical Society. This publication is licensed under

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Abstract

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Gut microbiota includes a vast collection of microorganisms residing within the gastrointestinal tract. It is broadly recognized that the gut and brain are in constant bidirectional communication, of which gut microbiota and its metabolic production are a major component, and form the so-called gut microbiome–brain axis. Disturbances of microbiota homeostasis caused by imbalance in their functional composition and metabolic activities, known as dysbiosis, cause dysregulation of these pathways and trigger changes in the blood–brain barrier permeability, thereby causing pathological malfunctions, including neurological and functional gastrointestinal disorders. In turn, the brain can affect the structure and function of gut microbiota through the autonomic nervous system by regulating gut motility, intestinal transit and secretion, and gut permeability. Here, we examine data from the CAS Content Collection, the largest collection of published scientific information, and analyze the publication landscape of recent research. We review the advances in knowledge related to the human gut microbiome, its complexity and functionality, its communication with the central nervous system, and the effect of the gut microbiome–brain axis on mental and gut health. We discuss correlations between gut microbiota composition and various diseases, specifically gastrointestinal and mental disorders. We also explore gut microbiota metabolites with regard to their impact on the brain and gut function and associated diseases. Finally, we assess clinical applications of gut-microbiota-related substances and metabolites with their development pipelines. We hope this review can serve as a useful resource in understanding the current knowledge on this emerging field in an effort to further solving of the remaining challenges and fulfilling its potential.

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Introduction

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The Earth microbiome represents the majority of the planet’s biodiversity. Microbial life was the first to inhabit Earth. (1) Microbes regulate global nutrient cycles, greenhouse gas exchange, as well as disease transmission and protection, thus providing essential life support to the planet. (2) Among many other harbors, including plants, animals, soil, and entire ecosystems, a wide diversity of microorganisms colonize the human body, which are now known to play an essential role in the human host by regulating key physiological functions.
The large collection of microorganisms inhabiting the human body are predominantly bacteria, but also viruses, protozoa, fungi, and archaea. They are collectively known as the human microbiota. Those microorganisms residing in the digestive tracts are known as gut flora or gut microbiota. As a matter of fact, there are more bacterial cells in the human body than human cells─roughly 40 trillion bacterial cells versus only 30 trillion human cells. Together, they function as an extra organ in the human body─a so-called “forgotten organ”─since these microbes have a collective metabolic activity equal to a virtual organ. (3) The collective genome of the gut microbes, the gut microbiome, exceeds over 100 times the amount of human genome in the body. (4) Considering such enormous genetic potential of the microbiota, it is anticipated that it plays a role in virtually all physiological processes in the human body, including metabolic functions and immune homeostasis. (5−11)
Despite being considered a relatively new field of research, the first reports of human-associated microbiota date back to the 17th century when Antonie van Leeuwenhoek described five different kinds of oral bacteria. (12) In the following decades, the foundations of microbiology were laid, and knowledge of the host–microorganism interactions has accumulated (Figure 1). (13−22) Despite these early findings, rapid development of the field only started when methods to culture anaerobic organisms were set up in the mid-20th century when representatives of the microbiota were grown and studied in the laboratory. (23)

Figure 1

Figure 1. Timeline of major research and development milestones related to the microbiome. (12−30,39,49−80)

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In the 2010s, the gut microbiome field burst into the life sciences research and industry, which prompted Forbes to declare the 2010s “The Decade of the Microbiome.” (24) This growth in the field was largely related to the National Institutes of Health’s “The Human Microbiome Project” (25) and the MetaHIT project funded by the European Union. (26) In 2005, the International Human Microbiome Consortium (IHMC) was founded in a cooperative effort to study the microbiome in human health and disease with the ultimate goal of applying this knowledge to prevent and/or treat diseases, and the abovementioned megaprojects have contributed to fulfilling this goal. They provided significant evidence for the relationship between metabolic, neurological, and autoimmune disorders; allergies, infections, and cancers; and the microorganisms that live on and in humans. Specifically, gastrointestinal diseases/disorders, such as inflammatory bowel diseases that include both Crohn’s disease and ulcerative colitis, irritable bowel syndrome (IBS), functional dyspepsia (FD), constipation, celiac disease, and more, are attracting attention with their close relation to the gut microbiome. Because of these findings and the essential part the gut microbiome plays in drug metabolism, the microbiome has become a popular target in the biotechnology industry. In 2010, the first extensive catalogue of human intestinal microbial genes was published on the basis of the studies of 124 individuals. (27) In 2011, the Human Microbiome Project published the sequences of 178 bacterial species. (28)
Although DNA sequencing has been used for decades, it was only after the development of next-generation sequencing when metagenomic studies became affordable. (29) The term metagenomics is used to describe genetic studies of microbial assemblies from environmental samples using sequence-based bioinformatics tools. (30) The goal of these studies is to identify the taxonomic diversity of the microbiota and to differentiate the biological roles of the representatives of such samples by performing functional metagenomics.
The human microbiota plays an essential role in human physiology and pathology. It collaborates closely with the digestive tract in several important aspects: (a) it promotes digestion by assisting the absorption of nutrients by gut cells or the fermentation of some food fractions, which generate important metabolites, including short-chain fatty acids; (31) (b) it supports the maturation of the digestive tract by participating in the assembly of gastrointestinal mucus and promoting the enzymatic activity of the mucosa; (32) (c) it performs a barrier function against pathogens and toxins, where some bacteria release antimicrobial agents that protect from the pathogenic bacteria; (33) (d) it plays a protective role in promoting the immune system development; and (e) it supports in the synthesis of essential vitamins like vitamin B: Magnúsdóttir et al. estimated that 86% of the recommended daily allowance (RDA) of vitamin B6, 37% of the RDA of vitamin B9, 31% of the RDA of vitamin B12, and 27% of the RDA of vitamin B3 could be provided by the human gut microbiota. (34)
Gut microbial disruption (dysbiosis) causes not only gastrointestinal disorders but also disorders in other distal organs and systems. Not long ago, it was found that gut bacteria can affect the central nervous system (CNS) functions. (35−38) Indeed, the gut and brain are in constant bidirectional communication, of which the microbiota and its metabolic production are a major component. The gut and brain connect via a neuro-immuno-humoral network of signaling pathways known as the gut microbiome–brain axis, which includes the vagus nerve, the immune system, the hormonal system, and bacterial metabolites and products. (39) The digestive system, including the inhabiting microbiota, was even called “the second brain” (40) at the time when scientists were beginning to realize that the gut and the brain in humans were involved in constant crosstalk and significantly modulate each other’s function. During disturbance of the microbiota homeostasis caused by an imbalance in their functional composition and metabolic activities, known as dysbiosis, these routes are dysregulated and cause changes in the permeability of the blood–brain barrier (BBB), neuroinflammation, and other pathological malfunctions, including a range of neurodevelopmental and neurodegenerative disorders. (41) Disorders of the gut–brain interaction (DGBI) is the recent term proposed by Rome Foundation guidelines for a range of functional gastrointestinal disorders including but not limited to IBS, FD, and functional constipation. This highlights the central role of the miscommunication between the gut and brain in these digestive disorders. (42) The gut microorganisms transform and metabolize dietary- and host-derived substances to generate a diverse set of metabolites with important local and systemic outcomes, thereby building a network of immunological, neuronal, and endocrine signaling pathways.
It is generally believed that bacterial colonization begins during birth. (43) The neonatal microbiota differs depending on mode of delivery: in vaginally delivered infants, it resembles the maternal vaginal microbiota, while the microbiota in those delivered by cesarean section resembles the maternal skin microbiota. (44) Premature birth, feeding method, and perinatal administration of antibiotics are also among the conditions affecting the development of the neonatal microbiome. (45) Recently, a new mode of horizontal mother-to-infant microbiome transmission has been revealed where microbes in the maternal gut shared genes with microbes in the infant gut during the perinatal period, which starts shortly before birth and prolongs throughout the first few weeks after birth. (46) A major factor of gut microbiota composition during adulthood is diet. Prompt changes in microbiota composition take place in response to dietary style changes. Specific patterns have been reported in plant-based versus animal-based diets. (47,48) The development and modifications of the gut microbiota are influenced by multiple other factors, such as exposure to stress, environmental conditions, medications intake, lifecycle, medical disorders, and procedures.
The human gut microbiota is divided into many groups called phyla. The gut microbiota primarily comprises four main phyla, including Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria, with the Firmicutes and Bacteroidetes representing 90% of gut microbiota. (81,82) The majority of bacteria reside within the gastrointestinal tract, with most predominantly anaerobic bacteria housed in the large intestine. (83)
In recent years, sizable technological progress and wealth of knowledge have promoted the advancement of microbiome research, thereby enhancing our understanding of its relationship to human physiology and pathologies. In this paper, we review the advances in the knowledge related to the human gut microbiome, its complexity and functionality, its communication with the central nervous system, and the effect of the gut microbiome–brain axis on mental and digestive health. We examine data from the CAS Content Collection, (15) the largest human-curated collection of published scientific information and analyze the publication landscape of recent research in order to provide insights into the scientific advances in the area. We also discuss the correlations between the gut microbiota composition and various diseases, specifically digestive system diseases, mental, and neurodegenerative disorders. We furthermore explore the gut microbiota metabolites with regard to their impact on brain, digestive functions, and their associated diseases. Subsequently, we assess the clinical applications of gut microbiota-related substances and metabolites, their development pipelines, disease categories, development stages, and publication trends. We hope this review can serve as a useful resource in understanding the current state of knowledge in the field of gut microbes and the gut microbiome–brain interactions in an effort to further solve the remaining challenges for fulfilling the potential of the field.

Landscape of Gut Microbiome Research─Insights from the CAS Content Collection

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The CAS Content Collection (84) is the largest human-curated collection of published scientific knowledge. It is a comprehensive resource to access and remain well-informed on the world’s available scientific literature across disciplines, including chemistry, biomedical sciences, engineering, materials science, agricultural science, and many more, thus allowing quantitative analysis of global scientific publications against variables, such as time, research area, application, disease association, and chemical composition. A search in the CAS Content Collection showed an intense increase of the documents related to microbiome research in the past decade, which overcame other “omics” exploration─for example, the number of proteomics-related documents held up after the initial burst in the early 2000s and were surpassed by the microbiome documents after 2016 (Figure 2, inset). Currently, there are over 250 000 scientific publications (mainly journal articles and patents) in the CAS Content Collection related to gut/intestinal microbiome/microbiota. Nearly 15 000 of them are related to various aspects of mental and gut health. There is a steady, exponential growth of the number of journal articles over time that has been rather explosive from 2021–2022 (Figure 2). The number of patents rapidly grew until 2004, which possibly correlated with the initial accumulation of knowledge and its transfer into patentable applications. Later on, the growth substantially slowed down, perhaps awaiting the forthcoming breakthroughs in the gut microbiome awareness (Figure 2).

Figure 2

Figure 2. Journal and patent publication trends on gut microbiome research related to mental and gut health according to the CAS Content Collection. Inset: microbiome vs proteome document yearly trends.

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The United States, China, Japan, and Korea are the leaders in the number of published journal articles (Figure 3A) and patents (Figure 3B) related to gut microbiome research in the areas of mental and gut health.

Figure 3

Figure 3. Top countries publishing journal articles (A) and patents (B) related to gut microbiome research in mental and gut health.

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Figure 4 presents the flow of patent filings from different applicant locations to various patent offices. Because patent protection is territorial, and the same invention may be filed for protection in multiple jurisdictions, we looked at all relevant filings on gut microbiome research in mental and gut health. One patent family may have been counted multiple times when it was applied in multiple patent offices. There are diverse patent filing strategies: some patent assignees, such as those from China and Korea, file foremost in their home country patent offices (CN, KR), with a smaller proportion filing through other patent offices or other jurisdictions. Others, for instance United States-based applicants, have a nearly equal number of US and WO filings and a considerable number of filings at other patent offices, such as the European Patent Office (EP) and Canada (CA).

Figure 4

Figure 4. Flow of patent filings related to gut microbiome research in mental and gut health from different patent assignee locations (left) to various patent offices of filing (right). The abbreviations on the right indicate the patent offices of United States (US), Australia (AU), World Intellectual Property Organization (WO), Canada (CA), Austria (AT), European Patent Office (EP), Israel (IL), Norway (NO), Hong Kong (HK), Mexico (MX), Japan (JP), Brazil (BR), Spain (ES), India (IN), Russian Federation (RU), China (CN), and Korea (KR).

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In order to better understand the advance in this research area, we examined the occurrence and trends of certain key concepts in the scientific publications relevant to the gut microbiome research in mental and gut health (Figure 5). With respect to the cumulative number of publications, “immunity” and “gut microbiome” appear as top concepts in the area (Figure 5A), thereby reflecting the rising interest in the relationship between the gut microbiome and systemic immune response pathways and the critical role the gut microbiome plays in training and development of the host’s innate and adaptive immune system. It is noteworthy that the concept concerning the gut–brain relationship exhibits the greatest growth rate in the past two years (Figure 5B), thereby characterizing it as the trendiest concept in the field.

Figure 5

Figure 5. Key concepts in the scientific publications relevant to the gut microbiome research in mental and gut health. (A) Number of publications exploring key concepts related to gut microbiome research in mental and gut health. (B) Trends in key concepts presented in the articles related to gut microbiome research in mental and gut health during the years 2016–2021. Percentages are calculated with yearly publication numbers for each key concept, normalized by the total number of publications for the same concept in the same time period.

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Gut-Microbiota-Participant Bacteria

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The human gut microbiome, as mentioned above, is a complex mixture of microorganisms, including viruses, archaea, bacteria, yeasts, and fungi, interacting with each other and with their host in complex ways. These interactions at various times involve symbiosis, mutualism, antagonism, and even predation. Not only does the gut microbiome interact directly with the gastrointestinal (GI) tract, but it also interacts with the immune system that is present in the GI tract and with the neurological system through various signaling systems. Gastrointestinal signaling is mediated in part by microbial metabolites and is involved in regulating the gut–brain axis in the host. (85) This section focuses on the bacterial microbiome by first discussing the techniques used to identify and study the gut microbiome. Then, we will discuss the human GI tract from an ecological viewpoint. The phyla commonly found in the gut microbiome will be defined and discussed. Finally, we will focus on probiotics and related compositions (prebiotics, postbiotics, synbiotics, and psychobiotics) and present recent examples of each class to illustrate the current state of the art.

Techniques Used to Study the Gut Microbiome

Until recently, about 400 bacterial species were identified in the human microbiome using conventional culturing techniques. (86) These techniques, by their nature, underestimate the actual number of species because, to culture a bacterium successfully, one needs to provide the correct nutrients, pH, and redox environment to enable growth. Conventional culture techniques favor fast-growing and nonfastidious species over those present in low concentration, which requires unusual culture conditions and/or complex nutritional requirements. (86) Most isolation methods use selective agents, such as bile salts, to enrich the numbers of a desired bacterial type over others in the sample. The choice of the proper selective agent then becomes important. Some gut bacteria depend on other microorganisms in the gut to provide the nutrients they require for growth “cross-feeding.” Devising culture media for these can be a hit-or-miss proposition. Some bacteria will only grow in niches that have a narrow range of pH and/or redox potential, which may be difficult to maintain in vitro. Although there have been methodological advances in anaerobic culturing techniques, they tend to be tedious, time-consuming, and require specialized equipment. (31) The successful culture of strict anaerobic bacteria requires training, experience, and careful planning. Additionally, some bacteria might be alive but unculturable. Intercellular adherence may reduce the number of organisms that can give rise to colonies. (87)
The development of culture-independent metagenomic approaches, such as 16S RNA gene sequencing and high-throughput sequencing, have been an enabling factor in the study of the human gut microbiome. This topic was reviewed in depth by Sankar et al. in 2015. (86) The 16S rRNA gene exhibits several advantages, including its distribution in all bacterial species, its absence in eukaryotes, its stability over time, and its size (∼1500 bp), that make it suitable for bioinformatic analyses. High-throughput sequencing methods have given unprecedented access to the analysis of the microbial diversity of complex microbiotas, particularly through metagenomic approaches. Two strategies used are high-throughput sequencing of pooled PCR-amplified 16S rRNA and shotgun sequencing of all DNA fragments present, which enables identification of the microorganisms present and their metabolic genes. With these molecular techniques, it is now estimated that the human GI microbiota comprises more than 2000 species using modern molecular methods. (86,88)
Recent impressive advances in next generation sequencing technologies, along with the progress and innovations of metagenomics, metabolomics, multiomics, bioinformatics, and artificial intelligence tools, have provided prospects to better characterize the microbial populations and their functions and help in better correlation prediction.

Gastrointestinal Tract

The gut microbiome varies according to the GI anatomy, which varies in terms of physiology, pH and O2 tension, flow rates (rapid from the mouth to the cecum, slower afterward), substrate availability, and host secretions. (89) Figure 6 presents a representation of the GI tract with some of the bacterial taxa present. The GI tract consists of the stomach, duodenum, jejunum, ilium, cecum, and colon, with each environment ascending in pH and growing progressively more anaerobic from stomach to colon. Each section of the GI tract presents a unique ecological niche that exerts selective pressure on the microbiome. It is an open system with nutrients entering the system intermittently and wastes also leaving intermittently. The microbiome is affected by many factors, including diet, medications (especially antibiotics), ethnicity, age, and general health. (82,83)

Figure 6

Figure 6. Gut-microbiota-participant bacteria.

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The stomach is an extreme habitat because it is highly acidic (pH = ∼1.5). Once, it was considered sterile because of its acidity until the discovery of Helicobacter pylori in this hostile environment in 1982. The microbial population in the gastric environment is low and in the range of 101–103 cells/mL. (87) Investigations since this discovery have revealed that the gastric fluid is predominated by the members of Firmicutes, Bacteroidetes, and Actinobacteria. (87) The gastric mucosa was found to have a rich diversity with bacterial members belonging to Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, and Actinobacteria. In healthy human stomach, the genera Streptococcus, Prevotella, Veillonella, Rothia, and Haemophilus were found to be predominant; however, the composition of the gastric microbiota is dynamic and affected by such factors as diet, drugs, and diseases. (90)
The small intestine comprises the duodenum, jejunum, and ileum. The duodenum has a pH of 5–6.8. Bacterial numbers are 103–104 cells/mL where Firmicutes predominate. (91) The jejunum and ileum have a higher pH (6–8) with a 104–108 cell/mL density that comprises strict to facultative anaerobic Gram-positive and Gram-negative bacteria. The small intestine is lined with simple columnar epithelial tissue, which is covered by a mucus layer, and has a large surface area because of the villi and microvilli. When food enters the duodenum, the pH and bacterial load are low. These small intestinal mucosae are associated with members of phyla Bacteroidetes and Firmicutes. Food is blended with bile, bicarbonate, and digestive enzymes in the duodenum, and when the intestinal contents reach the large intestine, the food blend has been converted to a neutral to alkaline pH. The small intestine provides a more challenging environment for microbial colonizers given the short transit times (3–5 h) and the high bile concentrations. (83,91)
The large intestine consists of the cecum and colon and is characterized by slow flow rates and pH varying from 6 to 7.8. It harbors by far the largest microbial community. The large intestine is strictly anaerobic, and the cell density reaches 1012 cells/mL. The large intestine is home to the most complex bacterial diversity in the GI tract because of several factors, such as its larger volume, moderate or less acidic pH, low concentration of bile salts, and the longer retention time caused by slower peristalsis. Five major phyla─Firmicutes, Bacteroidetes, Actinobacteria, Verrucomicrobia, and Proteobacteria─covering a wide range of bacterial genera─Clostridium, Fusobacterium, Bacteroidetes, Actinomyces, and Propionibacterium─are associated with the large intestine. Other Gram-positive cocci─Micrococci, Peptococci, Peptostreptococci, and Ruminococci─have been also reported to play crucial roles in the large intestine. Food that has not been degraded in the upper GI tract reaches the large intestines and supports the microbiota with nutrients and energy. The carbohydrates present are fermented to carbon dioxide, hydrogen, methane, and short-chain fatty acids (SCFA) (primarily acetate, propionate, and butyrate). Most of the SCFA produced in the large intestine are absorbed by the host and provide an energy source. The amount of energy derived from SCFA accounts for 6–9% of the total energy requirement. (82,88,91,92)
The microbiome composition of the intestinal lumen, known as mucosal and epithelial spaces of the GI tract, is highly diverse and comprises Verrucomicrobia, Fusobacteria, Asteroplasma, Cyanobacteria, Actinobacteria, Lentisphaera, Spirochaetes, Bacteroidetes, Proteobacteria, Bacilli, Clostridia, and Mollicutes. The predominating genera are Escherichia, Klebsiella, Enterococcus, Bacteroides, Ruminococcus, Dorea, Clostridium, Coprococcus, Weisella, and Lactobacillus. Other genera found include Granulicatella, Streptococcus, and Veillonella. (83,91)

Types of Bacteria Found in the GI Tract

The four dominant phyla residents in the human gut are Firmicutes (which contains lactobacilli), Bacteroidetes, Actinobacteria (which contains Bifidobacteria), and Proteobacteria. Other phyla found in lower numbers are the Fusobacteria and Verrucobacteria. Figure 7 presents the significant phyla, families, and genera of gut bacteria in terms of the number of records that cite them in the CAS Content Collection. This presentation reflects the relative level of research interest in each of these taxonomic groups. Most bacteria belong to the genera Bacteroides, Clostridium, Fusobacterium, Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium. Other genera, such as Escherichia and Lactobacillus, are present to a much lesser extent. Twenty-three species from the genus Bacteroides, alone, constitute about 30% of all bacteria in the human gut. (93)

Figure 7

Figure 7. Representation (as number of records) of the gut bacteria phyla and species in the CAS Content Collection.

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Bacteroidetes

Bacteroidetes are Gram-negative, nonspore-forming, anaerobic or aerobic, rod-shaped bacteria. Bacteroides fragilis, found in the human microbiome, is the type of species for this phylum. The majority of the Bacteroidetes species fall into three genera: Prevotella (bile-sensitive, moderately saccharolytic, with pigmented and nonpigmented species), Porphyromonas (bile-sensitive, pigmented, asaccharolytic species), and Bacteroides (bile-resistant, nonpigmented, saccharolytic species). Other genera in the phyla are Alistipes, Anaerorhabdus, Dichelobacter, Fibrobacter, Megamonas, Mitsuokella, Rikenella, Sebaldella, Tannerella, and Tissierella. (94) Some members of the Bacteroides genus, although belonging to the normal gastrointestinal microbiota, can cause opportunistic infections if the integrity of the intestinal mucosal barrier is broken. These infections are usually polymicrobial, but B. fragilis and B. thetaiotaomicron are the most frequent species isolated. Some members of the genera Porphyromonas, Prevotella, and Tannerella are well-known pathogens of the oral cavity, where they can notably cause periodontal disease and dental caries. (95) The ability of some members of the Bacteroidetes to degrade polysaccharides explains why they thrive in the GI tract. (96)

Firmicutes

The Firmicutes phylum comprises Gram-positive bacteria with low G + C DNA content and is composed of more than 200 different genera, such as Lactobacillus, Bacillus, Clostridium, Enterococcus, and Ruminicoccus. (82) They can be found in a variety of places, including soil, water, skin, and the GI tract. The phylum includes aerobes, anaerobes, spore-forming, saprophytic, and pathogenic bacteria. Notable among the latter are Clostridium difficile and Listeria monocytogenes. Firmicutes, such as Clostridium botulinum, Clostridium tetani, Clostridium perfringens, and Staphylococcus aureus, can produce proteinaceous toxins. Other important genera are Listeria, Paenibacillus, Staphylococcus, Streptococcus, Pediococcus, and Leuconostoc. (97) Some members of Firmicutes are involved in bile acid metabolism in the gut. Accumulating evidence suggests that bile acids play pivotal roles in gut inflammation and the development of intestinal bowel disease (IBD). Patients with IBD exhibit decreased microbial diversity and abnormal microbial composition marked by the depletion of phylum Firmicutes. (98)

Actinobacteria

The Actinobacteria are Gram-positive bacteria with high G + C DNA content and constitute one of the largest bacterial phyla. They are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. The phylum includes pathogens (species of Corynebacterium, Mycobacterium, Nocardia, and Propionibacterium), soil inhabitants (Micromonospora and Streptomyces species), plant commensals (Frankia spp.), and GI commensals (Bifidobacterium spp.) (99) The Bifidobacteria are among the first microbial colonizers of the intestines of newborns and play key roles in the development of their physiology, including maturation of the immune system and use of dietary components. Some Bifidobacterium strains are considered probiotic microorganisms because of their beneficial effects, and they have been included as bioactive ingredients in functional foods, mainly dairy products, as well as in food supplements and pharma products, alone or together with other microbes or microbial substrates. (100)

Proteobacteria

The name Proteobacteria was first proposed by Stackebrandt et al. in 1988. (101) The name was derived from Proteus the ancient Greek god of the sea capable of assuming different shapes, which reflected the high heterogeneity displayed by the bacteria belonging to this phylum. A common trait of Proteobacteria is Gram-negative staining, which indicates the presence of lipopolysaccharide in the outer membrane. On the basis of phylogenetic analysis of the 16S rRNA gene, the Proteobacteria phylum is divided into six classes (previously regarded as subclasses of the phylum): Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Deltaproteobacteria, Epsilonproteobacteria, and Zetaproteobacteria. Considering that the classes division is based on molecular relatedness, it is not surprising that no specific morphological or physiological trait characterizes members within each class. (102) Notable genera in the Proteobacteria are Escherichia, Salmonella, Shigella, Desulfovibrio, and Helicobacter. Included in the phyla is the Enterobacteriaceae family, which contains several enteropathogenic bacteria, including Shigella flexneri, Salmonella typhi, and Escherichia coli. Other enteric pathogens in this phylum are Vibrio cholerae and Helicobacter pylori.

Verrucomicrobia

The phylum Verrucomicrobia, like the Proteobacteria, is defined by as a distinct phylogenetic lineage, as determined by 16S rRNA gene sequences. The phylum has been recognized as separate since 1995 but currently counts only a few cultivated microorganisms as members. Verrucomicrobia is a divergent phylum that includes members of the microbial communities of soil and fresh and marine waters. Some extremely acidophilic members from hot springs have been found to oxidize methane. (103,104) Akkermansia muciniphila is a mucus-degrading member of the Verrucomicrobia found in the human GI tract. A. muciniphila represents from 1 to 4% of the bacterial population in the colon. (105) A. muciniphila prefers to colonize in the intestinal mucus layer and specifically degrades mucins to produce short-chain fatty acids, thereby providing energy for the host and promoting colonization of the bacterium itself. The degradation of mucins prompts the host to compensate with the production of more mucins, thereby maintaining the dynamics of these proteins. (106)

Fusobacteria

The phylum Fusobacteria is made up of Gram-negative, nonmotile, facultative aerobic to obligately anaerobic, fermentative, rod-shaped bacteria, which have generally fusiform (spindle-shaped) morphology. Fusobacteria have been known for more than 100 years, but recently, phylogenetic studies have shown that they should be grouped into a distinct phylum. The bacteria from this phylum are commonly associated with the mucous membrane of humans and animals. They are also commonly present in the human and animal GI tract, particularly in the jejunum, the ileum, and the colon. (83,107)

Gut Microbiome–Disease Correlations

The human microbiome has been recognized as an essential factor for human health. (108−110) Specifically, gut microbes contribute directly and/or indirectly to important physiological activities, including immunomodulation and the regulation of various neurotransmitters, hormones, and metabolites. Dysbiosis is a state characterized by distinct alterations in the microbiome that result in an imbalance in the microbiota, modifications in their functional composition and metabolic performance, or a change in their allocation. The impact of the microbiome on human physiology and pathology is so extensive that the microbiome has been considered as an essential organ of the human body. (111−113) A search in the CAS Content Collection identified a large collection of studies reporting correlations between gut microbiota and a wide range of diseases, including mental, metabolic, and digestive system disorders; cardiovascular and neurodegenerative diseases; various cancers; and immune and autoimmune diseases (Figure 8). Trends in the number of publications related to various diseases in the recent years (2016–2021) are depicted in Figure 9. The number of documents related to dysbiosis, in general, exhibits the greatest growth rate, thereby characterizing the dominant fundamental approach of the recent studies in the field.

Figure 8

Figure 8. Distribution of the publications in the CAS Content Collection related to gut microbiome-associated diseases.

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Figure 9

Figure 9. Trends in the number of publications concerning gut microbiome-related diseases during the years 2016–2021. Percentages are calculated with yearly publication numbers for each disease, normalized by the total number of publications for the same disease in the same time period.

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Digestive System Diseases and Disorders

Alterations to the gut microbiota composition have been associated with various digestive system disorders and diseases, specifically IBS; IBD, including Crohn’s disease and ulcerative colitis; diarrhea, and constipation (Figure 8). (114−116)
Irritable bowel syndrome is one of the most prevalent functional gastrointestinal disorders and is considered as the prototype of disorders of the gut–brain interaction. While alterations in gut–brain interactions have clearly been established in IBS, a causative role of the microbiome remains to be determined. Dysbiosis is one of the hallmarks in the miscommunication between gut and brain and could lead to IBS symptoms. The severity of IBS symptoms has been shown to be correlated with dysbiosis. (117,118) In IBS cases, the reduction of microbiome diversity, gut barrier deficiency, gut–brain signaling disorders, and immune disorders are significantly related to the abnormal function of the GI tract. (119) Modifications in the composition of the normal microbiota and perturbed colonic fermentation in IBS patients are supposed to play a role in the development of IBS, with a considerable, nearly 2-fold, increase in the ratio of Firmicutes to Bacteroidetes. (120) Recent studies have reported well-defined distinction between gut microbiota composition in patients with IBS compared with healthy controls. IBS was typified by enhanced quantities of Firmicutes and specifically in Ruminococcus, Clostridium, and Dorea, along with a distinct decrease of beneficial microbes, such as Bifidobacterium and Faecalibacterium spp. (121) Moreover, a decrease in probiotic species and an increase in pathogenic species have been reported in patients with IBS, including Proteobacteria, Enterobacteriaceae, Lactobacillaceae, and Bacteroides (Bacteroidetes). (122) Fecal transplantation from super donors and microbiome modulation either by pro- or prebiotics have shown beneficial effect in reducing IBS symptoms and improving patients’ quality of life. (119,123,124) To date, the guidelines on the treatment of IBS with probiotics remain controversial. The British Society of Gastroenterology guidelines (125) on the management of IBS, which were updated in 2021, reported that probiotics may be an effective treatment for improving global symptoms and abdominal pain in patients with IBS, which was consistent with the recommendations of the Canadian Association of Gastroenterology (126) and the Japanese Society of Gastroenterology. (127) In contrast, the guidelines from the American College of Gastroenterology (128) suggest against the use of probiotics for the treatment of global IBS symptoms. (129)
Like IBS, inflammatory bowel disease-related dysbiosis is associated with a general decrease in richness, diversity, and stability of the microbiota. (130) This decline in diversity is concomitant with a weakened immune response and setbacks with the cellular barrier functions that normally block bacterial entry from the gut lumen into gut tissue. These malfunctions trigger complications with antibacterial defense and consequent growth of pathogenic bacteria. (131) IBD-related dysbiosis is specifically associated with a comprehensive decrease in the quantity and diversity of Firmicutes and an increase in Proteobacteria. (132) The decrease in the numbers of Firmicutes is noteworthy since they produce essential short-chain fatty acids, such as acetic and butyric acids, that are known to exhibit anti-inflammatory properties. (133) A common feature of the microbial dysbiosis among IBD patients, especially in Crohn’s disease, is the decreased abundance of Firmicutes bacteria belonging to two families that are important functional members of the human gut microbiota─Ruminococcaceae and Lachnospiraceae─to which most butyrate-producing bacteria in the human gut belong. (134,135) Thus, depletion of these bacterial families in IBD is supposedly correlated to the detected disturbances, such as a lower butyrate-producing capacity of the IBD microbiota. (136) Butyrate has a significant potential in IBD therapy because it serves as the colonocytes key energy source, enhances the epithelial barrier integrity, and inhibits inflammation. A probiotics treatment, including consumption of butyrate-producing bacteria to increase in situ butyrate production, may restore gut homeostasis. (137−139) A recent study reported that an orally delivered cocktail of bacteriophages targeting an IBD-associated strain of the bacterium Klebsiella pneumoniae alleviated intestinal inflammation. (131)
A growing body of evidence shows that imbalance of the gut microbiota increases susceptibility to various pathogens and causes numerous diseases, including diarrhea. (140) At present, the pathogens causing diarrhea are believed to be Escherichia coli, Shigella, Salmonella, Campylobacter, Clostridium difficile, and Aeromonas. (141,142) It has been found that microbial intervention can regulate the composition of the intestinal flora to prevent and improve the occurrence of diarrhea. (143) Probiotics containing nonpathogenic live bacteria preparations, such as Lactobacillus, Yeast, Bifidobacterium, Enterococcus, and Bacillus, have been demonstrated to treat pathogens-caused diarrhea by preserving or amending the balance of gut microbiota. The mechanisms of the beneficial effect are supposedly related to the inhibitory effect on the colonization of pathogenic bacteria by competing for nutrients and producing antibacterial compounds. (144)
Accumulating evidence suggests an association between functional constipation and abnormal gut microbiota, with the relationship between gut microbiota and gut transit being likely bidirectional. (145) By controlling colonic motility, water content, secretion, and absorption, gut microbiota may promote the development of functional constipation through microbial metabolites, including bile acids, SCFAs, 5-hydroxytryptamine, and methane. Currently, there is no consensus on the gut microbial composition typical for functional constipation patients and the alteration trends of the various microbial classes compared with healthy controls. (146−150) However, recent studies showed that changes in the mucosal and fecal microorganisms are linked to functional idiopathic constipation. Taxonomic profiling of intestinal microbiota in constipated adults showed a higher abundance of Bacteroides and other pathogenic microorganisms than in healthy volunteers. (151) The increased richness and diversity of the gut microbiomes result in slow colonic transit. In addition, intestinal microbiota in constipated adults have genes involved in pathways that lead to methane, hydrogen, and glycerol production, which can explain the symptoms seen in patients with constipation. (151−153) Microbial interventions including probiotics, prebiotics, and synbiotics, which bring about compositional and functional changes of the gut microbiota, have frequently shown beneficial effects on functional constipation that are in favor of the concept of the significant role of gut microbiota in functional constipation. (145) This concept is supported also by the reports that many risk factors of functional constipation, including age, diet, obesity, and stress, have a considerable effect on the gut microbiota. (154,155)

Mental and Neurodegenerative Disorders

Gut microbiota have been reported to affect neurological functions along the so-called gut–brain axis (GBA). (156) Gut microbiota communicates with the brain through three major routes: the neural route (vagus nerve, enteric nervous system), the immune route (cytokines), and the endocrine route [hypothalamus–pituitary–adrenal (HPA) axis, gut hormones]. Disturbances in any of these routes can result in mental disorders. Dysbiosis in common intestine microbial species of the phylum Firmicutes and Actinobacteria and the genera Bacteroides and Bifidobacterium are supposedly responsible for mental health disorders. (157) Gut microbiota moderate the GBA via various ways, such as preserving gut permeability by controlling the integrity of tight junctions in gut epithelium and producing a large selection of metabolites that include neurotransmitters, SCFAs, and amino acids.
A plethora of research reports have indicated the significance of microbiota in the development of neurodegenerative diseases via a variety of microbial metabolites that transmit from the gut to the brain across the GBA. (158,159) Changes in the levels of gut microbial metabolites have been reported to be associated with neurological conditions like Parkinson’s disease, (160) anorexia nervosa, (161) Alzheimer’s disease, (162) autism spectrum disorders, (163) and chronic stress and depression. (164) It is not clear by now, however, whether these disruptions in mental health are the cause or a result of the changes in gut microbiota. Gut dysbiosis has been associated with increased gut permeability and inflammation and it may also cause enhanced levels of circulating gut microbiota metabolites, such as the neurotoxin β-N-methylamino-l-alanine and microbial amyloids. (165,166) β-N-Methylamino-l-alanine is one of the gut cyanobacteria-produced neurotoxins causing neurodegeneration, cognitive impairment, and the accumulation of neurofibrillary tangles. (167,168) The hypothesis that Parkinson’s disease starts in the gut and spreads to the brain (169) is gaining increasing support, thereby showing that the disease is associated with widespread dysbiosis. (170)
Alterations in the microbiota composition in patients with Alzheimer’s disease compared with matched healthy controls included a reduction in richness and diversity of gut microbiota with decreased Firmicutes and Bifidobacterium and increased Bacteroidetes. (171) Changes in Actinobacteria, Ruminococcus, Lachnospiraceae, and Selenomonadales (1686) have also been reported. (172) Cognitively impaired patients exhibited alterations in Bacteroidetes, Firmicutes, Proteobacteria, and Verrucomicrobia compared with age-matched cognitively intact individuals. (173)
Therapeutic interventions including the administration of pre- and probiotics (psychobiotics) to manage mental disorders and/or their symptoms have been undertaken. (174,175) These inventions have included probiotic combinations of lactobacilli and Bifidobacteria, which has resulted in a significant drop in psychological distress, (176) enhanced cognition and communication among patients with Alzheimer’s disease (177) and autism spectrum disorders, (178) and recovering symptoms among patients with Parkinson’s disease. (179) On the basis of the promising results of psychobiotics on controlling or modulating the GBA, additional clinical trials are currently being undertaken to identify bacterial strains as promising candidates for the treatment of mental disorders.
Humans are adapted to a circadian rhythm of 24 h associated with the light/dark cycle on earth. The central circadian clock is located in the hypothalamus, which synchronizes information on environmental light and dark signals to peripheral tissues to keep the body functioning in the same rhythm. (180) A disruption of circadian rhythms is associated with various diseases, including neurodegenerative diseases, sleep, and psychiatric disorders. (181,182) Recent studies have reported that gut microbiota are able to control or be controlled by the circadian clock. The mechanisms of such a relationship requires small molecule gut microbiota metabolites, such as bile acids and SCFAs, to act as intermediaries. (180) Thus, the levels of butyrate and propionate show obvious daily oscillations. Moreover, these oscillations are lost under high-fat diets. (183) The impacts of gut microbiota metabolites on circadian rhythm are extensive and are connected to other functions of gut microbiota metabolites, such as energy metabolism and immunity. These interconnections between different physiological functions via the link of gut microbiota metabolites are essential for understanding the functions of gut microbiota metabolites and the general role of gut microbes in human health and disease.

Metabolic Disorders

Systemic metabolic diseases that are believed to be strongly affected by gut microbiota status include obesity and diabetes. (184) Gut microbial composition is strongly affected by dietary routines. As a result of a high-fat diet, the intestinal microbiome is modified with rising amounts of Firmicutes and Proteobacteria and reduced levels of Bacteroidetes. The Firmicutes/Bacteroides ratio has been correlated to body weight, which means it is larger for obese people. (185) Clostridium difficile infections can also trigger obesity. Generally, obesity is affected by the inflammatory status induced by gut bacteria or their metabolites, which regulate the GBA. (108,185)
Diabetes is another metabolic disease that is strongly associated with the gut microbiome. Studies have reported an increased quantity of Villanella, Clostridium, and Bacteroides and a decreased quantity of Lactobacillus, Eubacterium rectale, Blautia coccoides, and Bifidobacterium in children with type 1 diabetes. Besides, negative correlation has been reported between plasma glucose level and Bifidobacterium, Lactobacillus spp., and Firmicutes and Bacteroidetes spp., while there has been positive correlation between Clostridium and plasma glucose level. The ratios of Bacteroidetes to Firmicutes were reported to exhibit a positive connection with plasma glucose levels. The Lactobacillus genus was also in lower quantity in type 2 diabetes patients, and Bifidobacterium was in higher quantity compared with control groups. (108,186) Risks for the development of type 2 diabetes have been correlated to the composition of gut microbiota, as well. The alterations in the gut microbiota of individuals with type 2 diabetes have been small compared with the control group, yet a consistent decline in the metabolically beneficial butyrate-producing bacteria was reported. (186) Overall, type 2 diabetes was associated with a reduced quantity of SCFAs-producing bacteria, in particular butyric acid, which has been related to insulin sensitivity. (187,188) The relation between SCFAs and insulin sensitivity stems from the capacity of SCFAs to stimulate the secretion of GLP-1 by intestinal L-cells via G protein receptors, which has a significant impact on insulin release. (189)
Close relations between the metabolic and immune systems are now largely supported, and intestinal microbiota is being progressively identified as an important factor connecting genes, environment, and the immune system. (190)

COVID-19

Recently, correlation has been reported between gut microbiota composition and levels of cytokines and inflammatory markers in patients with COVID-19. (191,192) It is suggested that the gut microbiome is involved in the magnitude of COVID-19 symptoms’ severity via modulation of the host’s immune responses. Moreover, gut microbiota dysbiosis could contribute to persistent symptoms even after disease resolution, thereby emphasizing a need to understand how gut microorganisms are involved in inflammation and COVID-19.A recent study demonstrated that SARS-CoV-2 infection indeed disrupts the gut microbiome. (193) This boosts secondary bacterial infections both by facilitating pathogenic bacteria to colonize the gut and by modifying gut lining to allow these bacteria to spread from the gut to the bloodstream of COVID-19 patients. These results confirm the direct role of gut microbiome dysbiosis in facilitating grave secondary infections upon COVID-19 malady. (193)
The alterations to the gut microbiota composition related to digestive system diseases, mental health, and metabolic disorders are summarized in Table 1.
Table 1. Gut Dysbiosis in Digestive System Diseases, Mental Health, and Metabolic Disorders
diseases↓ decreasing bacteria↑ increasing bacteria
digestive system diseases
irritable bowel syndrome (194−199)BifidobacteriumRuminococcus
Faecalibacterium prausnitziiDorea
BacteroidesEnterobacteriaceae
Lactobacillaceae
Bacteroides
Firmicutes/Bacteroidetes ratio
IBD: Crohn’s disease (200,201)Bacteroides 
Faecalibacterium prausnitzii
Bifidobacterium adolescentis
IBD: ulcerative colitis (139,200)Bifidobacteria 
Roseburia hominis
Faecalibacterium prausnitzii
Lachnospiraceae
Ruminococcaceae
mental health disorders
anxiety disorder (202,203)BacteriodetesBacteroidaceae
Ruminococcus gnavusEnterobacteriaceae
FusobacteriumBurkholderiaceae
post-traumatic stress disorder (204)Actinobacteria 
Lentisphaerae
Verrucomicrobia
depression (205−207)PrevotellaEggerthella
DialisterHoldemania
Turicibacter
Paraprevotella
dementia (172)ActinobacteriaEscherichia
BacteroidesBlautia
Bifidobacterium
Streptococcus
Lactobacillus
Dorea
metabolic disorders
diabetes type 1 (208,209)LactobacillusClostridium
BifidobacteriumBacteroides
Blautia coccoidesVeillonella
Eubacterium rectaleActinobacteria
PrevotellaProteobacteria
AkkermansiaLactococcus
Firmicutes 
diabetes type 2 (199,209,210)FirmicutesBetaproteobacteria
Clostridia 
LactobacillusBacteroidetes/Firmicutes ratio
Akkermansia muciniphilia
Roseburia
obesity (199,211)BacteroidetesEnterobacteria
Methanobrevibacter smithiiRuminococcus gnavus
Ruminococcus flavefaciensActinobacteria
BifidobacteriumPrevotellaceae

Gut Bacteria–Disease Correlations

In an effort to get better insight into the gut microbiota impact on well-being, we explored the correlations between the major classes of gut bacteria and certain mental and gastrointestinal disorders, as reflected in the number of records in the CAS Content Collection (Figure 10).

Figure 10

Figure 10. Correlation between major classes of gut bacteria with mental and gastrointestinal disorders, as reflected in the number of associated records in the CAS Content Collection.

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As seen from Figure 10, Bacteroidetes are the most studied class of gut bacteria with relation to gastrointestinal and mental health, specifically with relation to stress, depression, and anxiety. Bacteroidetes are known to have a very broad metabolic potential and are regarded as one of the most stable parts of gastrointestinal microflora that exhibits remarkable nutritional flexibility and an ability to respond to stress. (212) However, the exact mechanisms underlying any possible relationship between Bacteroidetes and mental and gastrointestinal health remains unclear, and further research is needed to fully understand this complex relationship.
Firmicutes are the second extensively studied class of gut bacteria with relation to gastrointestinal and mental health, especially in relation to stress and depression (Figure 10). Many members of the Firmicutes phylum, such as Lactobacillus, are probiotic. The relationship between Firmicutes and gastrointestinal disorders may be mediated by a number of different factors, such as the production of SCFAs by Firmicutes, which are an important energy source for the gut epithelium and have anti-inflammatory effects. In addition, some Firmicutes bacteria are involved in the fermentation of complex carbohydrates and the production of beneficial metabolites, such as butyrate, which has been shown to have protective effects against colorectal cancer. (213) Like with Bacteroidetes, the exact relationship between Firmicutes and mental and gastrointestinal disorders is still being studied and is not fully understood.
The interest in Fusobacteria with respect to the gastrointestinal and mental health is mainly related to diarrhea and constipation (Figure 10). Recent evidence is emerging that this bacterium may be related to human colon cancer. (214)
It is noteworthy that recent meta-analysis has reinforced the genetic correlations between Alzheimer’s disease and the gut microbiome genera. (215) For example, genus Actinobacterium Collinsella was confirmed to be associated with Alzheimer’s disease, as well as rheumatoid arthritis, atherosclerosis, and type 2 diabetes. (215) It is also worth reiterating that the gut microbiota is a complex and diverse community of microorganisms, and changes in any one particular phylum are unlikely to fully explain the development of any particular disorder or condition. Rather, the gut microbiota as a whole are likely to play a role in shaping our physical and mental health, and further research is needed to fully understand the complex relationships between the gut microbiota and overall well-being.

Therapeutic Strategies for the Treatment of Mental and Gastrointestinal Disorders

Imbalances within the gut microbiome–brain axis have been linked to a range of mental and gastrointestinal disorders. Assorted therapeutic interventions aimed at modulating the gut microbiome or the gut–brain axis may be effective in improving outcomes for these conditions.
Dietary Interventions
A high-fiber diet can increase the production of SCFAs, which can help to maintain gut barrier function and reduce inflammation. SCFAs can also promote the growth of beneficial gut bacteria, which can outcompete pathogenic bacteria and reduce inflammation. (216)
A diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) can reduce symptoms in individuals with irritable bowel syndrome by reducing the fermentation of certain carbohydrates in the gut, which can cause symptoms such as bloating and abdominal pain. However, the low-FODMAP diet can also reduce the diversity of gut bacteria and may have negative long-term effects on gut health. (217,218)
Probiotics and Prebiotics
Probiotics can improve gut barrier function by enhancing the production of mucus and tight junction proteins, which can prevent the entry of harmful molecules and pathogens into the bloodstream. They can also reduce the production of proinflammatory cytokines and modulate the activity of immune cells in the gut, thereby promoting an anti-inflammatory response. (219,220)
Prebiotics can increase the production of metabolites, such as SCFAs, which are important energy sources for gut cells and can help to maintain gut barrier integrity. SCFAs can also activate G protein-coupled receptors on immune cells, thereby leading to the production of anti-inflammatory cytokines and the suppression of proinflammatory cytokines. (221,222)
Antibiotics
Antibiotics can kill harmful bacteria in the gut, which reduces inflammation and restores gut barrier function. However, antibiotics can also have negative effects on the gut microbiome, such as by reducing the diversity of gut bacteria and promoting the growth of antibiotic-resistant bacteria. Antibiotics should be used judiciously and only when necessary. (223,224)
Fecal Microbiota Transplantation (FMT)
FMT can restore the composition and function of the gut microbiome, which can reduce inflammation and improve gut–brain communication. FMT has been shown to be effective in treating recurrent Clostridium difficile infection and is being investigated for other conditions, such as IBD and autism. (225−227)
Psychotherapeutic Interventions
Psychotherapeutic interventions can reduce stress and improve gut–brain communication. Stress can disrupt gut microbiome composition and function, which leads to inflammation and the development of diseases related to the gut microbiome–brain axis. The reduction of stress can be an effective way to improve gut health and reduce symptoms in these conditions. (228−230)
Pharmacological Interventions
Drugs that target the gut–brain axis can modulate gut microbiome composition and function and reduce inflammation. For example, certain drugs that target the serotonin system, such as selective serotonin reuptake inhibitors (SSRIs), can modulate gut–brain communication and have been shown to be effective in treating conditions, such as depression and anxiety. (231,232)
Figure 11 demonstrates the annual growth in the number of documents in the CAS Content Collection related to various therapeutic interventions applied for the treatment of mental and gastrointestinal disorders. Fecal transplant as a new therapeutic strategy exhibits the fastest growth rate recently.

Figure 11

Figure 11. Trends in the therapeutic strategies applied for the treatment of mental and gastrointestinal disorders, as presented in the documents related to gut microbiome research during the years 2017–2021. Percentages are calculated with yearly publication numbers for each type of therapeutic intervention normalized by the total number of publications for the same intervention in the same time period.

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The various strategies to treating diseases related to the gut microbiome–brain axis can work through multiple mechanisms, including modulating gut microbiome composition and function, reducing inflammation, and improving gut–brain communication. (233) However, the underlying mechanisms are complex and require further research to fully understand.

Gut Microbiota Metabolites

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It is estimated that the human gut microbiome contains more than 22 million microbial genes, (234) which exceeds the ∼22,000 genes present in the entire human genome. (235) These genes enable the gut microbiota in the host to synthesize a myriad of enzymes with versatile capabilities to ferment and degrade a variety of compounds that humans do not have the genetic machinery to metabolize. As a result, the gut microbiota can generate a battery of metabolites with a wide spectrum of bioactivities. The gut microbiota-derived metabolites can be broadly divided into three types according to their origination: (1) metabolites that are produced by gut microbiota directly from diets; (2) metabolites that are generated by the host and modified by gut microbiota; (3) metabolites that are produced de novo. (236) A selection of important gut microbiota metabolites related to gut–brain communication is shown in Table 2.
Table 2. Exemplary Gut Microbiota Metabolites, as Represented in the CAS Content Collection

Gut Microbiota Metabolites with Impact on Brain Function

The gut microbiota provides essential signaling metabolites that are vital for the host’s physiology. While in healthy individuals, gut microbiota metabolites are effective in maintaining the important functions of hosts, perturbations in the production of these metabolites can initiate various diseases, such as digestive system diseases, neurodegenerative and metabolic disorders, and cancer. (236)
Research has shown that gut microbiota is crucial for normal brain development and function. (237,238) For example, administration of 4-ethylphenylsulfate (4-EPS), a tyrosine derivative, to mice at 3–6 weeks postnatal induced anxiety-like behavior. The biosynthetic pathway analysis and mechanisms behind the detrimental effects of 4-EPS showed that 4-EPS interfered with oligodendrocyte maturation, myelination, and brain activity patterns. p-Cresol, another tyrosine derivative and a metabolite, has also been directly associated with neurodevelopmental disorders. (239,240) Further, certain bacteria-related metabolites, such as trimethylamine-N-oxide (TMAO), 5-aminovaleric acid (5-AVA), 5-AVA betaine (5-AVAB), imidazolepropionic acid, and hippuric acid have been reported to promote early-life axonogenesis both in vitro and in vivo. (241) Moreover, the neurogenic properties of microbe metabolites may not be limited to early life given that indole, a tryptophan metabolite, has been reported to increase neurogenesis in the hippocampus of adult mice. (242) Pilot studies using fecal microbiota transplantation in children enabled the assessment of whether early life interventions affecting the gut microbiota composition exerted long-term neurodevelopment effects. (243,244) Thus, maternal fecal microbiota transplantation in cesarean-born infants was found to rapidly restore normal gut microbial development. (244)
Gut microbiota and its metabolites can affect the host metabolism of neuroactive compounds. (245) The foremost examples of gut bacteria-derived neurotransmitters are aromatic amino acid derivatives dopamine and norepinephrine and glutamate derivative γ-aminobutyric acid. (246,247) Microbiota have been found to extensively contribute to the levels of dopamine and norepinephrine via the activity of β-glucuronidase. (248) Kynurenic acid, a tryptophan metabolite, functions as a glutamate modulator to reduce glutamate levels in the glutamatergic signaling in the hippocampus. Thus, enhanced cognitive abilities and memory in model animals have been achieved as a result of enhancing glutamate levels via limiting hippocampal kynurenic supply. (249,250) Over 90% of serotonin in the body is known to be produced in the gut in a process in which gut microbes play an important regulatory role. (251,252) Tyramine, deoxycholic acid, and 4-aminobenzoic acid have been reported to stimulate serotonin synthesis. (252) Furthermore, microbiota-related metabolites, such as norepinephrine, indole, indole-3-aldehyde, isovaleric acid, butyric acid, and isobutyric acid stimulate serotonin release from enterochromaffin cells. (253,254) Another gut microbiota metabolite with a likely connection to γ-aminobutyric acid (GABA) expression in brain is lactate. (255,256) It has been shown to affect neural plasticity and has a beneficial effect on learning and memory in model animals. (257) SCFAs, particularly butyric acid, may also have additional regulatory effects on the signal transduction to the brain via the vagal nerve and by inducing the biosynthesis of neurotransmitters in the CNS. (258) Administration of SCFAs, such as butyric, acetic, and propionic acid, has been reported to improve stress response, anxiety, and depression. (259) The presence of pipecolic acid in the CNS can be partially derived from the gut microbiota and has been also associated with GABA signaling and release. (245,260,261)
Gut microbiota has also proven vital for normal BBB function, especially during pre- and postnatal periods. (262) In a mice model of traumatic brain injury typified by acute BBB disruption, sodium butyrate administration exhibited an alleviating effect on BBB integrity. (263) Propionic acid, another SCFA gut microbiome metabolite, has also been shown to promote BBB integrity by mitigating oxidative and proinflammatory pathways. (264) It has been suggested that the effects of SCFAs on BBB integrity may rather be brought about by peripheral signaling instead of direct uptake to the brain, as implied by animal models. (258) Secondary bile acids, such as deoxycholic acid and ursodeoxycholic acid, may also modulate BBB integrity. (265,266) Trimethylamine, a metabolite of dietary choline, betaine, and l-carnitine, has been reported to exert detrimental impact on the BBB integrity. It is noteworthy that physiologically appropriate doses of the oxidized form of trimethylamine, TMAO, improved the BBB integrity. (267)
A large portion of the brain’s energy production is consumed by the neurons, the major component of the nervous tissue, in order to maintain the excitability of the synapses. (268) Lactate, a major gut microbiota metabolite, is known to augment neural activity as a primary energy source. (269) Modulation of brain energy metabolism in the hippocampus along the GBA is suggested to be responsible for improvement in the cognitive function after intermittent fasting in model animals. (270) It has been found that fasting considerably increased plasma levels of indolepropionic acid and tauroursodeoxycholic acid and fecal levels of SCFAs. Administrations of indolepropionic acid or tauroursodeoxycholic acid or a SCFAs mixture including acetic, propionic, and butyric acid have been able to reproduce the effects of fasting in cognition, hippocampal mitochondrial biogenesis, and energy metabolism-related gene expression. Findings connecting microbial metabolites to brain bioenergetics are preliminary but show that certain compounds are incorporated in the neuronal energy metabolism.
Gut microbiota metabolites reducing oxidative stress or neurotoxic proteins aggregation are functioning as neuroprotective agents. Metabolites that reduce inflammation or promote neurodevelopment or neurotransmission can also be considered as neuroprotectants. For example, ferulic acid is known to be metabolized by gut microbes. (271) It exerts neuroprotective effects by reducing neuronal cell death and recovers memory deficits in a cerebral ischemia and reperfusion injury model. (272) It has also ameliorated depressionlike behavior and oxidative stress. (273) Dihydroferulic acid, a microbiota metabolite, has also been shown to exhibit neuroprotective antioxidative properties. (274)
The gut microbiome metabolites and their mechanism of action in mental health and brain development are depicted in Figure 12, and their function and associated diseases are summarized in Table 3.

Figure 12

Figure 12. Exemplary gut microbiome metabolites and their mechanism of action in gut–brain communications.

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Table 3. Gut Microbiota Metabolites, Their Function, and Associated Diseases
metabolite class/referencesspecific functionsassociated diseases
short-chain fatty acids (258,285−290)– gut microbiota composition regulation– diabetes
– gut barrier integrity support– obesity
– energy homeostasis support– nonalcoholic fatty liver disease
– gut hormone production– ulcerative colitis
– circadian rhythm regulation– Crohn’s disease
– proinflammatory cytokines inhibition– colorectal cancer
– immunomodulation– autism spectrum disorder
– water, sodium, calcium, magnesium absorption– Parkinson’s disease
– regulation of intestinal pH value– diarrhea
– IBS
– constipation
– functional dyspepsia (FD)
bile acids (BAs) (291−295)– lipid and vitamin absorption regulation– obesity
– gut microbiota composition regulation– nonalcoholic steatohepatitis
– gut hormones production– ulcerative colitis
– intestinal immunity– cancer
– intestinal electrolyte and fluid balance– multiple sclerosis
– gut motility– Alzheimer’s disease
– gut barrier integrity– Parkinson’s disease
– lipid homeostasis– traumatic brain injury
– glucose homeostasis– stroke
– amino acid homeostasis– amyotrophic lateral sclerosis
– circadian rhythm– IBS
– neurotransmission 
tryptophan and indole derivatives (296−300)– gut microbial spore formation– ulcerative colitis
– drug resistance– Crohn’s disease
– biofilm formation– obesity
– intestinal barrier function regulation– stroke
– gut hormone secretion– mucosal candidiasis
– gut motility– autism spectrum disorder
– immunomodulation– Alzheimer’s disease
– Parkinson’s disease
– migraine
– schizophrenia
– IBS
choline metabolites (301−303)– bile acid synthesis inhibition– nonalcoholic fatty liver disease
– inflammation promotion– obesity
– thrombosis– diabetes
– myocardial hypertrophy and fibrosis– hypertension
– mitochondrial dysfunction exacerbation 
vitamins (304−306)– cellular metabolism regulation– vitamin-associated diseases
– immunomodulation– schizophrenia
– cell proliferation– autism
– vitamins supply– dementia
– IBS
– IBD
neurotransmitters (307−309)– gut motility regulation– Parkinson’s disease
– memory support– autism spectrum disorder
– stress response– IBD
– nervous system– IBS
– immune response
lipids (184,310,311)– systemic inflammation promotion– diabetes
– hyperinsulinemia regulation– obesity
– immunomodulation– nonalcoholic fatty liver disease
– bile acid synthesis– hyperinsulinemia
– hypercholesterolemia
– chronic hepatitis C
gases (307,312−316)– gut motility– colitis
– gut inflammation– ulcer
– epithelial secretion– IBS
– mucosal blood flow

Gut Microbiota Metabolites’ Role in Digestive System

Gut microbiota imparts specific function in the host’s digestive system, in nutrient metabolism, xenobiotic and drug metabolism, in preservation of the integrity of the intestinal mucosal barrier, and in protection against pathogens (Figure 13).

Figure 13

Figure 13. Gut microbiome metabolite classes and their roles in digestive system functions.

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Gut microbiota mostly get nutrients from dietary carbohydrates. Fermentation of the carbohydrates, including indigestible oligosaccharides by the microbes in the colon, such as Bacteroides, Roseburia, Bifidobacterium, Faecalibacterium, and Enterobacter, ends in the synthesis of SCFAs, such as butyric, propionic, and acetic acids, which are important sources of energy for the host. (275) Gut microbiota have a positive role in lipid metabolism, as well, by controlling the lipoprotein lipase activity inhibition in adipocytes. (31)
Intestinal microbiota also exhibit a resourceful protein metabolizing machinery, which operates by means of the microbial proteinases and peptidases in conjunction with the human proteinases. Examples include the conversion of l-histidine into histamine by the bacterial enzyme histamine decarboxylase and glutamate to γ-amino butyric acid by glutamate decarboxylases. (276,277)
SCFAs can regulate the pH value in the intestine and regulate the absorption of water, sodium, calcium, and magnesium. Furthermore, SCFAs, especially butyrate, provide more than 70% of the energy for the intestinal epithelial cells on top of their abilities to inhibit the multiplication and growth of pathogenic bacteria and the activity of intestinal inflammatory mediators, thus playing an anti-inflammatory role in the intestinal tract. (278)
Lipid metabolites can affect intestinal permeability and intestinal immunity. The gut microbiota can produce lipopolysaccharides that could stimulate proinflammatory mediators, thereby disrupting the body’s immune system and inducing local and systemic inflammatory responses. (279) Sphingolipids can be produced by the intestinal symbiotic bacteria Bacteroidetes and Prevotellaceae. It has been found in animal studies that sphingolipids can also aggravate intestinal inflammation. (280)
Indole-derived metabolites are produced by fermentation via Clostridium sporogenes and Escherichia coli. Such metabolites are able to participate in the regulation of gastrointestinal disorders by influencing the gut–brain axis and protecting against stress-induced damage in the gastrointestinal tract. Tryptophan is a key monoamine neurotransmitter involved in the regulation of central neurotransmission and intestinal physiological functions, and studies have shown that the gastrointestinal microbiome can regulate the gut–brain axis through tryptophan metabolism. (281,282)
Gases can be produced by gut microbiota as a result of the fermentation process. These gases include hydrogen (H2), methane (CH4), carbon dioxide (CO2), hydrogen sulfide (H2S), and nitric oxide (NO), which can modulate the gastrointestinal physiology of hosts. (236)
Xiao et al. (283) in a recent review article highlighted the important microbial metabolites in the context of host physiology in patients with different IBS subtypes. The abundance of microorganisms and their corresponding metabolites in constipation-predominant IBS (IBS-C) and diarrhea-predominant IBS (IBS-D) differ, thereby providing a new avenue for the diagnosis and treatment of different IBS subtypes in the future. These microbiota-derived metabolites, such as bile acids (BAs), SCFAs, vitamins, amino acids, 5-HT, and hypoxanthine, can be produced directly by bacteria, or from dietary or relevant substrates. Fluctuations and alterations in the levels of metabolites produced by the host or microbiota provide insights into their interactions during IBS. Moreover, low levels of hypoxanthine may be associated with colonic epithelial energy and capacity for mucosal repair with hypoxia. Purine starvation has been identified as a potential novel mechanism underlying IBS with lower fecal hypoxanthine abundance in IBS-C and IBS-D. Additionally, mucosal biofilms are an endoscopic feature of IBS and are associated with bacterial and BA metabolites dysbiosis. Additionally, deficiency in levels of both vitamins D and B6 have emerged as causative factors in IBS symptoms pathogenesis. (283)
Microbial dysbiosis and metabolites derived from interaction of the host and gut microbiota have been reported as an intermediate link contributing to the development of functional constipation via various signal pathways, including but not limited to SCFAs, BAs, and methane that occupied a more important position. (153) 5-HT is also involved in the modulation of gut motility and secretory, as well as sensory, transmission in patients with constipation. (284) Altogether, current studies have provided us with a new conception on the microbial mechanisms and therapeutic targets of constipation.
The gut microbiome metabolites and their function and associated digestive diseases/disorders are summarized in Table 3.

Gut Microbiome–Brain Axis

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CNS and the human GI tract communicate through the gut–brain axis (GBA). This bidirectional connection involves neuronal, endocrine, and immunological mechanisms. The gut is considered as our “second brain,” because of its hosting the enteric nervous system (ENS), a neural network that allows the gut to work without instructions from the brain. The ENS maintains control of our digestive system; it plays an important role in peristalsis, secretion, and pain perception. There is mounting data that gut microbiota are the source of a number of neuroactive and immunocompetent substances, as shown above, that help to shape the structure and function of brain regions involved in the control of emotions, cognition, and physical activity and contribute to the proper maintenance of gastrointestinal homeostasis. Most GI diseases are associated with altered transmission within the GBA that are influenced by both genetic and environmental factors. (317)
Functional gastrointestinal disorders (FGIDs) were previously considered as purely functional disorders with no scientific confirmation of a clear pathogenetic mechanism. According to Rome IV, the phenotype of FGIDs results from an altered transmission of nerve and biochemical signals within the gut microbiome–brain axis with mechanisms controlled by both genetic and environmental factors. Consequently, FGIDs were recently renamed into disorders of gut–brain interactions. (318) The overlap of DGBI and CNS disorders has been documented, and it has been demonstrated that approximately one-third of IBS patients suffer from depression. It is estimated that psychiatric symptoms occur in at least 36.5% of FGIDs patients. Stasi et al. found that the highest prevalence of mental or spectrum disorders is in patients with functional constipation (60%) compared with patients diagnosed with FD (52.4%), IBS (36.5), and/or functional bloating (47.6%). The most prevalent psychiatric disorders observed in FGIDs were general anxiety disorder and panic. (319)
Recent advances in this field have enabled us to better understand some of the pathophysiological consequences of an aberrant reciprocal gut–brain network, including exacerbated gut inflammation disorders, altered responses to stress, as well as altered behavioral states. Therefore, the GBA presents an attractive target for the development of novel therapeutics for an ever-growing list of disorders related to mental and digestive health. Improved targeting of the gut microbiome–brain axis, for example through application of biotics, is expected to pave the way for the development of novel disease therapies and self-care products to promote and maintain heathy status. (320)

Irritable Bowel Syndrome

IBS is one of the most common DGBI worldwide and typically presents in early adulthood with symptoms including abdominal pain, bloating, and altered bowel habits. On the basis of the bowel habits, IBS can be classified into four subtypes: constipation-predominant, diarrhea-predominant, mixed-type (IBS-M), and undefined IBS (IBS-U). Symptom intensity varies over time and between individuals, but IBS has been reported, in severe cases to affect quality of life as much as renal impairment or diabetes. (321) IBS represents up to 50% of all referrals to gastroenterologists with a prevalence rate of up to 11% globally. (322) The recent consensus view is that IBS results from abnormal gut–brain interactions. Recent epidemiological data has suggested that in individuals developing both IBS and psychological features, the former preceded the latter in two-thirds of cases, and the latter preceded the former in one-third. (323) IBS is associated with abnormalities of central pain processing but also increased gut permeability, mast cell activation, disordered motility, and dysbiosis.
A recent genome-wide analysis study for 53 400 IBS patients and 433 201 controls highlights shared genetic pathways between IBS and mood and anxiety disorders. The study identified and confirmed six genetic susceptibility loci for IBS, and four of them are associated with mood and anxiety disorders, thereby suggesting, for example, that shared pathogenic pathways rather than anxiety cause abdominal symptoms. (324)
5-HT signaling is one particular pathway of importance in IBS pathogenesis. It has been demonstrated that a functional GI tract involves 5-HT signaling between enterochromaffin cells acting as sensory transducers, and the majority of 5-HT is synthesized, stored, and released by these cells, which interact with intrinsic and extrinsic sensory nerve afferents in the mucosal layer of the gut. (320) 5-HT signaling controls many GI functions, including secretion; vasodilation; peristalsis; and sensory perception, such as pain and nausea. (325−327) Moreover, serotonergic function and tryptophan metabolism are known to be altered in IBS patients. (328−331)
IBS pathophysiology implicates altered gut microbiota composition, impaired intestinal mucosal integrity, and low-grade inflammation. In addition to pathways through the circulatory system, several of these factors may also trigger fluctuations in the activity of the ENS with subsequent effect on the brain. (332) Furthermore, the vagus nerve can be modulated by diet-responsive gut microbes and metabolites, such as short-chain fatty acids, or endocrine factors, enzymes, and neurotransmitters, such as serotonin, dopamine, acetylcholine, glutamate, γ-aminobutyric acid, and noradrenaline. (333−336) Each of these factors are potentially affected by alterations in microbiota composition and are involved in IBS pathology. (337)
Identifying a clear IBS microbial signature is not an easy task because of the heterogeneity of the healthy gut microbiota. However, multiple studies have shown differences in the gut microbiota between IBS and healthy controls. A recent systematic review showed that IBS patients have increased levels of the bacterial families Enterobacteriaceae, Lactobacillaceae, and Bacteroidales, whereas Bifidobacterium, Faecalibacterium, and Clostridiales were decreased compared with healthy controls. (122) On the contrary, Hugerth et al. recently reported no distinct microbiota signature of IBS in a random Swedish population of 3556 participants. (338) Interestingly, intestinal bacterial composition has been reported to be highly dependent on sample type and regional localization. Also, mucosa-associated bacterial composition of the sigmoid colon differs between patients with IBS and healthy controls. (339)
One of the most consistent findings in brain neuroimaging of IBS patients has been alterations in the structure and function of key regions of the somatosensory network, including the globus pallidus, putamen, and caudate, which composes the basal ganglia. (340) Increased gray matter density in the hypothalamus and decreased gray matter density in the prefrontal cortex have been reported in the IBS brain. (341) In rectal distention experiments, patients with IBS had a differential brain response in the pain matrix and default mode network. (342) IBS patients showed increased engagement of endogenous pain faciliatory pathways and decreased levels of the endogenous pain inhibitory mechanism in the brain regions associated with visceral afferent processing and emotional arousal, including the left dorsal anterior cingulate gyrus and the bilateral anterior insulae. (343) A meta-analysis of adult studies that evaluated brain response to rectal balloon distension by functional MRI (fMRI) reported differences between healthy control subjects and patients with IBS in these brain regions. (344) IBS patients with a history of abuse reported increased pain and anxiety with rectal distension accompanied by similar fMRI changes. (345) The stress and arousal circuit demonstrated in human subjects by fMRI shares significant homology with the stress circuit related to CRF–CRF1 receptor signaling in rodents, thereby potentially implicating the HPA axis as a facilitator of gut–brain axis communication. (346)
Recently, evidence for disrupted subcortical and cortical regions mediated by gut microbial modulation has been emerging in IBS. An association between brain region-to-region functional connectivity and microbiota has been reported. Labus et al. found a correlation between Clostridia and Bacteroidia with connectivity of the thalamus, the basal ganglia (caudate nucleus, putamen, pallidum, nucleus accumbens), the superior part of the precentral gyrus, the anterior insula, and the ventral prefrontal regions in IBS patients. (347) Recently, the same group also reported on fecal metabolites and resting state fMRI where the differences in histidine, cysteine, glycine, glutamate, spermidine, and anserine were significantly associated with the alteration in the left dorsal part of the posterior cingulate gyrus to the left putamen. Also, the changes in histidine, tryptophan, uracil, 2-deoxyuridine, thymidine, and succinate were differentially associated with the alteration in the right superior frontal gyrus to the right putamen. Interestingly, this interaction may be mediated by aberrant tryptophan signaling in IBS, which is important because it is a substrate for serotonin synthesis. (348)
Previous studies have compared brain differences between IBS-C and IBS-D. These studies have examined task states and have shown group-related differences in brain networks involved in integrating emotions [emotional arousal network, (EAN)], perception [sensorimotor network, (SMN); salience network, (SAL)], visceral functions [central autonomic network, (CAN)], and pain processing [default mode network, (DMN); central executive network, (CEN); SMN; SAL; EAN; and others). (349) Prior studies comparing IBS-C, IBS-D, and healthy controls (HCs) undergoing aversive rectal stimuli have identified abnormal connectivity in the SAL (350,351) and EAN (343,350) in IBS-C and in the occipital network (OCC) (351) in IBS-D. This may indicate a greater importance of alterations in sensory, emotional, and autonomic responses associated with the perception of visceral pain and discomfort in IBS-C. A recent study has tested the hypothesis that IBS-C exhibits bowel-habit-specific changes in the brain that reflect altered sensory and emotional regulation processing of visceral inputs from the “top-down,” while IBS-D would have widespread gut microbiome and metabolome changes (e.g., tryptophan, SCFAs), which may translate to “bottom-up” brain changes (e.g., SMN, DMN). (349) Indeed, in IBS-D, the study’s findings showed a correlation between high levels of gut metabolites tryptophan and phenylalanine and aberrant connectivity in brain regions involved in processing unpleasant visceral stimuli (SMN) and self-related thoughts (DMN). (349) These results suggest that increased tryptophan in the gut may lead to loosened stool, and tryptophan-related signaling may travel to the posterior insula and increase pain perception and emotional salience in IBS-D, thereby suggesting a “bottom-up” signaling direction. However, IBS-C’s microbiome and metabolome resembled HC, and the increased connectivity in the default mode (DMN) and salience (SAL) networks compared with IBS-D may indicate abnormalities in the emotional physiological processing of visceral signals. (349) IBS-C’s relatively isolated brain changes may indicate a more “top-down” mechanism to produce the constipation-predominant phenome. That study by Sarnoff et al. has shown a link between the chronicity of IBS symptoms, B. stercoris and F. prausnitzii, and brain connectivity in the caudate nuclei.
Thus, we might be in the mere beginning of understanding how alterations in gut microbiota may lead to the disruption of the intricate host–gut–microbiota interaction: is it a cause or a result of IBS pathology? In the past decade, much knowledge has been gained from clinical microbiota-altering interventions, such as the low-FODMAP diet and fecal microbiota transplantation (FMT), which have emerged as debatably successful treatment strategies. However, their effects on the gut microbiome–brain axis are still far from understood. It has been proposed that probiotic amelioration of IBS symptoms may be acting indirectly through an anti-inflammatory mechanism. (352) Such anti-inflammatory mechanisms may also be partially responsible for the positive effects of dietary restrictions, such as those seen in the low-FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet in IBS. (353−355) An alternate method for IBS treatment involves FMT from non-IBS individuals to patients with IBS. (356−359)

Functional Dyspepsia

Functional dyspepsia (FD) is a worldwide prevalent DGBI affecting 10%–30% of adults and 3.5%–27% of children worldwide. (360) The main clinical symptoms of patients are early satiety, postprandial discomfort, epigastric pain, epigastric distension, epigastric burning, loss of appetite, belching, nausea, and vomiting, which are often accompanied by anxiety and depression. (361) FD pathogenesis is linked to GI dysmotility, visceral hypersensitivity, impaired gastric tolerance, disrupted gastrointestinal mucosal integrity, abnormal function of the gut microbiome–brain axis, increased eosinophils in duodenum, dysbiosis, Helicobacter-pylori infection, postgastrointestinal infection, diet, genetics, and mental and psychological factors. (278)
An increasing number of studies have confirmed the close association between disturbance in the relative abundance and composition of the gastrointestinal microbiota and the occurrence and progression of FD. Actinomyces, Atopobium, Leptotrichia, Prevotella, and Veilonella counts differ between FD and control patients. (362) The finding was preceded by an observation that, in FD patients, gut barrier integrity is impaired and expressed as lowered transepithelial resistance; diminished expression of proteins of tight junctions; and lastly, elevated levels of mast cells, eosinophils, and interstitial lymphocytes. (363)
Surprisingly, FD patients not only had different gastrointestinal microbiota compared with non-FD, but also had different oral microbiota abundance and composition. Proteobacteria were the dominant bacteria in FD patients’ saliva, while Bacteroidetes were the dominant bacteria in healthy controls. The abundance of Spirochaetes in FD patients was higher than that in healthy controls, while the abundance of Fusobacteria, TM7, and Proteobacteria was lower than in healthy controls, and the levels of Kingella and Abiotrophia genus levels were also significantly different. (364)
Mental illness plays a significant role in the pathogenesis of FD. Anxiety at baseline has been shown to increase the risk of developing FD by almost 8 times after 10 years follow-up. (365) Interestingly, multiple studies highlighted that the prevalence of anxiety and depression is significantly increased in patients with FD compared with healthy people. Furthermore, pathophysiological research indicates that psychosocial factors and mental disorders may play a role in FD by modulating both visceral signal processing in the brain (366) and the effects of stress hormones on pain perception. (367) Furthermore, it is known that psychosocial factors and stress hormones also affect other aspects of the GI tract, such as motility, immune system activation, permeability, and microbiota.
However, FD symptoms are thought to induce anxiety or depression because of a cytokine response in low-grade intestinal inflammation, which plays an important role in the development of psychological distress in patients with FD. (368) A growing body of evidence suggests that the gut microbiota communicates with the central nervous system, possibly neuro-immuno-humoral pathways, thereby influencing brain function. (369) Furthermore, microbiota release neuroactive compounds, such as GABA, serotonin, dopamine, and acetylcholine, thereby acting locally on the enteric nervous system. Some of these neuroactive substances access the brain through the blood and the circumventricular organs or via the vagus nerve. Therefore, it could be hypothesized that a disturbed microbiome might affect mental health, followed by anxiety and depression. Thus, the mental disorders might be a consequence of the dysbiosis and, therefore, promote the development of FD, which may explain the findings that anxiety increases the risk of FD (365) and observations indicating that psychosocial factors and mental disorders may play a role in FD by modulating visceral signal processing in the brain. (366,370)

Functional Constipation

Functional constipation (FC) is a common DGBI with a global prevalence ranging approximately from 10.1 to 15.3% (371) and is characterized by difficult bowel movements and/or a sense of incomplete evacuation, thus influencing quality of life. (372) Previous studies showed that the gastrointestinal microbiota composition of constipation is clearly distinct from that of normal individuals. The species diversity of microbiota in the patient samples was lower than that in healthy subjects; it was also accompanied by significantly reduced levels of Bifidobacterium and Lactobacillus and an increased abundance of Desulfovibrionaceae. (373) Levels of butyrate-producing bacteria, such as Faecalibacterium and Roseburia, were significantly reduced in patients with FC. (373) It has also been confirmed that the relative abundance of methanogenic bacteria is increased in patients with slow transit constipation relative to healthy subjects. (373,374) In another study, Chen et al. collected 3056 fecal amplicon sequence data from five research cohorts and used machine-learning methods to construct the constipation discriminant model. The model identified 15 top-ranking biomarkers, particularly inflammation-related pathogenic bacterial genera Serratia, Dorea, and Aeromonas. (375) A recent shotgun metagenomics study confirmed the results of previous studies by showing that the relative abundance of Roseburia intestinalis, a prominent butyrate-producing bacterium, was reduced in patients with constipation in comparison with healthy controls, and the microbiome corresponding to constipation was enriched for pathways implicated in methanogenesis. (376) In contrast, the microbiome of healthy individuals was characterized by high levels of genes associated with carbohydrate, fatty acid, and lipid metabolism. (150)
Notably, different intestinal sites harbor certain gut microbiomes, yet the majority of recent research has focused on the analysis of fecal-derived microbiota, which are accessible via noninvasive sampling methods. However, luminal microbiota is generally considered to be representative of the distal large intestinal content. The mucosa-associated microbiota, which live in more intimate contact with the host, cannot be fully replicated by fecal microbiota. (377) In patients with constipation, there is even less similarity between fecal- and mucosa-associated microbiota compared with healthy controls and patients with diarrhea. (116) These differences may be due to drier stool allowing fewer signaling molecules to enter the mucosa (378) or the longer transit time providing more opportunities for the communities to diverge. (116) Hence, mucosa-associated microbiota are more likely to affect the host’s epithelial and mucosal function than luminal microbiota. (379) Comparative analyses between fecal and mucosal microbiota showed that the colonic mucosal microbiota composition was correlated with constipation (and was accompanied by a significant increase in Bacteroidetes), while the fecal microbial communities were correlated with colonic transit and methane production rather than constipation. (380) However, more evidence is needed to prove the relationship between the mucosal profile and constipation.
Slow gut transit has been associated with reduced fecal water content, higher fecal pH, higher microbial cell density and diversity, and a shift in microbial metabolism from saccharolysis toward proteolysis, as reflected by reduced levels of short-chain fatty acids and increased levels of branched-chain fatty acids (BCFA). (381) It is likely that once easily accessible carbohydrate sources become scarce in the colon, the gut microbes switch to ferment dietary and mucin-derived proteins. While saccharolysis by the gut microbiota gives rise to SCFA that are beneficial for the host and a source of energy for the colonocytes, proteolysis can lead to the accumulation of compounds such as BCFA, phenols, indoles, ammonium (NH3) and hydrogen sulfide (H2S) that are generally considered detrimental for health. Moreover, hydrogen (H2) with carbon dioxide (CO2) or formate can be converted into methane (CH4) by methanogenic archaea, which are also linked to slower transit time. In addition, the production and circulation of secondary bile acids and hydrolysis of host-derived glucuronides excreted via bile can also be affected by alterations in gut transit time. (381)
FC in patients would accompany mental disorders like anxiety and varying severity of depression. (382) Evidence from recent neuroimaging studies illustrated that FC patients had significant structural and functional alterations in brain regions that are involved in visceral sensorimotor, cognitive control, and emotional regulation, (383−389) thereby confirming its reclassification as DGBI. Among these altered brain regions in FC patients is the anterior insula, which is generally regarded as a critical node for its essential role in processing interoceptive signals, modulating visceral activities, and regulating emotions and cognitions. (383,385,389−391)

Stress and Stress Resilience

Chronic stress is rapidly becoming a global societal challenge. Stress constitutes a state of threatened homeostasis triggered by intrinsic or extrinsic adverse forces (stressors) and is counteracted by an intricate repertoire of physiological and behavioral responses aiming to maintain/reestablish the optimal body equilibrium (eustasis). Stress is a nonspecific response of the body to any demand imposed upon it that disrupts the body homeostasis and manifests with symptoms such as anxiety, depression, or even headache. (392) Stress can be hardly avoided in the present-day, modern, competitive life. Although eustress is important for people’s rapid reaction to threats, chronic stress is associated with detrimental effects on physical health and adverse implications on the immune, neuroendocrine, and central nervous systems. (392)
Acute stress activates the HPA axis, thereby resulting in an immediate release of cortisol. This response prepares the individual to defend against or escape from a threat. After the threat subsides, normal homeostasis should return. However, when that fails to occur, chronic activation of the stress response results in dysregulation of the HPA axis and an increased risk of subsequent diseases/disorders. (320) It also acts on the gut to increase the release of proinflammatory mediators, which leads to increased gut permeability. (393) Repeated exposure to stress can initiate a vicious cycle of low-grade inflammation and negatively impacts the intestinal barrier and immune signaling within the gut. (394,395)
A link between stress and the abundance of lactobacilli in mice was discovered for the first time more than 40 years ago. (396) Several preclinical studies have documented that stress impacts gut microbial composition in a number of different hosts using different stress models ranging from water avoidance to maternal separation, heat, and acoustic stress and overcrowding. (320) These results have shown clinical relevance and translated into human studies, thereby showing the influence of stress on gut microbiota and gut microbiota on stress modulation through different stressors, such as surgical intervention, academic examination, or military training, among others. (397−400)
Maternal stress during pregnancy displays a distinct fecal microbiota profile, which has generational consequences. The maternal microbiota influences offspring microbiota and correlates with hyper-reactivity of the HPA axis, together with other perinatal factors, as a key determinant of offspring outcomes. These findings have been confirmed in humans in a population-based study whereby infants born to mothers with high cumulative stress during pregnancy exhibited an aberrant microbial composition. (401)
The effects of early life stress on the microbiota may extend to adulthood. (49) It is, therefore, plausible that changes in the gut microbiota due to stress at least partially mediate the onset of stress-related depressive or anxious episodes. Correlational studies have shown that fecal microbiota composition in individuals with anxiety or depression differs from that in healthy controls. (202,402,403) Women with a higher fecal Prevotella abundance experienced increased negative emotional response to viewing negative images and lower brain activity in the hippocampus than those with a higher Bacteroides abundance. (404)
Stress resilience is the ability to experience stressful events without the development of chronic elevated stress (psychological and/or biological) and associated changes in emotional behavior. (405,406) Stress susceptibility is related to psychological factors, such as passive coping skills and high emotional reactivity, but is also associated with biological factors such as hypo- or hyper-responsiveness of the stress response system, sex hormones, central and peripheral immune activation, and glucocorticoid resistance. (407) The gut microbiome is a biological factor that is emerging as a possible influencer of stress resilience. The broad influence of the gut microbiota on human health, including psychiatric health, has begun to be realized and understood over the past decade. Preclinical studies have reinforced this principle showing a connection between the gut microbiome–brain axis and stress resilience. Li et al. recently reported that certain mice exposed to chronic stress were found to be resilient to stress-induced corticosterone and anxiety-like behavior. These mice contained a relative abundance of Lactobacillus species within their gut microbiome. Subsequent stress-susceptible mice saw decreased anxiety-like behavior and corticosterone levels with Lactobacillus murinus supplementation. (408)
Modulation of the gut microbiome has emerged as a possible way to improve stress resilience and mental health. In 2013, Dinan et al. coined the term psychobiotics, which refers to live microorganisms when ingested in adequate amounts that produce a health benefit in patients suffering from psychiatric illness; the definition has been expanded to include other interventions that modulate the gut microbiome, such as prebiotic. (409) The term psychobiotics has since been widely adopted by neuroscientists conducting research on neurodegenerative diseases and depressive disorders in order to describe the use of different biotics to tackle depression, stress, anxiety, and other mental health complaints through the GBA.

Sleep

Adequate sleep quality and sufficient duration are necessary to support both mental and physical health and overall quality of life. (410) Inadequate sleep in either duration and/or quality has been increasingly recognized as a global public health issue. Sleep disturbances are typically characterized by a decrease in one’s ability to initiate and maintain sleep and by a reduced proportion of the deeper, more restorative sleep. (411) Increased risk of developing chronic diseases, such as obesity, type 2 diabetes, heart disease, some types of cancer and mental illness, has been associated with inadequate sleep. (411,412)
Evolving evidence has shown the impact of gut microbiota on sleep. In humans, previous research has shown that partial sleep deprivation can alter the gut microbiome composition in as little as 48 h; (413) however, longer periods of sleep deprivation apparently do not have this effect. (414) A more recent study showed that high sleep quality was associated with a gut microbiome containing a high proportion of bacteria from the Verrucomicrobia and Lentisphaerae phyla and that this was associated with improved performance on cognitive tasks. (415)
Microbiome diversity was positively correlated with sleep efficiency and total sleep time and was negatively correlated with the sleep fragmentation, thereby indicating that diversity of the gut microbiome promotes healthier sleep. However, two previous studies in humans suggested that microbiome diversity is insignificantly affected following a period of sleep restriction. (413,414) A critical difference between these studies is that the former study measured sleep over an extended period of time (one month), while the latter two studies manipulated sleep by experimentally restricting sleep. Accordingly, it is possible that short-term manipulations to sleep do not influence the gut microbiome diversity, but rather that microbiome diversity can influence sleep in the long term.
Gut microbiota may affect sleep status via degradation products, such as muramyl peptides (MPs), lipopolysaccharide, and melatonin. (416) These degradation products could activate immune cells that lead to the release of cytokines, which could affect sleep. Cytokines represent a potential critical interface between sleep physiology and gut microbiome composition. The acute phase pathway, cytokines IL-1β and IL-6, in particular, are strongly associated with sleep physiology. IL-1β is a major somnogenic factor. (416) IL-1β administration in human and nonhuman animals increases spontaneous sleep and fatigue, and IL-1β increases with ongoing sleep loss. (416) Unlike IL-1β, IL-6 is not a direct somnogenic factor, but sleep loss results in increased IL-6 levels. (417) In the gut, IL-6 and IL-1β-mediated inflammation fluctuates in response to stress and disease. (418) For example, intestinal mucositis results in an increased expression of IL-6 and-IL-1β in the small intestine (419) and in serum and colon tissue (420) in mice. In humans, chronic stress, alone, increases IL-6 and-IL-1β.
Alterations in the microbiome have been shown to influence neurotransmission of serotonin in both the peripheral and central nervous system. (411) While this may convey a positive impact on mood and psychological well-being, (421) it also has the potential to influence sleep (422) as serotonin is acetylated and, then, methylated to yield melatonin─the hormone important in helping regulate sleep/wake cycles. (423)
A recent meta-analysis involving 36 studies showed that sleep disorders were common in IBS, and the prevalence rate was 37.6% (95% confidence interval: 31.4% to 44.3%). (424) The pooled odd ratio revealed that sleep disorders were significantly associated with IBS. The reason why sleep disorders are associated with IBS remains unclear; however, the gut microbiome–brain axis could play an important role in the pathogenesis of both. Modification of the autonomic nervous system activity has been observed in cases of sleep deprivation, which indicates that sleep disorder might be associated with autonomic dysregulation. (425,426) It has been postulated that sleep inhibits the HPA axis, and sleep disorder may result in a 24 h increased secretion of cortisol. (427) Moreover, IBS symptoms, such as abdominal pain, may activate the sympathetic nervous system and, hence, reduce sleep efficiency. (428) Microbiome modulation has been shown to influence melatonin production and modulate IBS symptoms in individuals with a normal circadian rhythm. (429) Overall, although the reason for sleep disorders seen commonly among IBS patients is obscure, a gut microbiome–brain axis disorder may underlie this association. (427)
An additional layer of evidence has been shown by the intertwined interactions between the gut microbiome and the central and peripheral circadian rhythms. (430) The disruption of the host circadian rhythm alters the gut microbiome equilibrium. In addition, the microbiome is able to mediate host clock gene expression in peripheral organs and the suprachiasmatic nucleus.
Intestinal bacteria have shown inherent circadian rhythms, as shown in previous metagenomic studies. (430) Diurnal fluctuations in abundance and activity have been observed in Clostridiales, Lactobacillales, and Bacteroidales, which account for ∼60% of the microbiota. (431) Studies on human stool samples of Enterobacter aerogenes have demonstrated responsivity to the circadian hormone melatonin, as well as a daily rhythm. (432) The gut epithelium experiences differential bacterial species and metabolites depending on the time of day and expresses toll-like receptors that sense microbiotal metabolites in a rhythmic pattern. (433) It has been proposed that the gut microbiome influences the rhythmic expression of the host’s internal clock by signaling molecules, such as butyrate, and by oscillations in microbiotal bacterial content in response to feeding patterns. (434)

Cognitive Function

Abundant evidence supporting the role of the gut microbiota in modulating cognitive function is mostly based on animal research. However, few studies have examined the influence of gut microbes on human cognition and supported the clinical relevance. One of these studies showed that the gut microbiota composition of obese and nonobese subjects was linked with scores in speed, attention, and cognitive flexibility coupled with alterations in neural activity in the thalamus, hypothalamus, and amygdala, thereby suggesting that obesity affects the microbiota composition and subsequent cognitive performance. (435) Additionally, the microbiota composition in 1-year-old babies was associated with cognitive development. Three groups of microbial composition have been identified where better performance was seen in the group with higher levels of Bacteroides. (436) This group was also less likely to be born via C-section, which supports the previous observation linking delivery mode with child cognitive development, (437) thereby highlighting the importance of gut microbiota colonization in cognitive development and function. (436)
Microbiome modulation has demonstrated beneficial effects on cognitive performance. Lactobacillus strains have improved cognitive performance in healthy elderly subjects. (438) Fermented milk product supplemented with a probiotic has been shown to modulate the activity of brain regions involved in cognitive performance during an emotional attention test in healthy women. (439) Also, the modulation of the microbiome via inulin prebiotic has been shown to improve memory and mood in healthy individuals. (440)
These results taken together indicate the potential role of the gut microbiome–brain axis in regulating cognitive performance and that microbiome modulation could be a promising approach for improving cognitive function in both healthy and vulnerable individuals. However, much more work is needed to understand why specific microbiome-related interventions have the potential to modulate cognition.

Emotional Well-being

Gut microbiota is emerging as a key mechanism for modulating emotional well-being. (441) In fact, emotional disorders, such as depression and anxiety, are frequently accompanied by functional gastrointestinal disorders, which suggests an association between gut function and psychiatric diseases. (442,443) Recent research reveals the gut–brain axis association with the vagus nerve plays an important role in emotional well-being. The subdiaphragmatic vagus nerve is a major modulatory pathway between the brain and gut microbiota. (444) Data suggest that fecal microbiota from depressed mice produce depression-like phenotypes and abnormal gut microbiome composition when transplanted to nondepressed mice via the subdiaphragmatic vagus nerve. (445)
Gut microbiota is emerging as a key mechanism for the modulation of emotional well-being. (441) In fact, emotional disorders, such as depression and anxiety, are frequently accompanied by functional gastrointestinal disorders, which suggests an association between gut function and psychiatric diseases. (442,443) Findings from a longitudinal study further suggest that intestinal infections significantly predict the future onset of anxiety disorder. (446)
Evolving clinical evidence indicates the significant links between the gut and emotion; for example, altered gut microbiota composition (447) was reported in patients with depressive disorder in terms of fecal microbial diversity, as well as the level of the genus Faecalibacterium. (403) In healthy adults, self-rated higher quality of life and favorable personality types (high in openness and conscientiousness) were associated with the composition of certain gut microbiota (i.e., Faecalibacterium, Coprococcus, and Lachnospiraceae), as well as an enriched diversity of the gut microbiota community. (448,449)
Recent studies suggest that enterotypes play a role in regulating the association between the gut microbiome and mental health. (404,449) Enterotypes refer to robust stratified clusters on the basis of the variation found in the levels of one of three genera in the gut: Bacteroides (enterotype 1), Prevotella (enterotype 2), and Ruminococcus (enterotype 3). (450) Individuals’ enterotype cluster depends on, in part, long-term diet─i.e., the amount of ingested animal protein/saturated fats (Bacteroides-type) versus carbohydrates/simple sugars (Prevotella-type)─whereas they are less influenced by the hosts’ body mass, age, and sex. (450−452)
A recent brain imaging study found distinct patterns of the emotional process and brain connectivity between stratified enterotypes; clusters with a greater abundance of Prevotella show higher levels of emotional response, along with prominence in the connectivity of emotional, attentional, and sensory-processing brain regions when compared with Bacteroides-dominant clusters. (404) A large-scale microbiome study also revealed that the Bacteroides-enriched enterotype is significantly associated with a lower score on the subjective feeling of quality of life, as well as a higher score regarding depressive symptoms.
A recent exploratory study revealed that gut microbiome diversity is related to emotional well-being and that enterotypes significantly moderate the links between emotional well-being and gut microbiome diversity. (441) The enterotypes did not alter mood status, itself, but moderated the strength of the association between one’s mood and gut microbiome diversity. In the Prevotella-dominant group, emotional status was more closely related to gut microbiota diversity, such that a positive effect was associated with increased gut microbiota diversity. However, in the Bacteroides-dominant group, one’s mood status was not significantly associated with gut microbiome diversity. This finding is in line with the results of Tillisch et al. (404) in that only the high-Prevotella group displayed an increased response to affective images in the limbic system. Such findings suggest a significantly tighter connection between emotional well-being and the well-being of the gut microbiota community, particularly in the Prevotella-dominant condition.
There is an evolving body of evidence suggesting that the modulation of the gut microbiome by biotics administration or via food supplements (i.e., psychobiotics) may closely affect one’s mood. Benton et al. (421) showed that the consumption of probiotic-containing yogurt improved the self-reported mood of those whose mood was initially poor. Messaoudi et al. (176) showed that consumption of the probiotics reduced anxiety and depression scores in subjects with reduced urinary free cortisol. Also, consumption of Lactobacillus helveticas and Bifidobacterium longum reduced somatization, depression, anger and hostility, hospital anxiety, depression-scale global scores, and self-blame scores on coping checklists and increased focus on problem solving, but there was no effect on perceived stress. (176) Moreover, the administration of a combination of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum for 8 weeks improved the depression score. (453) In a 2017 systematic review by Wallace and Milev of 10 clinical trials, most of the studies found positive results on measures of depressive symptoms. (454) A recent meta-analysis (455) included 30 randomized placebo-controlled studies and revealed that most probiotics did not affect mood, anxiety, depression, and psychiatric distress when compared with placebo at the qualitative questionnaire level; however, on the quantitative meta-analysis level, probiotics intervention showed slightly significant effect compared with placebo. In addition, EEG and imaging studies summarized in a recent review proved that probiotics are able to exert effects on CNS function in humans; although, the number of studies is still low. (455)
Overall, there is emerging evidence on the link between one’s emotional status and gut microbiome diversity and composition. The current evidence suggests that emotional well-being and the feeling of happiness can be associated with gut microbiota profiles in healthy adults, especially when stratified by enterotype. The enterotype-specific links between emotional well-being and gut microbiome diversity suggest that enterotypes may work as an individually tailored intervention. With the expanding interest in the role of the gut microbiome–brain axis in mental health, this nascent field still needs to build up empirical evidence to fill the gap in our understanding of how gut microbiota communicates with the brain to affect emotional well-being and the feeling of happiness.

Prebiotics, Probiotics, Synbiotics, Postbiotics, and Psychobiotics

Probiotics

Probiotics are defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. (93,456) Probiotics usually comprise bacteria, including, among others, Lactobacillus, Bifidobacterium, and Bacillus, although a few strains of the yeast Saccharomyces have also been included in probiotic cultures. Probiotic microorganisms must have several features, including a demonstrated benefit to the host and the recognition that they are safe for human consumption, i.e., they have generally been recognized as a safe designation. They are resistant to acid and bile salts that are encountered in the GI tract. The ability to adhere to the intestinal epithelium is a useful trait that promotes both the persistence of the probiotic and host interactions. Other useful features are that they are easily cultured and are resistant to drying, freezing, and freeze-drying so that the probiotic may be produced and stored in bulk. Probiotics can enhance immune function, promote fiber assimilation for SCFA production, and help suppress pathogens in the GI tract. (93,457,458)

Prebiotics

Prebiotics are defined by ISAPP as a substrate that is selectively utilized by host microorganisms conferring a health benefit. (31,93) Therefore, such a definition expands beyond the classical prebiotics composed of polysaccharide carbohydrates and could include any other nondigestible microbiome-fermentable ingredients, such as herbal secondary metabolites and flavobiotics. The definition stresses that the effects must be microbiota-mediated and that the beneficial health effects must be documented for a substance to be considered a prebiotic. (459) The most well-known products of microbiome-derived fermentation are SCFAs, such as butyric acid, acetic acid, or propionic acid, which have a beneficial effect on the host. Moreover, prebiotics modulate lipid metabolism, increase calcium absorption, have a positive effect on the immune system, and reduce the risk of broad diseases. (458)

Synbiotics

ISAPP defined synbiotic as a mixture comprising live microorganisms and substrate(s) selectively used by host microorganisms that confer a health benefit on the host. The panel concluded that defining synbiotics as simply mixtures of probiotics and prebiotics could suppress the innovation of synbiotics that are designed to function cooperatively. The ISAPP panel differentiated synbiotics into two groups: complementary synbiotics and synergistic synbiotics. A complementary synbiotic that has not been designed so that its component parts function cooperatively must be composed of a probiotic plus a prebiotic. A synergistic synbiotic is a synbiotic for which the substrate is designed to be selectively utilized by the coadministered microorganisms. (460)

Postbiotics

Postbiotics are a class of products that has emerged in the last 10 years. Postbiotics are defined by the ISAPP as preparations of inanimate microorganisms and/or their components that confer a health benefit on the host. Effective postbiotics must contain inactivated microbial cells or cell components, with or without metabolites, that contribute to observed health benefits. (458,461) Postbiotics, because they are derived from probiotic microorganisms, have many of the same benefits as probiotics. The effects of postbiotics are often more reliable and predictable than probiotics. Postbiotics tend to have a longer shelf life than probiotics and they are more target-specific and safer in terms of their interaction with the human GI tract. (93)

Psychobiotics

The term psychobiotic was coined to describe bacteria that confer mental health benefits. Psychobiotics have demonstrated the ability to improve mood, reduce anxiety, and enhance cognitive function in both healthy populations and patient groups. While the term psychobiotics originally referred to beneficial live organisms, such as bacteria that are specifically beneficial for mental health, (409) the definition has been expanded in recent years to include prebiotics whose effect on the brain is bacteria-mediated. (462) It is also worthwhile considering a wider definition of psychobiotics to include any substance that exerts a microbiome-mediated psychological effect or at least possesses psychobiotic properties, such as probiotics, prebiotics, synbiotics, and postbiotics. (462,463) Recently a new term “phyto-psychobiotics” has been coined to describe medicinal plants whose mental effects are mediated via gut microbiota modulation by prebiotic-like effects, postbiotic-like effects mediated by the active secondary metabolites produced by the gut microbiome from the nondigestible herbal ingredients, or even by antibiotic-like effects as in the case with some medicinal herbs that have a mental impact by reducing the level of pathogenic bacteria. (464)

Pre-, Pro-, Postbiotics, and Fecal Microbiota Transplantation in the Development Pipelines

A search of the CAS Content Collection (84) reveals the top organizations for research and journal publications related to the gut microbiome and mental and digestive health. All these top players are universities and research institutes, and the University College Cork, the Chinese Academy of Science, the University of California, and McMaster University lead the field (Figure 14A). The lead universities and medical centers related to patenting activity for the gut microbiome in mental and gut health include the University of California, Johns Hopkins University, and the University of Texas (Figure 14B).

Figure 14

Figure 14. Top universities, research institutes, and hospitals publications (1967–2022) related to gut microbiome research in mental and gastrointestinal health: (A) journal publications and (B) patents.

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Private Investment

Researching the overall global private investment activities of the microbiome field provides insight into the commercial interest into this area. Performing a search of prebiotics, probiotics, and the microbiome within PitchBook, an online source for investment data, reveals the overall venture capital activities. The search revealed that both capital raised and deal counts from venture capital investment are rising within this industry. (465) From 2014 through 2018, the total capital raised increased from $250 million to over $1 billion. Deal counts followed the same pattern from 2014 to 2018 and increased from 25 to 125. The number of deal counts in 2019 further increased; however, the overall capital raised fell to just under $900 million. Deal counts continued to rise for 2020 and 2021, along with capital raised, which totaled over $2.1 billion, while 2022 ended with a slight decrease in total venture capital investment (Figure 15). The venture capital investment data in this area clearly shows a recent and increasing commercial interest surrounding prebiotics, probiotics, and the microbiome, thereby revealing its potential promise for therapeutic applications.

Figure 15

Figure 15. Overall capital raised and deal counts of venture capital investment for the prebiotic, probiotic, and the microbiome field ($) (source: pitchbook.com).

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Companies and Academic Institutions Investigating Treatment of Mental Disorders and DGBI through Gut Microbiome Modulation

With the GBA being a bidirectional communication network, we herein examine a highlighted selection of global companies and academic institutions researching and producing prebiotics, probiotics, postbiotics, and utilizing fecal microbiota transplantation to treat a variety of consumer health-related mental disorders and DGBI. This global analysis of worldwide companies and academic institutions, while extensive, is not comprehensive and provides insight into both the present and future state of the field.

Probiotics

Companies, along with universities and health institutions, are utilizing probiotics for the treatment of mental disorders at slightly different rates (Figure 16). Companies are focusing more on stress than universities and medical institutions, with all organizations researching anxiety at about the same rate. Universities and medical institutions are researching depression, cognition impairment, and sleep disorders at a higher rate than industry. With universities and medical institutions on the forefront of research, this shows the up-and-coming possibilities for probiotic products for the treatment of depression, cognition impairment, and sleep disorders being produced for consumers in the future. Research in the area of utilizing probiotics for DGBI is much more extensive and historically established (Supplemental Table 1) than mental health disorders (Figure 16). Companies, universities, and medical institutions research most DGBI at a similar rate, with universities and medical institutions having a higher focus on IBS. IBS is more prevalent among those who eat a Western diet. With more of the world’s population adopting a Western diet, the prevalence of IBS is expected to increase. (466) The research among universities and medical institutions is shadowing this trend as researchers evaluate probiotic treatment options for this DGBI increasing in prevalence (Figure 16).

Figure 16

Figure 16. (Left) The percentage and number of analyzed global organizations utilizing probiotics for mental disorders and DGBI treatment. (Right) The percentage and number of analyzed global organizations utilizing prebiotics for mental disorders and DGBI treatment.

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Prebiotics

Fewer organizations are researching prebiotics for the treatment of mental disorders and DGBI when compared with probiotics (Figure 16). Prebiotics for DGBI are researched more than mental disorders, with more focus on IBS and functional constipation (Figure 16). This field has many future growth opportunities for both industry and research as it grows and becomes established. Similar to the number of organizations, the number of documents in the CAS Content Collections related to prebiotics is about three times lower compared with those related to probiotics. However, the growth rate in the prebiotics research has increased in the last two years.

Postbiotics

Postbiotics are the least researched therapeutic examined and are mainly limited to a small commercial presence (Figure 16). With such a small commercial and research presence, the opportunities are also abundant for postbiotic therapeutics.

Fecal Microbiota Transplantation

FMT research is found to be rare in comparison with other microbiome modulation strategies in mental disorders and newly established with only a very small number of companies and universities participating in this field (Figure 17). Most of the FMT research in DGBI focuses on IBS treatment (Figure 17). This field is currently showing clinical scientific evidence for the successful treatment of the serious and sometimes deadly condition of Clostridium difficile (C. Diff) infection. (467) Recently, Australia’s Therapeutic Goods Administration gave the world’s first regulatory approval to company BiomeBank for its biologic microbiome product called Biomictra for the treatment of C. Diff infection. (468) The US FDA followed a few weeks later with its official approval for the biologic drug consisting of live human-derived fecal microbiota, RBX2600 (Rebyota), produced by Ferring Pharmaceuticals, which is also for the treatment of C. Diff infection. (469) These first regulatory approvals open this method to endless opportunities for the treatment of many different diseases, and more studies are needed to prove its safety and efficacy.

Figure 17

Figure 17. (Left) The percentage and number of analyzed global organizations utilizing postbiotics for mental disorders and DGBI treatment. (Right) The percentage and number of analyzed global organizations utilizing fecal transplant for mental disorders and DGBI treatment.

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Clinical Trials Landscape for Probiotics in Mental Disorders and DGBI

When examining clinical trials utilizing probiotics for the treatment of the mental disorders discussed within, there are currently a total of 52 clinical trials covering all stages between 2004 and 2022 listed on the US NIH clinical trials website. (470) The most studied mental health disorders are stress, followed by depression, anxiety, cognition impairment, and sleep disorders. Clinical trials utilizing probiotics for the treatment of DGBI are the most prolific and historically studied with 174 clinical trials. (470) The most studied DGBI are IBS followed by functional constipation, functional diarrhea, and functional dyspepsia.
The most researched probiotics for the treatment of mental disorders are the Lactobacillus species and a combination of Lactobacillus and Bifidobacterium species (Supplemental Table 1). For DGBI, the most widely used probiotic is the Lactobacillus species followed by the Bifidobacterium species, a combination of Lactobacillus and Bifidobacterium species, and finally the Saccharomyces species (471) (Supplemental Table 1).
Highlighted clinical trials examining probiotics as a treatment option for mental disorders and DGBI are explored in Tables 4 and 5. A select few are also examined in further detail below to showcase a variety of interventions and targeted conditions in clinical development, along with their status. While experimental data in this area is showing promising results, there are still conflicting results being reported.
Table 4. Highlighted Clinical Trials Utilizing Probiotics for the Treatment of Mental Health Disorders
clinical trial identifierconditioninterventionstatus
NCT05564767 (472)depression, anxiety, stressBifidobacterium adolescentis Bif-038, Lacticaseibacillus rhamnosus LGG, Bifidobacterium BB-12recruiting
NCT03494725 (477)stress, anxietyLacticaseibacillus paracasei Lpc-37complete
NCT04767997 (474)sleep disorderundisclosed probiotic formulationrecruiting
NCT03601559 (478)cognitive impairmentLactobacillus paracasei Lpc-37complete
NCT03615651 (479)stress, cognition impairmentLactobacillus helveticus, Bifidobacterium longum, Lactiplantibacillus plantarumcomplete
NCT05567653 (473)stressLactobacillus helveticus Rosell-52, Bifidobacterium longum Rosell-175recruiting
NCT03370458 (480)stressLactobacillus plantarum DR7complete
Table 5. Highlighted Clinical Trials Utilizing Probiotics for the Treatment of DGBI
clinical trial identifierconditionprobiotic interventionstatus
NCT02592200 (485)functional constipationLactobacillus gasseri DSM 27123complete
NCT04304170 (486)functional constipationBifidobacterium animalis lactis (LMG P-28145)complete
NCT04662957 (487)diarrhea-predominant irritable bowel syndromeBifidobacterium breve BB010, Bifidobacterium longum BL020, Bifidobacterium bifidum BF030, Bifidobacterium lactis BL040, Lactobacillus rhamnosus LR110, Lactobacillus paracasei LPC100, Lactobacillus acidophilus LA120, Lactobacillus casei LC130, Lactobacillus plantarum LP140, Streptococcus thermophilus ST25complete
NCT05566171 (488)functional constipationBifidobacterium lactis CNCM I-2494, Bifidobacterium lactis DN 173-010enrolling by invitation
NCT01463293 (489)functional constipationBifidobacterium lactis HN019complete
NCT01102036 (490)functional constipationLactobacillus paracasei F19, Lactobacillus paracasei LA-5, Bifidobacterium lactis BB-12complete
NCT03721107 (491)diarrhea- and constipation-predominant irritable bowel syndromeBlautia hydrogenotrophicacomplete
NCT00534170 (492)functional diarrheaLactobacillus casei Shirota, Bifidobacterium breve Yakultcomplete
NCT00794924 (493)functional diarrhea, functional constipationStreptococcus thermophilus, Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium infantis, Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus paracasei, Lactobacillus delbrueckii subsp. bulgaricuscomplete
NCT02213172 (494)irritable bowel syndromeBifidobacterium longum R0175, Lactobacillus paracasei HA-196complete
NCT00807326 (495)functional diarrheaSaccharomyces boulardiicomplete
NCT05054309 (496)irritable bowel syndromeBifidobacterium longum NCC3001recruiting
NCT01099696 (497)functional dyspepsiaBifidobacterium infantis 35624complete
NCT01887834 (498)irritable bowel syndromeLactobacillus gasseri, Bifidobacterium bifidum, Bifidobacterium longumcomplete
NCT04605783 (499)functional diarrheaSaccharomyces boulardii CNCM I-745not yet recruiting
NCT04950296 (500)irritable bowel syndrome with diarrheaLactobacillus plantarum UALp-05complete
NCT05149599 (501)irritable bowel syndromeSaccharomyces cerevisiaecomplete

Mental Disorders

Clinical trial number NCT05564767 is currently recruiting participants to assess the treatment of depression and anxiety in adults by utilizing probiotics Bifidobacterium alone and Lacticaseibacillus combined with Bifidobacterium. (472) Clinical trial number NCT05567653 is also recruiting for its study researching the treatment of stress in dancers with a probiotic product combination including Lactobacillus and Bifidobacterium. (473) Another study (NCT04767997) looking at the effects of probiotics on sleep disorders is also currently recruiting subjects. (474) Clinical trial number NCT03615651 researched the effect of a probiotic mixture containing Lactobacillus helveticus, Bifidobacterium longum, and Lactiplantibacillus plantarum on subjects’ functional brain responses during an emotionally stressful attention task. (472) Their findings showed a positive effect on brain responses in regions implicated in emotional and cognition processing, which supports the growing evidence that probiotics can help positively influence emotional regulation and brain function. (475) Another study (NCT04767997) that is looking at the effects of probiotics on sleep disorders is also currently recruiting subjects. Finally, a recently completed study (NCT03494725) found that supplementation with probiotic Lacticaseibacillus paracasei Lpc-37 significantly reduced perceived stress and anxiety in study participants. (476)

DGBI

Clinical trial number NCT05566171 is currently recruiting participants to research the treatment of functional constipation with two Bifidobacterium strains. Bifidobacterium was also researched in clinical trial number NCT04304170 and NCT01463293 for the treatment of functional constipation. Lactobaccillus and a combination of Bifidobacterium species and Lactobacillus were also researched for the treatment of functional constipation in completed clinical trials NCT01102036 and NCT02592200, respectively. Utilizing a combination of Streptococcus, Bifidobacterium, and Lactobacillus species, clinical trial number NCT00794924 researched the treatment of functional constipation and diarrhea in elderly hospitalized patients. The study showed positive results with the probiotics reducing days patients suffered from diarrhea or received laxatives, thereby displaying a positive effect on bowel movements. With diarrhea remaining a major public health concern in developing countries, study NCT00534170 researched the use of a probiotic drink containing both Lactobacillus and Bifidobacterium species for the treatment of diarrhea in young children. The study revealed the ingestion of a daily probiotic drink could prevent diarrhea in young children in a community setting within a developing country. (481) Another study (NCT00807326) also researched the treatment of functional diarrhea. They compared the treatment results of antigas/antidiarrheal drug combination loperamide/simeticone and probiotic yeast Saccharomyces boulardii. They discovered that while the probiotic did help alleviate symptoms, it was inferior to loperamide/simeticone. (482) Clinical trial number NCT01099696 also had discouraging results researching the treatment of functional dyspepsia with probiotic Bifidobacterium infantis 35624. While previous studies showed promise in patients with IBS, Bifidobacterium infantis 35624 did not show significant improvement in symptoms of abdominal discomfort and bloating in that study’s participants. Finally, a study (NCT04662957) researching a multistrain probiotic mixture of four Bifidobacterium, five Lactobacillus, and one Streptococcus species concluded its probiotic could offer benefits for patients with diarrhea-predominant IBS. (483) Another study (NCT03721107) showed more positive results for the treatment of both diarrhea and constipation-predominant IBS. Patients reported improvement in bowel symptoms and pain with the use of Blautia hydrogenotrophica. (484)

Clinical Trials Landscape for Prebiotics in Mental Disorders and DGBI

When examining clinical trials utilizing prebiotics for treatment of the mental disorders discussed within, there are currently a total of 15 clinical trials. (470) The most studied mental health disorder is stress, followed by anxiety, depression, sleep disorders, and cognition impairment. (470) A total of 50 clinical trials utilize prebiotics for the treatment of DGBI. (470) Similar to probiotics, the most studied DGBI using prebiotics is IBS, followed by functional constipation, functional diarrhea, and functional dyspepsia. (470) The most commonly used prebiotic in clinical trials is galacto-oligosaccharides (GOS), followed by other sugars such as fructan, glucan, and dextrose, along with various fibers.
Highlighted clinical trials examining the treatment of mental disorders and DGBI with prebiotics are explored in Tables 6 and 7. A select few are also examined in further detail below to showcase the variety of interventions and targeted conditions, along with their status in clinical development. The use of prebiotics for the relief of mental and gastrointestinal disorder symptoms is producing promising results.
Table 6. Highlighted Clinical Trials Utilizing Prebiotics for the Treatment of Mental Health Disorders
clinical trial identifierconditioninterventionstatus
NCT05372601 (504)stressGOScomplete
NCT05239845 (505)sleep disorderpolydextrose, GOSrecruiting
NCT04324749 (506)cognitive impairment, stressroasted peanuts, peanut buttercomplete
NCT05528575 (507)stressGOS, inulin, resistant potato starch RS2active
NCT04616937 (508)anxiety, cognitive impairmentGOScomplete
Table 7. Highlighted Clinical Trials Utilizing Prebiotics for the Treatment of DGBI
clinical trial identifierconditioninterventionstatus
ISRCTN54052375 (512)irritable bowel syndromeGOScomplete
NCT04491734 (513)gastresophageal refluxmaltosyl-isomaltooligosaccharides (MIMO)complete
NCT05207618 (514)irritable bowel syndrome with diarrheachestnut and quebracho tannin extractcomplete
ACTRN12612001270808 (510)functional constipationgreen kiwi prebiotic, gold kiwi prebioticcomplete
NCT05340712 (515)functional constipationinfant formula with lactose (prebiotic) along with probioticsrecruiting
Mental Disorders
Clinical study NCT04616937 researches the use of GOS for the treatment of anxiety by altering the gut microbiota. GOS increases probiotic bacteria Bifidobacterium abundance in the gut microbiome. The study reports that the supplementation of GOS may improve signs of anxiety and cognition impairment with an increase of reported attention. (502) Another recent study (NCT04324749) researched the prebiotic effect of peanut and peanut butter consumption on the cognitive and stress response of college students. The peanut prebiotic fiber and polyphenol content appears to enhance memory function and reduce stress because of the presence of both short-chain and very long-chain saturated fatty acids for healthy young subjects. (503)
DGBI
A published case study from 2019 showed a new observation that some patients taking a specific prebiotic soluble fiber, maltosyl-isomaltooligosaccharide (MIMO), had their gastroesophageal reflux symptoms resolve. (509) Clinical trial NCT04491734 followed about a year later to research this effect. The prebiotic MIMO reduced the severity and frequency of gastroesophageal reflux symptoms and improved the quality of life for participants. Clinical study ACTRN12612001270808 researched the use of a green kiwi prebiotic (inulin) and a gold kiwi prebiotic to treat functional constipation. The study showed a successful increase in bowel movements and also revealed that green kiwi prebiotic (inulin) supports the increase of two probiotic bacteria, Bifidobacteria and Lactobacillus, within the gut microbiome. (510) Another research study shows that gold kiwi prebiotic increased the abundance of Faecalibacterium prausnitzii within the gut microbiome, as well. (511) F. prausnitzii is a butyrate producer and displays anti-inflammatory effects. (511) When prebiotic GOS was tested in a clinical trial (ISRCTN54052375), it increased the probiotic bacteria Bifidobacteria within the gut. This helped alleviate symptoms of IBS, thereby showing that GOS is a potential therapeutic agent for this disorder. (512)

Clinical Trials Landscape for Postbiotics and FMT in Mental Disorders and DGBI

Postbiotic and FMT are the least researched among all clinical trials explored. When examining clinical trials utilizing postbiotics for the treatment of mental disorders, anxiety is the only disorder studied (Supplemental Table 1). Clinical trials utilizing postbiotics for the treatment of DGBI focus on IBS. (470) Only three clinical trials are researching FMT for the mental health disorders of depression, anxiety, and sleep disorders. Fecal microbiota transplants researching DGBI is higher with 27 trials researching both IBS and constipation.
Highlighted clinical trials examining the treatment of mental disorders and DGBI with postbiotics and FMT are explored in Tables 8 and 9. A select few are also examined in further detail below to showcase a variety of interventions and targeted conditions, along with their status in clinical development.
Table 8. Highlighted Clinical Trials Utilizing Postbiotics for the Treatment of Mental Disorders and DGBI
clinical trial identifierconditioninterventionstatus
NCT05475314 (517)irritable bowel syndromemicrobially fermented postbiotic oat drinkcomplete
NCT05562739 (518)anxietymultistrain postbioticnot yet recruiting
NCT05339243 (519)irritable bowel syndrome with diarrheaheat-treated Bifidobacterium longum ES1recruiting
Table 9. Highlighted Clinical Trials Utilizing Fecal Microbiota Transplantation for the Treatment of Mental Disorders and DGBI
clinical trial identifierconditioninterventionstatus
NCT03822299 (522)irritable bowel syndromefecal microbiota transplantationcomplete
NCT02092402 (523)irritable bowel syndromefecal microbiota transplantationcomplete
NCT05035784 (524)functional constipationfecal microbiota transplantationrecruiting
NCT05427331 (525)chronic insomniafecal microbiota transplantation capsulerecruiting

Postbiotic Clinical Trials Landscape for the Treatment of Mental Disorders and DGBI

Clinical study NCT05562739 (recruiting) is researching a multistrain postbiotic for anxiety treatment in individuals who were placebo nonresponders from part one of the trial. A recently completed study (NCT05475314) researched the use of a postbiotic fermented oat drink for the treatment of IBS. The study resulted in positive outcomes and showed symptom relief in IBS subjects. (516) Lastly, clinical trial NCT05339243 is currently recruiting for their study investigating both Bifidobacterium longum ES1 and the postbiotic heat-treated Bifidobacterium longum ES1 for the treatment of IBS symptoms in subjects with diarrhea-predominant IBS.

FMT Clinical Trials Landscape for the Treatment of Mental Disorders and DGBI

Clinical trial NCT05427331 is currently recruiting for its study examining sleep disorders. FMT through oral capsule administration will be researched to access sleep improvement in patients with insomnia. While fecal transplants are less prevalent for mental disorders, they have shown promise for DGBI with clinical trials by showing favorable results for the treatment of IBS. Clinical trial NCT02092402 showed effective treatment for patients with IBS when using a donor with a diverse microbial gut composition. (520) Another study (NCT03822299) also showed success for FMT in IBS. Just as with trial NCT02092402, it also found that the donor’s fecal composition with a favorable microbial signature and diverse gut microbiota was essential for successful treatment. (123) Three years after treatment, the study was still experiencing high response rates and long-standing effects. (521)

Noteworthy Probiotic and Prebiotic Patents

There are a diverse and growing number of patents related to probiotics and prebiotics in the CAS Content Collection. Listed in Table 10 are noteworthy prebiotic and probiotic patents related to the treatment of mental disorders and DGBI.
Table 10. Notable Prebiotic, Probiotic, and Postbiotic Patents
patent numbertitlesummary
WO2016085356A1gold kiwifruit compositions and methods of preparation and use thereofPrebiotic compositions prepared from gold varieties of Actinidia chinensis. These prebiotic compositions treat or prevent DGBI, such as constipation, and IBS.
WO2022191767A1GOS preconditioning L. reuteri and GOS in final formulationEnhancing the survival and activity of probiotic Lactobacillus reuteri strains by preconditioning L. reuteri with GOS. This method produces high synbiotic and beneficial effects of the probiotic bacteria in the gastrointestinal tract, such as boosting calcium and iron solubility, along with enhancing the production of lactic and acetic acid.
US20160058808A1microbe-based modulation of serotonin biosynthesisMethods and probiotic compositions that can be used to modulate serotonin levels and adjust the composition of gut microbiota along with adjusting the level of serotonin-related metabolites.
WO2022182908A1probiotic therapies for social deficit and stress responseBacterial species, including probiotic Enterococcus faecalis, for use in the treatment of social behavioral deficit symptoms, such as depression, by increasing social behavior and decreasing corticosterone levels along with c-Fos expression in the brain.
US9192618B2method of treating constipation-predominant irritable bowel syndromePrebiotic or probiotic agent that inhibits the growth of methanogenic bacteria or promotes the growth of competing intestinal microbiotia for the treatment of constipation predominant IBS.
US10022408B2probiotic Bifidobacterium adolescentis strainsNovel isolated strains of probiotic Bifidobacterium adolescentis for the prevention, alleviation of symptoms, or treatment of intestinal inflammatory conditions, such as IBS.
WO2005003329A1novel GOS composition and the preparation thereofNovel strains of Bifidobacterium hifidum capable of producing a novel galactosidase enzyme activity that converts lactose to a novel mixture of GOS. The mixture of prebiotic oligosaccharides improves gut health by promoting the growth of bifidobacteria in the gut.
US20220040242A1modulation of the gut microbiome to treat mental disorders or diseases of the central nervous systemMethods of treating at least one symptom of a mental disorder and the central nervous system by modulating the amount of GABA produced in the gut. Also disclosed are methods of identifying and creating probiotic bacterial strains capable of producing GABA.
WO2016029198A1process for the production of isomaltooligosaccharideProvides a method for the production of prebiotic oligosaccharides by the fermentation of dextransucrase-producing microorganisms.
WO2022214700A1Lacticaseibacillus paracasei EM025-11 and uses thereofA probiotic strain of Lacticaseibacillus paracasei EM025-11 that adheres to intestinal epithelial cells and has anti-inflammatory activity by upregulating genes associated with immune engagement for the treatment of IBS with constipation.
US20220280576A1Bifidobacterium longum and functional GI disordersMethods for treating functional GI disorders with probiotic Bifidobacterium longum ATCC BAA-999.
WO2019149941A1postbiotic-based composition for the modulation of immune system activation and protection of mucosal barriersA fermented supernatant of Lactobacillus casei or paracasei species for the promotion of human health and prevention of inflammatory disorders. The postbiotic was shown to stimulate peripheral blood mononuclear cells and protect from endotoxic shock and Salmonella infection.
US8551498B2solid composition containing Bacillus-type nonpathogenic bacterial sporesComposition of spores of probiotic bacteria Bacillus useful in the pharmaceutical, veterinary, and nutrition fields.
ES2824536T3use of microbial communities for human and animal healthMixture of probiotic bacteria belonging to at least six or seven bacterial species to prevent or treat GI disorders.
US20220233559A1xylooligosaccharide as a multifunctional prebioticPrebiotic mixture of xylooligosaccharides derived from sugar cane that were shown to modulate the levels of probiotic bacteria Bifidobacteria and Lactobacillus in the microbiome.
WO2022173764A1nutritional plant-based foods and beverages, methods of manufacture, and methods of treatmentFormulation of a prebiotic beverage whose ingestion modulates the gut microbiome by enhancing the growth of Bifidobacterium, improving the production of SCFAs, and reducing the levels Escherichia coli.
US20220315960A1method for producing gamma-aminobutyric acid and fermented culture prepared therebyProcess to produce gamma-aminobutyric acid from glutamic acid and a probiotic composition capable of this biotransformation. Ideally, the composition contains different probiotic bacteria Bifidobacterium and Lactobacillus strains.
WO2022208458A1inactivated strains of bacteria, such as viable but nonculturable bacteria, compositions, and use thereofPostbiotic composition of different gamma-irradiated members of bacterial species Lactobacillus, Lacticaseibacillus, Bifidobacterium, and Lactiplantibacillus to treat several gastrointestinal disorders.
EP3932415A1gut microbiota composition and uses thereofProbiotic composition for the prevention and/or treatment of a mental disorder with memory impairment by gut microbiome modulation for an increase in memory scores.

Conclusions and Perspective

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Gut microbiota in humans evolving throughout life has been demonstrated to play a key role in health and disease. In healthy individuals, the intestinal microbiota has a multitude of beneficial functions, including metabolic energy utilization, protection from pathogenic attack, and immunomodulation. Furthermore, it is becoming increasingly documented that bidirectional signaling takes place between the gut and the brain and involves gut microbiota. This relationship encompasses various pathways, such as the vagus nerve; the hypothalamic–pituitary–adrenal axis; and immune, hormonal, and metabolic pathways to control various aspects of homeostasis, including the appropriate development and maintenance of digestive and mental functions. A dysbiosis of the intestinal microbiota is becoming documented as a factor in the pathogenesis of various pathological conditions, including a plethora of mental, metabolic, and digestive disorders. The diverse etiology of these disorders has been related to different microbes, although insufficient information is currently available on the causal direction of the association. Recent impressive advances in next generation sequencing technologies, along with the progress and innovations of metagenomics, metabolomics, multiomics, bioinformatics, and artificial intelligence tools, have provided prospects to better characterize the microbial populations and their functions and help in better correlation prediction. Moreover, studies using germ-free animals have provided important knowledge on causality rather than association. The research focus needs to be further shifted from individual microbes and their role in influencing health and disease toward the gut microbiome ecosystem. A better understanding of fundamental rules driving interactions within gut microbial communities and the dynamics through which they are acquired, transmitted, and adapted to single individuals is needed to make further progress.
The gut microbiome–brain axis embodies a sophisticated network of biological constructs that scientists are only beginning to understand. The nutritional and therapeutic approaches to modulate this axis are ultimately aimed at improving human quality of life. Some products are even already on the market, including foods and supplements that promise to improve gut, mood, sleep, or cognitive performance. The scientific background behind some of these promises is, however, still arguable or unknown.
The gut microbiome offers interesting possibilities to enhance therapies. Future studies should focus on identifying if gut microbiome signatures correlate with fecal/luminal metabolites and/or cytokines that might translate into marked differences in patients’ life. Moreover, more studies evaluating the potential of therapeutic modulation of the microbiome by biotics/fecal transplant to enhance therapeutic options for diseases are needed. Nowadays, research has shown that fecal transplants can restore healthy bacteria in the lower intestine, which can help control diseases caused by pathogenic bacteria. As a result, the first approved fecal transplant drugs are already a fact. Australia’s Therapeutic Goods Administration was the first to grant approval to biotechnology company BiomeBank for its microbiome-based therapy product Biomictra for treating infections from Clostridioides difficile bacteria. (526,527) Days later, the US FDA also approved its first fecal microbiota product Rebyota produced by Ferring Pharmaceuticals for the prevention of recurrence of C. difficile infection in adults. (528)
The multitude of relations between the microbiota, gut, and brain are now well-documented. The next step─moving on from correlative analysis toward understanding the mechanisms behind these relations and identifying the best ways to adapt and adjust the microbiota for potential therapeutic approaches─is now the required pathway. Some of the key setbacks in existing knowledge include understanding the immunological function of specific microbes in the human gut microbiota and their role in neurodegenerative and psychiatric disorders and how microbial metabolites influence brain function in tandem with immunological and neurological signaling molecules.
Despite the advances in microbiome knowledge, a lack of standardization significantly complicates and obstructs comparisons across studies, thus hampering insights into the structure and function of microbial populations. Recent efforts in the introduction of standardized protocols and analytical methods to characterize microbiota and explore the relationships and co-occurrences of microbially related metabolites and microbial taxa (529) would allow for great improvements in examinations of microbial diversity.
One of the significant challenges in microbiota-based medicine is the delineation of healthy microbiota. Variations in microbiota composition between individuals can be large, i.e., microbiota turn out to be pretty much person-specific, which greatly complicates a “one size fits all” strategy in targeting it. However, it also offers chances since the microbiota might be the outlet for an effective future personalized medicine approach. (530) Overall, clinical studies are hampered by the deficiency of specific biomarkers. Yet, recent meta-analyses have validated a positive assessment of the use of psychobiotic interventions for anxiety, schizophrenia, or cognitive performance, which aim at the diversity and complexity of gut microbiota, as well as the various confounding factors that may affect it. (462,531−536)
Although the prevention of brain disorders still remains out of reach, the knowledge of healthy microbiota and their communication pathways could enable an early prediction of such disorders. Thus, the first signs of neurodegenerative conditions, such as Alzheimer’s and Parkinson’s diseases, are known to develop many years before diagnosis. It might become thinkable to slow down neurodegenerative processes by altering the microbiome. Such possibilities have inspired a growing number of scientists to initiate start-up companies examining therapeutics for the treatment of neurological and other disorders through microbiome modulation. Private investors are showing a strong upward trend to fund such clinical research.
Perfecting the gut microbiota through fecal transplants; pro-, pre-, post-, and syn-biotics; healthy diet; and/or healthy lifestyle to control gut micriobiome–brain axis functions and promote mental and digestive health will be a promising field in the future. Patients suffering from mental and/or digestive disorders will get help through such treatments. Healthy individuals will promote their homeostasis and resilience from these remedies.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.3c00127.

  • Prebiotic, probiotic, postbiotic, and fecal transplant therapeutic clinical trial data investigating the treatment of mental disorders and DGBI through gut microbiome modulation (XLSX)

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Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
  • Authors
    • Janet M. Sasso - CAS, a division of the American Chemical Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United States;  Orcidhttps://orcid.org/0000-0002-1156-5184
    • Ramy M. Ammar - Bayer Consumer Health, R&D Digestive Health, Darmstadt 64295, Germany
    • Rumiana Tenchov - CAS, a division of the American Chemical Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United States;  Orcidhttps://orcid.org/0000-0003-4698-6832
    • Steven Lemmel - CAS, a division of the American Chemical Society, 2540 Olentangy River Rd, Columbus, Ohio 43202, United States
    • Olaf Kelber - Bayer Consumer Health, R&D Digestive Health, Darmstadt 64295, Germany
    • Malte Grieswelle - Bayer Consumer Health, R&D Digestive Health, Darmstadt 64295, Germany
  • Author Contributions

    J.M.S., R.M.A., and R.T. contributed equally to this work.

  • Notes
    The authors declare the following competing financial interest(s): R.M.A and O.K. are employed by Bayer Consumer Health, Germany. M.G. was an intern in Bayer consumer health, Germany during writing this manuscript.

Acknowledgments

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The authors sincerely appreciate the CAS Data, Analytics & Insights team for their assistance in data extraction. The authors also appreciate Dharmini Patel for project coordination, Manuela Pausan for ideation, and Peter Jap and Cristina Tomeo for insightful discussion. The authors are also grateful to Manuel Guzman, Gilles Georges, Michael Dennis, Dawn Riedel, Dawn George, and Hong Xie for executive sponsorship.

Abbreviations

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4-EPS

4-ethylphenylsulfate

5-AVAB

5-aminovaleric acid betaine

BAs

bile acids

BBB

blood-brain barrier

BCFA

branched-chain fatty acids

CAN

central autonomic network

CEN

central executive network

CNS

central nervous system

DGBI

disorders of gut–brain interaction

DMN

default mode network

EAN

emotional arousal network

ENS

enteric nervous system

FC

functional constipation

FCT

fecal microbiota transplantation

FD

functional dyspepsia

FGIDs

functional gastrointestinal disorders

GBA

gut–brain axis

HC

healthy controls

HPA

hypothalamus–pituitary–adrenal

IBS

irritable bowel syndrome

IHMC

International Human Microbiome Consortium

MPs

muramyl peptides

OCC

occipital network

RDA

recommended daily allowance

SAL

salience network

SCFA

short-chain fatty acids

SMN

sensorimotor network

TMAO

trimethylamine-N-oxide

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    Nature (London, United Kingdom) (2019), 568 (7753), 499-504CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    The compn. of the human gut microbiota is linked to health and disease, but knowledge of individual microbial species is needed to decipher their biol. roles. Despite extensive culturing and sequencing efforts, the complete bacterial repertoire of the human gut microbiota remains undefined. We identify 1952 uncultured candidate bacterial species by reconstructing 92,143 metagenome-assembled genomes from 11,850 human gut microbiomes. These uncultured genomes substantially expand the known species repertoire of the collective human gut microbiota, with a 281% increase in phylogenetic diversity. Although the newly identified species are less prevalent in well-studied populations compared to ref. isolate genomes, they improve classification of understudied African and South American samples by >200%. These candidate species encode hundreds of newly identified biosynthetic gene clusters and possess a distinctive functional capacity that might explain their elusive nature. Our work expands the known diversity of uncultured gut bacteria, which provides unprecedented resoln. for taxonomic and functional characterization of the intestinal microbiota.
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    To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. This report describes the Illumina-based metagenomic sequencing, assembly, and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from fecal samples of 124 European individuals. The gene set, ∼150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbors between 1000 and 1150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. The minimal gut metagenome and the minimal gut bacterial genome are defined and described in terms of functions present in all individuals and most bacteria, resp. Sequence data are deposited in the European Short Read Archive with accession no. ERA000116.
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    Cell Host & Microbe (2011), 10 (4), 287-291CODEN: CHMECB; ISSN:1931-3128. (Cell Press)
    A review. The human microbiome comprises the genes and genomes of the microbiota that inhabit the body. The authors highlight Human Microbiome Project (HMP) resources, including 600 microbial ref. genomes, 70 million 16S sequences, 700 metagenomes, and 60 million predicted genes from healthy adult microbiomes. Microbiome studies of specific diseases and future research directions are also discussed.
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    Birney, E.; Stamatoyannopoulos, J. A.; Dutta, A.; Guigó, R.; Gingeras, T. R.; Margulies, E. H.; Weng, Z.; Snyder, M.; Dermitzakis, E. T.; Stamatoyannopoulos, J. A. Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 2007, 447, 799– 816,  DOI: 10.1038/nature05874
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J.; Sabo, Peter J.; Sandstrom, Richard; Shafer, Anthony; Vetrie, David; Weaver, Molly; Wilcox, Sarah; Yu, Man; Collins, Francis S.; Dekker, Job; Lieb, Jason D.; Tullius, Thomas D.; Crawford, Gregory E.; Sunyaev, Shamil; Noble, William S.; Dunham, Ian; Dutta, Anindya; Guigo, Roderic; Denoeud, France; Reymond, Alexandre; Kapranov, Philipp; Rozowsky, Joel; Zheng, Deyou; Castelo, Robert; Frankish, Adam; Harrow, Jennifer; Ghosh, Srinka; Sandelin, Albin; Hofacker, Ivo L.; Baertsch, Robert; Keefe, Damian; Flicek, Paul; Dike, Sujit; Cheng, Jill; Hirsch, Heather A.; Sekinger, Edward A.; Lagarde, Julien; Abril, Josep F.; Shahab, Atif; Flamm, Christoph; Fried, Claudia; Hackermueller, Joerg; Hertel, Jana; Lindemeyer, Manja; Missal, Kristin; Tanzer, Andrea; Washietl, Stefan; Korbel, Jan; Emanuelsson, Olof; Pedersen, Jakob S.; Holroyd, Nancy; Taylor, Ruth; Swarbreck, David; Matthews, Nicholas; Dickson, Mark C.; Thomas, Daryl J.; Weirauch, Matthew T.; Gilbert, James; Drenkow, Jorg; Bell, Ian; Zhao, Xiao Dong; Srinivasan, K. 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James; Stone, Eric A.; Gerstein, Mark; Antonarakis, Stylianos E.; Batzoglou, Serafim; Goldman, Nick; Hardison, Ross C.; Haussler, David; Miller, Webb; Pachter, Lior; Green, Eric D.; Sidow, Arend; Weng, Zhiping; Trinklein, Nathan D.; Fu, Yutao; Zhang, Zhengdong D.; Karaoez, Ulas; Barrera, Leah; Stuart, Rhona; Zheng, Deyou; Ghosh, Srinka; Flicek, Paul; King, David C.; Taylor, James; Ameur, Adam; Enroth, Stefan; Bieda, Mark C.; Koch, Christoph M.; Hirsch, Heather A.; Wei, Chia-Lin; Cheng, Jill; Kim, Jonghwan; Bhinge, Akshay A.; Giresi, Paul G.; Jiang, Nan; Liu, Jun; Yao, Fei; Sung, Wing-Kin; Chiu, Kuo Ping; Vega, Vinsensius B.; Lee, Charlie W. 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    Nature (London, United Kingdom) (2007), 447 (7146), 799-816CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    We report the generation and anal. of functional data from multiple, diverse expts. performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a no. of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examn. of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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    Metagenomics: Genomic analysis of microbial communities
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    A review. Uncultured microorganisms comprise the majority of the planet's biol. diversity. Microorganisms represent two of the three domains of life and contain vast diversity that is the product of an estd. 3.8 billion years of evolution. In many environments, as many as 99% of the microorganisms cannot be cultured by std. techniques, and the uncultured fraction includes diverse organisms that are only distantly related to the cultured ones. Therefore, culture-independent methods are essential to understand the genetic diversity, population structure, and ecol. roles of the majority of microorganisms. Metagenomics, or the culture-independent genomic anal. of an assemblage of microorganisms, has potential to answer fundamental questions in microbial ecol. This review describes progress toward understanding the biol. of uncultured Bacteria, Archaea, and viruses through metagenomic analyses.
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    Jandhyala, S. M.; Talukdar, R.; Subramanyam, C.; Vuyyuru, H.; Sasikala, M.; Nageshwar Reddy, D. Role of the normal gut microbiota. World J. Gastroenterol. 2015, 21, 8787– 8803,  DOI: 10.3748/wjg.v21.i29.8787
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    World Journal of Gastroenterology (2015), 21 (29), 8787-8803CODEN: WJGAF2; ISSN:2219-2840. (Baishideng Publishing Group Inc.)
    Relation between the gut microbiota and human health is being increasingly recognized. It is now well established that a healthy gut flora is largely responsible for overall health of the host. The normal human gut microbiota comprises of two major phyla, namely Bacteroidetes and Firmicutes. Though the gut microbiota in an infant appears haphazard, it starts resembling the adult flora by the age of 3 years. Nevertheless, there exist temporal and spatial variations in the microbial distribution from esophagus to the rectum all along the individual's life span. Developments in genome sequencing technologies and bioinformatics have now enabled scientists to study these microorganisms and their function and microbehost interactions in an elaborate manner both in health and disease. The normal gut microbiota imparts specific function in host nutrient metab., xenobiotic and drug metab., maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Several factors play a role in shaping the normal gut microbiota. They include (1) the mode of delivery (vaginal or caesarean); (2) diet during infancy (breast milk or formula feeds) and adulthood (vegan based or meat based); and (3) use of antibiotics or antibiotic like mols. that are derived from the environment or the gut commensal community. A major concern of antibiotic use is the long-term alteration of the normal healthy gut microbiota and horizontal transfer of resistance genes that could result in reservoir of organisms with a multidrug resistant gene pool.
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    Tomas, J.; Wrzosek, L.; Bouznad, N.; Bouet, S.; Mayeur, C.; Noordine, M. L.; Honvo-Houeto, E.; Langella, P.; Thomas, M.; Cherbuy, C. Primocolonization is associated with colonic epithelial maturation during conventionalization. FASEB J. 2013, 27, 645– 655,  DOI: 10.1096/fj.12-216861
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    FASEB Journal (2013), 27 (2), 645-655, 10.1096/fj.12-216861CODEN: FAJOEC; ISSN:0892-6638. (Federation of American Societies for Experimental Biology)
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    Magnúsdóttir, S.; Ravcheev, D.; de Crécy-Lagard, V.; Thiele, I. Systematic genome assessment of B-vitamin biosynthesis suggests co-operation among gut microbes. Frontiers in Genetics 2015, 6, 148,  DOI: 10.3389/fgene.2015.00148
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    The human gut microbiota supplies its host with essential nutrients, including B-vitamins. Using the PubSEED platform, we systematically assessed the genomes of 256 common human gut bacteria for the presence of biosynthesis pathways for eight B-vitamins: biotin, cobalamin, folate, niacin, pantothenate, pyridoxine, riboflavin, and thiamin. On the basis of the presence and absence of genome annotations, we predicted that each of the eight vitamins was produced by 40-65% of the 256 human gut microbes. The distribution of synthesis pathways was diverse; some genomes had all eight biosynthesis pathways, whereas others contained no de novo synthesis pathways. We compared our predictions to experimental data from 16 organisms and found 88% of our predictions to be in agreement with published data. In addition, we identified several pairs of organisms whose vitamin synthesis pathway pattern complemented those of other organisms. This analysis suggests that human gut bacteria actively exchange B-vitamins among each other, thereby enabling the survival of organisms that do not synthesize any of these essential cofactors. This result indicates the co-evolution of the gut microbes in the human gut environment. Our work presents the first comprehensive assessment of the B-vitamin synthesis capabilities of the human gut microbiota. We propose that in addition to diet, the gut microbiota is an important source of B-vitamins, and that changes in the gut microbiota composition can severely affect our dietary B-vitamin requirements.
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    Gut microbes and the brain: paradigm shift in neuroscience
    Mayer Emeran A; Knight Rob; Mazmanian Sarkis K; Cryan John F; Tillisch Kirsten
    The Journal of neuroscience : the official journal of the Society for Neuroscience (2014), 34 (46), 15490-6 ISSN:.
    The discovery of the size and complexity of the human microbiome has resulted in an ongoing reevaluation of many concepts of health and disease, including diseases affecting the CNS. A growing body of preclinical literature has demonstrated bidirectional signaling between the brain and the gut microbiome, involving multiple neurocrine and endocrine signaling mechanisms. While psychological and physical stressors can affect the composition and metabolic activity of the gut microbiota, experimental changes to the gut microbiome can affect emotional behavior and related brain systems. These findings have resulted in speculation that alterations in the gut microbiome may play a pathophysiological role in human brain diseases, including autism spectrum disorder, anxiety, depression, and chronic pain. Ongoing large-scale population-based studies of the gut microbiome and brain imaging studies looking at the effect of gut microbiome modulation on brain responses to emotion-related stimuli are seeking to validate these speculations. This article is a summary of emerging topics covered in a symposium and is not meant to be a comprehensive review of the subject.
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    Clarke, G.; Grenham, S.; Scully, P.; Fitzgerald, P.; Moloney, R. D.; Shanahan, F.; Dinan, T. G.; Cryan, J. F. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol. Psychiatry 2013, 18, 666– 673,  DOI: 10.1038/mp.2012.77
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    The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner
    Clarke, G.; Grenham, S.; Scully, P.; Fitzgerald, P.; Moloney, R. D.; Shanahan, F.; Dinan, T. G.; Cryan, J. F.
    Molecular Psychiatry (2013), 18 (6), 666-673CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)
    Bacterial colonization of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclin. tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concn. of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonized control animals. Moreover, this alteration is sex specific in contrast with the immunol. and neuroendocrine effects which are evident in both sexes. Concns. of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonization of the GF animals post weaning is insufficient to reverse the CNS neurochem. consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addn., reduced anxiety in GF animals is also normalized following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochem., but not behavioral, profile is resistant to restoration of a normal gut flora in later life. Mol. Psychiatry (2013) 18, 666-673; doi:10.1038/mp.2012.77; published online 12 June 2012.
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    Bray, N. The microbiota–gut–brain axis. https://www.nature.com/articles/d42859-019-00021-3 (accessed October 6, 2022).
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    Dinan, T. G.; Cryan, J. F. The impact of gut microbiota on brain and behaviour: implications for psychiatry. Curr. Opin. Clin. Nutr. Metab. Care 2015, 18, 552– 558,  DOI: 10.1097/MCO.0000000000000221
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    The impact of gut microbiota on brain and behaviour: implications for psychiatry
    Dinan Timothy G; Cryan John F
    Current opinion in clinical nutrition and metabolic care (2015), 18 (6), 552-8 ISSN:.
    PURPOSE OF REVIEW: The gut microbiota has become a focus of research for those interested in the brain and behaviour. Here, we profile the gut microbiota in a variety of neuropsychiatric syndromes. RECENT FINDINGS: Multiple routes of communication between the gut and brain have been established and these include the vagus nerve, immune system, short chain fatty acids and tryptophan. Developmentally, those born by caesarean section have a distinctly different microbiota in early life to those born per vaginum. At the other extreme, individuals who age with considerable ill-heath tend to show narrowing in microbial diversity. Recently, the gut microbiota has been profiled in a variety of conditions including autism, major depression and Parkinson's disease. There is still debate as to whether or not these changes are core to the pathophysiology or merely epiphenomenal. SUMMARY: The current narrative suggests that certain neuropsychiatric disorders might be treated by targeting the microbiota either by microbiota transplantation, antibiotics or psychobiotics.
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    Bravo, J. A.; Forsythe, P.; Chew, M. V.; Escaravage, E.; Savignac, H. M.; Dinan, T. G.; Bienenstock, J.; Cryan, J. F. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 16050– 16055,  DOI: 10.1073/pnas.1102999108
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    Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve
    Bravo, Javier A.; Forsythe, Paul; Chew, Marianne V.; Escaravage, Emily; Savignac, Helene M.; Dinan, Timothy G.; Bienenstock, John; Cryan, Ohn F.
    Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (38), 16050-16055, S16050/1-S16050/7CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiol. and psychol. processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABAB1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant redns. in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addn., L. rhamnosus (JB-1) reduced GABAAα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABAAα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone. and anxiety- and depression-related behavior. Moreover, the neurochem. and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut-brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress- related disorders such as anxiety and depression.
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    Cohen-Sacks, H.; Elazar, V.; Gao, J.; Golomb, A.; Adwan, H.; Korchov, N.; Levy, R. J.; Berger, M. R.; Golomb, G. Delivery and expression of pDNA embedded in collagen matrices. J. Controlled Release 2004, 95, 309– 320,  DOI: 10.1016/j.jconrel.2003.11.001
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    Delivery and expression of pDNA embedded in collagen matrices
    Cohen-Sacks, Hagit; Elazar, Victoria; Gao, Jianchuan; Golomb, Assaf; Adwan, Hassan; Korchov, Nikoly; Levy, Robert J.; Berger, Martin R.; Golomb, Gershon
    Journal of Controlled Release (2004), 95 (2), 309-320CODEN: JCREEC; ISSN:0168-3659. (Elsevier)
    Collagen matrixes can be used as non-viral biocompatible gene carriers for localized implantable gene therapy. Collagen matrixes embedding pDNA with enhanced binding through condensing agent linkage to the matrix or to the pDNA have been formulated, and characterized in various systems. PDNA and condensed pDNA were released intact from the matrixes within 1-2 days. In vitro transfection with collagen matrixes contg. pDNA (luciferase encoding), pDNA in liposome (LIP), and pDNA with polyethylenimine (PEI) resulted in significantly higher expression levels in comparison to naked pDNA. PDNA-LIP matrixes exhibited a dose response transfection of NIH 3T3, 293, MDA-MB-231 and smooth muscle cells (SMCs) in cell cultures. Subdermal implantations of collagen-polylysine-pDNA matrixes in rats resulted in significantly higher gene expression levels in comparison to non-condensed pDNA matrixes. Perivascular treatment with pDNA matrix and of naked pDNA soln. in balloon-injured rat carotid arteries resulted in significant expression. In conclusion, a facile method for embedding cationic formulations of pDNA in collagen matrixes was developed. These bioactive matrixes seem to be suitable for tissue engineering and local gene therapy strategies.
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    Rutsch, A.; Kantsjö, J. B.; Ronchi, F. The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology. Front. Immunol. 2020, 11, 604179,  DOI: 10.3389/fimmu.2020.604179
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    The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology
    Rutsch, Andrina; Kantsjo, Johan B.; Ronchi, Francesca
    Frontiers in Immunology (2020), 11 (), 604179CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    A review. The human microbiota has a fundamental role in host physiol. and pathol. Gut microbial alteration, also known as dysbiosis, is a condition assocd. not only with gastrointestinal disorders but also with diseases affecting other distal organs. Recently it became evident that the intestinal bacteria can affect the central nervous system (CNS) physiol. and inflammation. The nervous system and the gastrointestinal tract are communicating through a bidirectional network of signaling pathways called the gutbrain axis, which consists of multiple connections, including the vagus nerve, the immune system, and bacterial metabolites and products. During dysbiosis, these pathways are dysregulated and assocd. with altered permeability of the blood-brain barrier (BBB) and neuroinflammation. However, numerous mechanisms behind the impact of the gut microbiota in neuro-development and -pathogenesis remain poorly understood. There are several immune pathways involved in CNS homeostasis and inflammation. Among those, the inflammasome pathway has been linked to neuroinflammatory conditions such as multiple sclerosis, Alzheimer's and Parkinson's diseases, but also anxiety and depressivelike disorders. The inflammasome complex assembles upon cell activation due to exposure to microbes, danger signals, or stress and lead to the prodn. of proinflammatory cytokines (interleukin-1b and interleukin-1β) and to pyroptosis. Evidences suggest that there is a reciprocal influence of microbiota and inflammasome activation in the brain. However, how this influence is precisely working is yet to be discovered. Herein, we discuss the status of the knowledge and the open questions in the field focusing on the function of intestinal microbial metabolites or products on CNS cells during healthy and inflammatory conditions, such as multiple sclerosis, Alzheimer's and Parkinson's diseases, and also neuropsychiatric disorders. In particular, we focus on the innate inflammasome pathway as immune mechanism that can be involved in several of these conditions, upon exposure to certain microbes.
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    Drossman, D. A.; Hasler, W. L. Rome IV-Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology 2016, 150, 1257– 1261,  DOI: 10.1053/j.gastro.2016.03.035
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    Rome IV-Functional GI Disorders: Disorders of Gut-Brain Interaction
    Drossman Douglas A; Hasler William L
    Gastroenterology (2016), 150 (6), 1257-61 ISSN:.
    There is no expanded citation for this reference.
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    Perez-Muñoz, M. E.; Arrieta, M.-C.; Ramer-Tait, A. E.; Walter, J. A critical assessment of the “sterile womb” and “in utero colonization” hypotheses: implications for research on the pioneer infant microbiome. Microbiome 2017, 5, 48,  DOI: 10.1186/s40168-017-0268-4
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    A critical assessment of the "sterile womb" and "in utero colonization" hypotheses: implications for research on the pioneer infant microbiome
    Perez-Munoz Maria Elisa; Walter Jens; Arrieta Marie-Claire; Arrieta Marie-Claire; Ramer-Tait Amanda E; Walter Jens
    Microbiome (2017), 5 (1), 48 ISSN:.
    After more than a century of active research, the notion that the human fetal environment is sterile and that the neonate's microbiome is acquired during and after birth was an accepted dogma. However, recent studies using molecular techniques suggest bacterial communities in the placenta, amniotic fluid, and meconium from healthy pregnancies. These findings have led many scientists to challenge the "sterile womb paradigm" and propose that microbiome acquisition instead begins in utero, an idea that would fundamentally change our understanding of gut microbiota acquisition and its role in human development. In this review, we provide a critical assessment of the evidence supporting these two opposing hypotheses, specifically as it relates to (i) anatomical, immunological, and physiological characteristics of the placenta and fetus; (ii) the research methods currently used to study microbial populations in the intrauterine environment; (iii) the fecal microbiome during the first days of life; and (iv) the generation of axenic animals and humans. Based on this analysis, we argue that the evidence in support of the "in utero colonization hypothesis" is extremely weak as it is founded almost entirely on studies that (i) used molecular approaches with an insufficient detection limit to study "low-biomass" microbial populations, (ii) lacked appropriate controls for contamination, and (iii) failed to provide evidence of bacterial viability. Most importantly, the ability to reliably derive axenic animals via cesarean sections strongly supports sterility of the fetal environment in mammals. We conclude that current scientific evidence does not support the existence of microbiomes within the healthy fetal milieu, which has implications for the development of clinical practices that prevent microbiome perturbations after birth and the establishment of future research priorities.
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    Dominguez-Bello, M. G.; Costello, E. K.; Contreras, M.; Magris, M.; Hidalgo, G.; Fierer, N.; Knight, R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 11971– 11975,  DOI: 10.1073/pnas.1002601107
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    Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns
    Dominguez-Bello Maria G; Costello Elizabeth K; Contreras Monica; Magris Magda; Hidalgo Glida; Fierer Noah; Knight Rob
    Proceedings of the National Academy of Sciences of the United States of America (2010), 107 (26), 11971-5 ISSN:.
    Upon delivery, the neonate is exposed for the first time to a wide array of microbes from a variety of sources, including maternal bacteria. Although prior studies have suggested that delivery mode shapes the microbiota's establishment and, subsequently, its role in child health, most researchers have focused on specific bacterial taxa or on a single body habitat, the gut. Thus, the initiation stage of human microbiome development remains obscure. The goal of the present study was to obtain a community-wide perspective on the influence of delivery mode and body habitat on the neonate's first microbiota. We used multiplexed 16S rRNA gene pyrosequencing to characterize bacterial communities from mothers and their newborn babies, four born vaginally and six born via Cesarean section. Mothers' skin, oral mucosa, and vagina were sampled 1 h before delivery, and neonates' skin, oral mucosa, and nasopharyngeal aspirate were sampled <5 min, and meconium <24 h, after delivery. We found that in direct contrast to the highly differentiated communities of their mothers, neonates harbored bacterial communities that were undifferentiated across multiple body habitats, regardless of delivery mode. Our results also show that vaginally delivered infants acquired bacterial communities resembling their own mother's vaginal microbiota, dominated by Lactobacillus, Prevotella, or Sneathia spp., and C-section infants harbored bacterial communities similar to those found on the skin surface, dominated by Staphylococcus, Corynebacterium, and Propionibacterium spp. These findings establish an important baseline for studies tracking the human microbiome's successional development in different body habitats following different delivery modes, and their associated effects on infant health.
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    Hill, C. J.; Lynch, D. B.; Murphy, K.; Ulaszewska, M.; Jeffery, I. B.; O’Shea, C. A.; Watkins, C.; Dempsey, E.; Mattivi, F.; Tuohy, K. Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort. Microbiome 2017, 5, 4,  DOI: 10.1186/s40168-016-0213-y
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    Evolution of gut microbiota composition from birth to 24 weeks in the INFANTMET Cohort
    Hill Cian J; Lynch Denise B; Murphy Kiera; Jeffery Ian B; Ross R Paul; O' Toole Paul W; Hill Cian J; Lynch Denise B; Murphy Kiera; Ross R Paul; Ryan C Anthony; O' Toole Paul W; Stanton Catherine; Murphy Kiera; Watkins Claire; Stanton Catherine; Ulaszewska Marynka; Mattivi Fulvio; Tuohy Kieran; O'Shea Carol Anne; Dempsey Eugene; Ryan C Anthony
    Microbiome (2017), 5 (1), 4 ISSN:.
    BACKGROUND: The gut is the most extensively studied niche of the human microbiome. The aim of this study was to characterise the initial gut microbiota development of a cohort of breastfed infants (n = 192) from 1 to 24 weeks of age. METHODS: V4-V5 region 16S rRNA amplicon Illumina sequencing and, in parallel, bacteriological culture. The metabolomic profile of infant urine at 4 weeks of age was also examined by LC-MS. RESULTS: Full-term (FT), spontaneous vaginally delivered (SVD) infants' microbiota remained stable at both phylum and genus levels during the 24-week period examined. FT Caesarean section (CS) infants displayed an increased faecal abundance of Firmicutes (p < 0.01) and lower abundance of Actinobacteria (p < 0.001) after the first week of life compared to FT-SVD infants. FT-CS infants gradually progressed to harbouring a microbiota closely resembling FT-SVD (which remained stable) by week 8 of life, which was maintained at week 24. The gut microbiota of preterm (PT) infants displayed a significantly greater abundance of Proteobacteria compared to FT infants (p < 0.001) at week 1. Metabolomic analysis of urine at week 4 indicated PT-CS infants have a functionally different metabolite profile than FT (both CS and SVD) infants. Co-inertia analysis showed co-variation between the urine metabolome and the faecal microbiota of the infants. Tryptophan and tyrosine metabolic pathways, as well as fatty acid and bile acid metabolism, were found to be affected by delivery mode and gestational age. CONCLUSIONS: These findings confirm that mode of delivery and gestational age both have significant effects on early neonatal microbiota composition. There is also a significant difference between the metabolite profile of FT and PT infants. Prolonged breastfeeding was shown to have a significant effect on the microbiota composition of FT-CS infants at 24 weeks of age, but interestingly not on that of FT-SVD infants. Twins had more similar microbiota to one another than between two random infants, reflecting the influence of similarities in both host genetics and the environment on the microbiota..
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    Vatanen, T.; Jabbar, K. S.; Ruohtula, T.; Honkanen, J.; Avila-Pacheco, J.; Siljander, H.; Stražar, M.; Oikarinen, S.; Hyöty, H.; Ilonen, J. Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism. Cell 2022, 185, 4921– 4936.e4915,  DOI: 10.1016/j.cell.2022.11.023
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    Mobile genetic elements from the maternal microbiome shape infant gut microbial assembly and metabolism
    Vatanen, Tommi; Jabbar, Karolina S.; Ruohtula, Terhi; Honkanen, Jarno; Avila-Pacheco, Julian; Siljander, Heli; Strazar, Martin; Oikarinen, Sami; Hyoty, Heikki; Ilonen, Jorma; Mitchell, Caroline M.; Yassour, Moran; Virtanen, Suvi M.; Clish, Clary B.; Plichta, Damian R.; Vlamakis, Hera; Knip, Mikael; Xavier, Ramnik J.
    Cell (Cambridge, MA, United States) (2022), 185 (26), 4921-4936.e15CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The perinatal period represents a crit. window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the co-development of microbiomes and metabolomes from late pregnancy to 1 yr of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes assocd. with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite assocns. not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular-but not extensively hydrolyzed-formula were distinct from those of exclusively breastfed infants. Taken together, our integrative anal. expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.
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    Baleato, C. L.; Ferguson, J. J. A.; Oldmeadow, C.; Mishra, G. D.; Garg, M. L. Plant-Based Dietary Patterns versus Meat Consumption and Prevalence of Impaired Glucose Intolerance and Diabetes Mellitus: A Cross-Sectional Study in Australian Women. Nutrients 2022, 14, 4152,  DOI: 10.3390/nu14194152
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    Plant-Based Dietary Patterns versus Meat Consumption and Prevalence of Impaired Glucose Intolerance and Diabetes Mellitus: A Cross-Sectional Study in Australian Women
    Baleato, Courtney L.; Ferguson, Jessica J. A.; Oldmeadow, Christopher; Mishra, Gita D.; Garg, Manohar L.
    Nutrients (2022), 14 (19), 4152CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
    This study aimed to compare the prevalence of impaired glucose tolerance (IGT) and diabetes mellitus (DM) among Australian women following plant-based diets (PBD) compared to regular meat eaters. A cross sectional anal. of the mid-aged cohort (1946-1951) of the Australian Longitudinal Study on Women's Health was conducted on completers of Survey 7 in 2013 with complete FFQ data available (n = 9102). Dietary patterns were categorized as PBD (vegan, lacto-ovo vegetarian, pesco-vegetarian, semi-vegetarian) and regular meat eaters. Meat eaters were further categorized into high and low consumption and outcomes included self-reported prevalence of IGT and DM. Participants were identified as regular meat eaters (n = 8937) and PBD (n = 175). Prevalence of IGT was lower in PBD (0-1.2%) compared to regular meat eaters (9.1%). Consolidation of PBD to a single group (vegetarians) indicated a lower prevalence of DM in vegetarians compared to regular meat eaters (3.9% vs. 9.1%). Women consuming meat daily/multiple times per day had significantly higher odds of IGT (OR 1.5, 95%CI 1.1 to 2.1, p = 0.02). Individuals consuming processed meat daily/multiple times per day had significantly higher odds of DM compared to those consuming less than daily (Odds ratio (OR) 1.7, 95% confidence interval (CI) 1.3 to 2.3, p < 0.0001). After adjustment for covariates, statistical significance was lost largely due to the addn. of BMI to the model. Prevalence of IGT and DM were lower in women following PBD and higher in high consumers of meat and processed meat. The relationship between meat consumption and IGT/diabetes status appears to be mediated, at least in part, by an increase in body mass index (BMI). Future studies are warranted to investigate the mechanisms and other lifestyle factors underpinning the assocn. between high meat consumption and increased risk of IGT and DM.
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    Keaver, L.; Ruan, M.; Chen, F.; Du, M.; Ding, C.; Wang, J.; Shan, Z.; Liu, J.; Zhang, F. F. Plant- and animal-based diet quality and mortality among US adults: a cohort study. Br. J. Nutr. 2021, 125, 1405– 1415,  DOI: 10.1017/S0007114520003670
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    Plant- and animal-based diet quality and mortality among US adults: a cohort study
    Keaver, Laura; Ruan, Mengyuan; Chen, Fan; Du, Mengxi; Ding, Chenyueyi; Wang, Jiaqi; Shan, Zhilei; Liu, Junxiu; Zhang, Fang Fang
    British Journal of Nutrition (2021), 125 (12), 1405-1415CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    Not all plant-based and animal foods exert the same health effects due to their various nutrient compns. We aimed to assess the quality of plant-based v. animal foods in relation to mortality in a prospective cohort study. Using data collected from a nationally representative sample of 36 825 adults in the National Health and Nutrition Examn. Survey 1999-2014, we developed a de novo Comprehensive Diet Quality Index (cDQI) that assesses the quality of seventeen foods based on the healthfulness and sep. scored the quality of eleven plant-based foods in a plant-based Diet Quality Index (pDQI) and six animal foods in an animal-based Diet Quality Index (aDQI). Mortality from all causes, heart disease and cancer were obtained from linkage to the National Death Index up to 31 Dec. 2015. Cox proportional hazard models were used to est. hazard ratios (HR) and 95 % CI after multivariable adjustments. During a median follow-up of 8·3 years, 4669 all-cause deaths occurred, including 798 deaths due to heart disease and 1021 due to cancer. Compared with individuals in the lowest quartile, those in the highest quartile of cDQI had a lower risk of all-cause mortality (HR 0·75, 95 % CI 0·65, 0·86; P trend < 0·001), which largely reflected the inverse relationship between quality of plant-based foods (pDQI) and all-cause mortality (HR 0·66, 95 % CI 0·58, 0·74; P trend < 0·001). No independent assocn. was found for the quality of animal foods (aDQI) and mortality. Our results suggest that consuming healthy plant-based foods is assocd. with lower all-cause mortality among US adults.
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    O’Mahony, S. M.; Marchesi, J. R.; Scully, P.; Codling, C.; Ceolho, A.-M.; Quigley, E. M. M.; Cryan, J. F.; Dinan, T. G. Early Life Stress Alters Behavior, Immunity, and Microbiota in Rats: Implications for Irritable Bowel Syndrome and Psychiatric Illnesses. Biol. Psychiatry 2009, 65, 263– 267,  DOI: 10.1016/j.biopsych.2008.06.026
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    Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses
    O'Mahony Siobhain M; Marchesi Julian R; Scully Paul; Codling Caroline; Ceolho Anne-Marie; Quigley Eamonn M M; Cryan John F; Dinan Timothy G
    Biological psychiatry (2009), 65 (3), 263-7 ISSN:.
    BACKGROUND: Adverse early life events are associated with a maladaptive stress response system and might increase the vulnerability to disease in later life. Several disorders have been associated with early life stress, ranging from depression to irritable bowel syndrome. This makes the identification of the neurobiological substrates that are affected by adverse experiences in early life invaluable. METHODS: The purpose of this study was to assess the effect of early life stress on the brain-gut axis. Male rat pups were stressed by separating them from their mothers for 3 hours daily between postnatal days 2-12. The control group was left undisturbed with their mothers. Behavior, immune response, stress sensitivity, visceral sensation, and fecal microbiota were analyzed. RESULTS: The early life stress increased the number of fecal boli in response to a novel stress. Plasma corticosterone was increased in the maternally separated animals. An increase in the systemic immune response was noted in the stressed animals after an in vitro lipopolysaccharide challenge. Increased visceral sensation was seen in the stressed group. There was an alteration of the fecal microbiota when compared with the control group. CONCLUSIONS: These results show that this form of early life stress results in an altered brain-gut axis and is therefore an important model for investigating potential mechanistic insights into stress-related disorders including depression and IBS.
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    Jernberg, C.; Löfmark, S.; Edlund, C.; Jansson, J. K. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology (Reading) 2010, 156, 3216– 3223,  DOI: 10.1099/mic.0.040618-0
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    Long-term impacts of antibiotic exposure on the human intestinal microbiota
    Jernberg, Cecilia; Loefmark, Sonja; Edlund, Charlotta; Jansson, Janet K.
    Microbiology (Reading, United Kingdom) (2010), 156 (11), 3216-3223CODEN: MROBEO; ISSN:1350-0872. (Society for General Microbiology)
    A review. Although it is known that antibiotics have short-term impacts on the human microbiome, recent evidence demonstrates that the impacts of some antibiotics remain for extended periods of time. In addn., antibiotic-resistant strains can persist in the human host environment in the absence of selective pressure. Both mol.- and cultivation-based approaches have revealed ecol. disturbances in the microbiota after antibiotic administration, in particular for specific members of the bacterial community that are susceptible or alternatively resistant to the antibiotic in question. A disturbing consequence of antibiotic treatment has been the long-term persistence of antibiotic resistance genes, for example in the human gut. These data warrant use of prudence in the administration of antibiotics that could aggravate the growing battle with emerging antibiotic-resistant pathogenic strains.
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    Caporaso, J. G.; Kuczynski, J.; Stombaugh, J.; Bittinger, K.; Bushman, F. D.; Costello, E. K.; Fierer, N.; Peña, A. G.; Goodrich, J. K.; Gordon, J. I. QIIME allows analysis of high-throughput community sequencing data. Nat. Methods 2010, 7, 335– 336,  DOI: 10.1038/nmeth.f.303
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    QIIME allows analysis of high-throughput community sequencing data
    Caporaso, J. Gregory; Kuczynski, Justin; Stombaugh, Jesse; Bittinger, Kyle; Bushman, Frederic D.; Costello, Elizabeth K.; Fierer, Noah; Pena, Antonio Gonzalez; Goodrich, Julia K.; Gordon, Jeffrey I.; Huttley, Gavin A.; Kelley, Scott T.; Knights, Dan; Koenig, Jeremy E.; Ley, Ruth E.; Lozupone, Catherine A.; McDonald, Daniel; Muegge, Brian D.; Pirrung, Meg; Reeder, Jens; Sevinsky, Joel R.; Turnbaugh, Peter J.; Walters, William A.; Widmann, Jeremy; Yatsunenko, Tanya; Zaneveld, Jesse; Knight, Rob
    Nature Methods (2010), 7 (5), 335-336CODEN: NMAEA3; ISSN:1548-7091. (Nature Publishing Group)
    There is no expanded citation for this reference.
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    Tang, L. Sequence-based identification of human-associated microbiota. https://www.nature.com/articles/d42859-019-00011-5 (accessed October 24, 2022).
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    Collins, S. M.; Surette, M.; Bercik, P. The interplay between the intestinal microbiota and the brain. Nat. Rev. Microbiol. 2012, 10, 735– 742,  DOI: 10.1038/nrmicro2876
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    The interplay between the intestinal microbiota and the brain
    Collins, Stephen M.; Surette, Michael; Bercik, Premysl
    Nature Reviews Microbiology (2012), 10 (11), 735-742CODEN: NRMACK; ISSN:1740-1526. (Nature Publishing Group)
    A review. The intestinal microbiota consists of a vast bacterial community that resides primarily in the lower gut and lives in a symbiotic relationship with the host. A bidirectional neurohumoral communication system, known as the gut-brain axis, integrates the host gut and brain activities. Here, we describe the recent advances in our understanding of how the intestinal microbiota communicates with the brain via this axis to influence brain development and behavior. We also review how this extended communication system might influence a broad spectrum of diseases, including irritable bowel syndrome, psychiatric disorders and demyelinating conditions such as multiple sclerosis.
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    Lagier, J.-C.; Armougom, F.; Million, M.; Hugon, P.; Pagnier, I.; Robert, C.; Bittar, F.; Fournous, G.; Gimenez, G.; Maraninchi, M. Microbial culturomics: paradigm shift in the human gut microbiome study. Clinical Microbiology and Infection 2012, 18, 1185– 1193,  DOI: 10.1111/1469-0691.12023
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    Microbial culturomics: paradigm shift in the human gut microbiome study
    Lagier, J.-C.; Armougom, F.; Million, M.; Hugon, P.; Pagnier, I.; Robert, C.; Bittar, F.; Fournous, G.; Gimenez, G.; Maraninchi, M.; Trape, J.-F.; Koonin, E. V.; La Scola, B.; Raoult, D.
    Clinical Microbiology and Infection (2012), 18 (12), 1185-1193CODEN: CMINFM; ISSN:1198-743X. (Wiley-Blackwell)
    Abstr. : Comprehensive detn. of the microbial compn. of the gut microbiota and the relationships with health and disease are major challenges in the 21st century. Metagenomic anal. of the human gut microbiota detects mostly uncultured bacteria. We studied stools from two lean Africans and one obese European, using 212 different culture conditions (microbial culturomics), and tested the colonies by using mass spectrometry and 16S rRNA amplification and sequencing. In parallel, we analyzed the same three samples by pyrosequencing 16S rRNA amplicons targeting the V6 region. The 32 500 colonies obtained by culturomics have yielded 340 species of bacteria from seven phyla and 117 genera, including two species from rare phyla (Deinococcus-Thermus and Synergistetes), five fungi, and a giant virus (Senegalvirus). The microbiome identified by culturomics included 174 species never described previously in the human gut, including 31 new species and genera for which the genomes were sequenced, generating c. 10 000 new unknown genes (ORFans), which will help in future mol. studies. Among these, the new species Microvirga massiliensis has the largest bacterial genome so far obtained from a human, and Senegalvirus is the largest virus reported in the human gut. Concurrent metagenomic anal. of the same samples produced 698 phylotypes, including 282 known species, 51 of which overlapped with the microbiome identified by culturomics. Thus, culturomics complements metagenomics by overcoming the depth bias inherent in metagenomic approaches.
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    Smith, P. M.; Howitt, M. R.; Panikov, N.; Michaud, M.; Gallini, C. A.; Bohlooly, Y. M.; Glickman, J. N.; Garrett, W. S. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 2013, 341, 569– 573,  DOI: 10.1126/science.1241165
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    The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis
    Smith, Patrick M.; Howitt, Michael R.; Panikov, Nicolai; Michaud, Monia; Gallini, Carey Ann; Bohlooly-Y, Mohammad; Glickman, Jonathan N.; Garrett, Wendy S.
    Science (Washington, DC, United States) (2013), 341 (6145), 569-573CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Regulatory T cells (Tregs) that express the transcription factor Foxp3 are crit. for regulating intestinal inflammation. Candidate microbe approaches have identified bacterial species and strain-specific mols. that can affect intestinal immune responses, including species that modulate Treg responses. Because neither all humans nor mice harbor the same bacterial strains, the authors posited that more prevalent factors exist that regulate the no. and function of colonic Tregs. The authors detd. that short-chain fatty acids, gut microbiota-derived bacterial fermn. products, regulate the size and function of the colonic Treg pool and protect against colitis in a Ffar2-dependent manner in mice. This study reveals that a class of abundant microbial metabolites underlies adaptive immune microbiota coadaptation and promotes colonic homeostasis and health.
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    Atarashi, K.; Tanoue, T.; Oshima, K.; Suda, W.; Nagano, Y.; Nishikawa, H.; Fukuda, S.; Saito, T.; Narushima, S.; Hase, K. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 2013, 500, 232– 236,  DOI: 10.1038/nature12331
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    Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota
    Atarashi, Koji; Tanoue, Takeshi; Oshima, Kenshiro; Suda, Wataru; Nagano, Yuji; Nishikawa, Hiroyoshi; Fukuda, Shinji; Saito, Takuro; Narushima, Seiko; Hase, Koji; Kim, Sangwan; Fritz, Joelle V.; Wilmes, Paul; Ueha, Satoshi; Matsushima, Kouji; Ohno, Hiroshi; Olle, Bernat; Sakaguchi, Shimon; Taniguchi, Tadatsugu; Morita, Hidetoshi; Hattori, Masahira; Honda, Kenya
    Nature (London, United Kingdom) (2013), 500 (7461), 232-236CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Manipulation of the gut microbiota holds great promise for the treatment of inflammatory and allergic diseases. Although numerous probiotic microorganisms have been identified, there remains a compelling need to discover organisms that elicit more robust therapeutic responses, are compatible with the host, and can affect a specific arm of the host immune system in a well-controlled, physiol. manner. Here the authors use a rational approach to isolate CD4+FOXP3+ regulatory T (Treg)-cell-inducing bacterial strains from the human indigenous microbiota. Starting with a healthy human fecal sample, a sequence of selection steps was applied to obtain mice colonized with human microbiota enriched in Treg-cell-inducing species. From these mice, the authors isolated and selected 17 strains of bacteria on the basis of their high potency in enhancing Treg cell abundance and inducing important anti-inflammatory mols.-including interleukin-10 (IL-) and inducible T-cell co-stimulator (ICOS)-in Treg cells upon inoculation into germ-free mice. Genome sequencing revealed that the 17 strains fall within clusters IV, XIVa and XVIII of Clostridia, which lack prominent toxins and virulence factors. The 17 strains act as a community to provide bacterial antigens and a TGF-β-rich environment to help expansion and differentiation of Treg cells. Oral administration of the combination of 17 strains to adult mice attenuated disease in models of colitis and allergic diarrhoea. Use of the isolated strains may allow for tailored therapeutic manipulation of human immune disorders.
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    Arpaia, N.; Campbell, C.; Fan, X.; Dikiy, S.; van der Veeken, J.; deRoos, P.; Liu, H.; Cross, J. R.; Pfeffer, K.; Coffer, P. J. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 2013, 504, 451– 455,  DOI: 10.1038/nature12726
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    Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation
    Arpaia, Nicholas; Campbell, Clarissa; Fan, Xiying; Dikiy, Stanislav; van der Veeken, Joris; de Roos, Paul; Liu, Hui; Cross, Justin R.; Pfeffer, Klaus; Coffer, Paul J.; Rudensky, Alexander Y.
    Nature (London, United Kingdom) (2013), 504 (7480), 451-455CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    Intestinal microbes provide multicellular hosts with nutrients and confer resistance to infection. The delicate balance between pro- and anti-inflammatory mechanisms, essential for gut immune homeostasis, is affected by the compn. of the commensal microbial community. Regulatory T cells (Treg cells) expressing transcription factor Foxp3 have a key role in limiting inflammatory responses in the intestine. Although specific members of the commensal microbial community have been found to potentiate the generation of anti-inflammatory Treg or pro-inflammatory T helper 17 (TH17) cells, the mol. cues driving this process remain elusive. Considering the vital metabolic function afforded by commensal microorganisms, the authors reasoned that their metabolic byproducts are sensed by cells of the immune system and affect the balance between pro- and anti-inflammatory cells. The authors tested this hypothesis by exploring the effect of microbial metabolites on the generation of anti-inflammatory Treg cells. The authors found that in mice a short-chain fatty acid (SCFA), butyrate, produced by commensal microorganisms during starch fermn., facilitated extrathymic generation of Treg cells. A boost in Treg-cell nos. after provision of butyrate was due to potentiation of extrathymic differentiation of Treg cells, as the obsd. phenomenon was dependent on intronic enhancer CNS1 (conserved non-coding sequence 1), essential for extrathymic but dispensable for thymic Treg-cell differentiation. In addn. to butyrate, de novo Treg-cell generation in the periphery was potentiated by propionate, another SCFA of microbial origin capable of histone deacetylase (HDAC) inhibition, but not acetate, which lacks this HDAC-inhibitory activity. The results suggest that bacterial metabolites mediate communication between the commensal microbiota and the immune system, affecting the balance between pro- and anti-inflammatory mechanisms.
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    Donia, M. S.; Cimermancic, P.; Schulze, C. J.; Wieland Brown, L. C.; Martin, J.; Mitreva, M.; Clardy, J.; Linington, R. G.; Fischbach, M. A. A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell 2014, 158, 1402– 1414,  DOI: 10.1016/j.cell.2014.08.032
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    A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics
    Donia, Mohamed S.; Cimermancic, Peter; Schulze, Christopher J.; Wieland Brown, Laura C.; Martin, John; Mitreva, Makedonka; Clardy, Jon; Linington, Roger G.; Fischbach, Michael A.
    Cell (Cambridge, MA, United States) (2014), 158 (6), 1402-1414CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    In complex biol. systems, small mols. often mediate microbe-microbe and microbe-host interactions. Using a systematic approach, the authors identified 3118 small-mol. biosynthetic gene clusters (BGCs) in genomes of human-assocd. bacteria and studied their representation in 752 metagenomic samples from the NIH Human Microbiome Project. Remarkably, they discovered that BGCs for a class of antibiotics in clin. trials, thiopeptides, are widely distributed in genomes and metagenomes of the human microbiota. The authors purified and solved the structure of a thiopeptide antibiotic, lactocillin, from a prominent member of the vaginal microbiota. They demonstrated that lactocillin has potent antibacterial activity against a range of Gram-pos. vaginal pathogens, and they showed that lactocillin and other thiopeptide BGCs are expressed in vivo by analyzing human metatranscriptomic sequencing data. These findings illustrate the widespread distribution of small-mol.-encoding BGCs in the human microbiome, and they demonstrate the bacterial prodn. of drug-like mols. in humans.
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    Lurie, I.; Yang, Y. X.; Haynes, K.; Mamtani, R.; Boursi, B. Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study. J. Clin. Psychiatry 2015, 76, 1522– 1528,  DOI: 10.4088/JCP.15m09961
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    Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study
    Lurie Ido; Lurie Ido; Yang Yu-Xiao; Haynes Kevin; Mamtani Ronac; Boursi Ben
    The Journal of clinical psychiatry (2015), 76 (11), 1522-8 ISSN:.
    OBJECTIVE: Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways. Our aim was to assess whether exposure to specific antibiotic groups increases the risk for depression, anxiety, or psychosis. METHOD: We conducted 3 nested case-control studies during the years 1995-2013 using a large population-based medical record database from the United Kingdom. The study included 202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls, respectively. Cases were defined as individuals aged 15-65 years with any medical Read code for depression, anxiety, or psychosis. Subjects with diagnosis-specific psychotropic prescriptions > 90 days before index date were excluded. For every case, 4 controls were selected using incidence density sampling, matching on age, sex, practice site, calendar time, and duration of follow-up before index date. The primary exposure of interest was therapy with 1 of 7 antibiotic classes > 1 year before index date. Odds ratios (ORs) and 95% CIs were calculated for the association between each psychiatric disorder and exposure to individual classes of antibiotics using conditional logistic regression analysis. The risk was adjusted for obesity, smoking history, alcohol consumption, socioeconomic status, and number of infectious events before diagnosis. RESULTS: Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones. The risk increased with recurrent antibiotic exposures to 1.40 (95% CI, 1.35-1.46) and 1.56 (95% CI, 1.46-1.65) for 2-5 and > 5 courses of penicillin, respectively. Similar association was observed for anxiety and was most prominent with exposures to penicillins and sulfonamides, with an AOR of 1.17 (95% CI, 1.01-1.36) for a single course of penicillin and 1.44 (95% CI, 1.18-1.75) for > 5 courses. There was no change in risk for psychosis with any antibiotic group. There was a mild increase in the risk of depression and anxiety with a single course of antifungals; however, there was no increase in risk with repeated exposures. CONCLUSION: Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis.
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    Zheng, P.; Zeng, B.; Zhou, C.; Liu, M.; Fang, Z.; Xu, X.; Zeng, L.; Chen, J.; Fan, S.; Du, X. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host’s metabolism. Mol. Psychiatry 2016, 21, 786– 796,  DOI: 10.1038/mp.2016.44
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    Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism
    Zheng, P.; Zeng, B.; Zhou, C.; Liu, M.; Fang, Z.; Xu, X.; Zeng, L.; Chen, J.; Fan, S.; Du, X.; Zhang, X.; Yang, D.; Yang, Y.; Meng, H.; Li, W.; Melgiri, N. D.; Licinio, J.; Wei, H.; Xie, P.
    Molecular Psychiatry (2016), 21 (6), 786-796CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)
    Major depressive disorder (MDD) is the result of complex gene-environment interactions. According to the World Health Organization, MDD is the leading cause of disability worldwide, and it is a major contributor to the overall global burden of disease. However, the definitive environmental mechanisms underlying the pathophysiol. of MDD remain elusive. The gut microbiome is an increasingly recognized environmental factor that can shape the brain through the microbiota-gut-brain axis. We show here that the absence of gut microbiota in germ-free (GF) mice resulted in decreased immobility time in the forced swimming test relative to conventionally raised healthy control mice. Moreover, from clin. sampling, the gut microbiotic compns. of MDD patients and healthy controls were significantly different with MDD patients characterized by significant changes in the relative abundance of Firmicutes, Actinobacteria and Bacteroidetes. Fecal microbiota transplantation of GF mice with 'depression microbiota' derived from MDD patients resulted in depression-like behaviors compared with colonization with 'healthy microbiota' derived from healthy control individuals. Mice harboring 'depression microbiota' primarily exhibited disturbances of microbial genes and host metabolites involved in carbohydrate and amino acid metab. This study demonstrates that dysbiosis of the gut microbiome may have a causal role in the development of depressive-like behaviors, in a pathway that is mediated through the host's metab.
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    Davis, D. J.; Hecht, P. M.; Jasarevic, E.; Beversdorf, D. Q.; Will, M. J.; Fritsche, K.; Gillespie, C. H. Sex-specific effects of docosahexaenoic acid (DHA) on the microbiome and behavior of socially-isolated mice. Brain, Behavior, and Immunity 2017, 59, 38– 48,  DOI: 10.1016/j.bbi.2016.09.003
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    Sex-specific effects of docosahexaenoic acid (DHA) on the microbiome and behavior of socially-isolated mice
    Davis, Daniel J.; Hecht, Patrick M.; Jasarevic, Eldin; Beversdorf, David Q.; Will, Matthew J.; Fritsche, Kevin; Gillespie, Catherine H.
    Brain, Behavior, and Immunity (2017), 59 (), 38-48CODEN: BBIMEW; ISSN:0889-1591. (Elsevier)
    Dietary supplementation with the long-chain omega-3 polyunsatd. fatty acid docosahexaenoic acid (DHA) has been shown to have a beneficial effect on reducing the symptoms assocd. with several neuropsychiatric conditions including anxiety and depression. However, the mechanisms underlying this effect remain largely unknown. Increasing evidence suggests that the vast repertoire of commensal bacteria within the gut plays a crit. role in regulating various biol. processes in the brain and may contribute to neuropsychiatric disease risk. The present study detd. the contribution of DHA on anxiety and depressive-like behaviors through modulation of the gut microbiota in a paradigm of social isolation. Adult male and female mice were subjected to social isolation for 28 days and then placed either on a control diet or a diet supplemented with 0.1% or 1.0% DHA. Fecal pellets were collected both 24 h and 7 days following the introduction of the new diets. Behavioral testing revealed that male mice fed a DHA diet, regardless of dose, exhibited reduced anxiety and depressive-like behaviors compared to control fed mice while no differences were obsd. in female mice. As the microbiota-brain-axis has been recently implicated in behavior, compn. of microbial communities were analyzed to examine if these sex-specific effects of DHA may be assocd. with changes in the gut microbiota (GM). Clear sex differences were obsd. with males and females showing distinct microbial compns. prior to DHA supplementation. The introduction of DHA into the diet also induced sex-specific interactions on the GM with the fatty acid producing a significant effect on the microbial profiles in males but not in females. Interestingly, levels of Allobaculum and Ruminococcus were found to significantly correlate with the behavioral changes obsd. in the male mice. Predictive metagenome anal. using PICRUSt was performed on the fecal samples collected from males and identified enrichment in functional KEGG pathway terms relevant to processes such as the biosynthesis of unsatd. fatty acids and antioxidant metab. These results indicate that DHA alters commensal community compn. and produces beneficial effects on anxiety and depressive-like behaviors in a sex-specific manner. The present study provides insight into the mechanistic role that gut microbes may play in the regulation of anxiety and depressive-like behaviors and how dietary intervention can modulate these effects.
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    Pasolli, E.; Asnicar, F.; Manara, S.; Zolfo, M.; Karcher, N.; Armanini, F.; Beghini, F.; Manghi, P.; Tett, A.; Ghensi, P. Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle. Cell 2019, 176, 649– 662.e20,  DOI: 10.1016/j.cell.2019.01.001
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    Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle
    Pasolli, Edoardo; Asnicar, Francesco; Manara, Serena; Zolfo, Moreno; Karcher, Nicolai; Armanini, Federica; Beghini, Francesco; Manghi, Paolo; Tett, Adrian; Ghensi, Paolo; Collado, Maria Carmen; Rice, Benjamin L.; DuLong, Casey; Morgan, Xochitl C.; Golden, Christopher D.; Quince, Christopher; Huttenhower, Curtis; Segata, Nicola
    Cell (Cambridge, MA, United States) (2019), 176 (3), 649-662.e20CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs [uSGBs]). uSGBs are prevalent (in 93% of well-assembled samples), expand underrepresented phyla, and are enriched in non-Westernized populations (40% of the total SGBs). We annotated 2.85 M genes in SGBs, many assocd. with conditions including infant development (94,000) or Westernization (106,000). SGBs and uSGBs permit deeper microbiome analyses and increase the av. mappability of metagenomic reads from 67.76% to 87.51% in the gut (median 94.26%) and 65.14% to 82.34% in the mouth. We thus identify thousands of microbial genomes from yet-to-be-named species, expand the pangenomes of human-assocd. microbes, and allow better exploitation of metagenomic technologies.
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    Nayfach, S.; Shi, Z. J.; Seshadri, R.; Pollard, K. S.; Kyrpides, N. C. New insights from uncultivated genomes of the global human gut microbiome. Nature 2019, 568, 505– 510,  DOI: 10.1038/s41586-019-1058-x
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    New insights from uncultivated genomes of the global human gut microbiome
    Nayfach, Stephen; Shi, Zhou Jason; Seshadri, Rekha; Pollard, Katherine S.; Kyrpides, Nikos C.
    Nature (London, United Kingdom) (2019), 568 (7753), 505-510CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    The genome sequences of many species of the human gut microbiome remain unknown, largely owing to challenges in cultivating microorganisms under lab. conditions. We address this problem by reconstructing 60,664 draft prokaryotic genomes from 3810 fecal metagenomes, from geog. and phenotypically diverse humans. These genomes provide ref. points for 2058 newly identified species-level operational taxonomic units (OTUs), which represents a 50% increase over the previously known phylogenetic diversity of sequenced gut bacteria. On av., the newly identified OTUs comprise 33% of richness and 28% of species abundance per individual, and are enriched in humans from rural populations. A meta-anal. of clin. gut-microbiome studies pinpointed numerous disease assocns. for the newly identified OTUs, which have the potential to improve predictive models. Finally, our anal. revealed that uncultured gut species have undergone genome redn. that has resulted in the loss of certain biosynthetic pathways, which may offer clues for improving cultivation strategies in the future.
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  64. 64
    Pusceddu, M. M.; Barboza, M.; Schneider, M.; Stokes, P.; Sladek, J. A.; Torres-Fuentes, C.; Goldfild, L. R.; Gillis, S. E.; Brust-Mascher, I.; Rabasa, G. Nod-like receptors are critical for gut-brain axis signaling in mice. J. Physiol. 2019, 597, 5777– 5797,  DOI: 10.1113/JP278640
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    64
    Nod-like receptors are critical for gut-brain axis signalling in mice
    Pusceddu, Matteo M.; Barboza, Mariana; Keogh, Ciara E.; Schneider, Melinda; Stokes, Patricia; Sladek, Jessica A.; Kim, Hyun Jung D.; Torres-Fuentes, Cristina; Goldfild, Lily R.; Gillis, Shane E.; Brust-Mascher, Ingrid; Rabasa, Gonzalo; Wong, Kyle A.; Lebrilla, Carlito; Byndloss, Mariana X.; Maisonneuve, Charles; Baeumler, Andreas J.; Philpott, Dana J.; Ferrero, Richard L.; Barrett, Kim E.; Reardon, Colin; Gareau, Melanie G.
    Journal of Physiology (Oxford, United Kingdom) (2019), 597 (24), 5777-5797CODEN: JPHYA7; ISSN:1469-7793. (Wiley-Blackwell)
    Key points : ·Nucleotide binding oligomerization domain (Nod)-like receptors regulate cognition, anxiety and hypothalamic-pituitary-adrenal axis activation. ·Nod-like receptors regulate central and peripheral serotonergic biol. ·Nod-like receptors are important for maintenance of gastrointestinal physiol. ·Intestinal epithelial cell expression of Nod1 receptors regulate behavior. Gut-brain axis signalling is crit. for maintaining health and homeostasis. Stressful life events can impact gut-brain signalling, leading to altered mood, cognition and intestinal dysfunction. In the present study, we identified nucleotide binding oligomerization domain (Nod)-like receptors (NLR), Nod1 and Nod2, as novel regulators for gut-brain signalling. NLR are innate immune pattern recognition receptors expressed in the gut and brain, and are important in the regulation of gastrointestinal physiol. We found that mice deficient in both Nod1 and Nod2 (NodDKO) demonstrate signs of stress-induced anxiety, cognitive impairment and depression in the context of a hyperactive hypothalamic-pituitary-adrenal axis. These deficits were coupled with impairments in the serotonergic pathway in the brain, decreased hippocampal cell proliferation and immature neurons, as well as reduced neural activation. In addn., NodDKO mice had increased gastrointestinal permeability and altered serotonin signalling in the gut following exposure to acute stress.
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    Pellegrini, C.; Antonioli, L.; Calderone, V.; Colucci, R.; Fornai, M.; Blandizzi, C. Microbiota-gut-brain axis in health and disease: Is NLRP3 inflammasome at the crossroads of microbiota-gut-brain communications?. Prog. Neurobiol. 2020, 191, 101806,  DOI: 10.1016/j.pneurobio.2020.101806
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    Microbiota-gut-brain axis in health and disease: Is NLRP3 inflammasome at the crossroads of microbiota-gut-brain communications
    Pellegrini, Carolina; Antonioli, Luca; Calderone, Vincenzo; Colucci, Rocchina; Fornai, Matteo; Blandizzi, Corrado
    Progress in Neurobiology (Oxford, United Kingdom) (2020), 191 (), 101806CODEN: PGNBA5; ISSN:0301-0082. (Elsevier Ltd.)
    A review. Growing evidence highlights the relevance of microbiota-gut-brain axis in the maintenance of brain homeostasis as well as in the pathophysiol. of major neurol. and psychiatric disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), autism spectrum disorder (ASD) and major depressive disorder (MDD). Of note, the nucleotide-binding oligomerization domain leucine rich repeat and pyrin domain-contg. protein 3 (NLRP3) inflammasome acts as a key player in both coordinating the host physiol. and shaping the peripheral and central immune/inflammatory responses in CNS diseases. The present review provides an overview of current knowledge on the role of microbiota-gut-inflammasome-brain axis in the major CNS diseases, including PD, AD, MS, ASD and MDD. In particular, though no direct and causal correlation among altered gut microbiota, NLRP3 activation and brain pathol. has been demonstrated and in-depth studies are needed in this setting, our purpose was to pave the way to a novel and pioneering perspective on the pathophysiol. of CNS disorders. Our intent was also to highlight and discuss whether alterations of microbiota-gut-inflammasome-brain axis support a holistic view of the pathophysiol. of CNS diseases, even though each disorder displays a different clin. picture.
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    Zhao, K.; Yao, M.; Zhang, X.; Xu, F.; Shao, X.; Wei, Y.; Wang, H. Flavonoids and intestinal microbes interact to alleviate depression. Journal of the Science of Food and Agriculture 2022, 102, 1311– 1318,  DOI: 10.1002/jsfa.11578
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    Flavonoids and intestinal microbes interact to alleviate depression
    Zhao, Ke; Yao, Mei; Zhang, Xin; Xu, Feng; Shao, Xingfeng; Wei, Yingying; Wang, Hongfei
    Journal of the Science of Food and Agriculture (2022), 102 (4), 1311-1318CODEN: JSFAAE; ISSN:0022-5142. (John Wiley & Sons Ltd.)
    A review. Flavonoids have a variety of biol. activities that are beneficial to human health. However, owing to low bioavailability, most flavonoids exert beneficial effects in the intestine through metab. by the flora into a variety of structurally different derivs. Also, flavonoids can modulate the type and structure of intestinal microorganisms to improve human health. It has been reported that the development of depression is accompanied by changes in the type and no. of intestinal microorganisms, and gut microbes can significantly improve depressive symptoms through the gut-brain axis. Therefore, the interaction between flavonoids and intestinal microbes to alleviate depression is discussed.
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    Segre, J. A. What does it take to satisfy Koch’s postulates two centuries later? Microbial genomics and Propionibacteria acnes. J. Invest. Dermatol. 2013, 133, 2141– 2142,  DOI: 10.1038/jid.2013.260
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    What Does It Take to Satisfy Koch's Postulates Two Centuries Later?: Microbial Genomics and Propionibacteria acnes
    Segre, Julia A.
    Journal of Investigative Dermatology (2013), 133 (9), 2141-2142CODEN: JIDEAE; ISSN:0022-202X. (Nature Publishing Group)
    For two centuries, Koch's postulates have set the gold std. for establishing the microbiol. etiol. of infection and disease. Genomic sequencing now brings finer resoln. to both bacterial strain variation and the host genetic state that may predispose to disease. In this issue of the JID, Fitz-Gibbons and colleagues present strain-based resoln. of Propionibacterium acnes and its assocn. with the common teenage malady acne vulgaris. Here I examine how Koch's postulates were envisioned and incorporate this finer resoln. of both host and microbial states.
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    Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis
    EISEMAN B; SILEN W; BASCOM G S; KAUVAR A J
    Surgery (1958), 44 (5), 854-9 ISSN:0039-6060.
    There is no expanded citation for this reference.
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    Schaedler, R. W.; Dubos, R.; Costello, R. ASSOCIATION OF GERMFREE MICE WITH BACTERIA ISOLATED FROM NORMAL MICE. J. Exp. Med. 1965, 122, 77– 82,  DOI: 10.1084/jem.122.1.77
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    ASSOCIATION OF GERMFREE MICE WITH BACTERIA ISOLATED FROM NORMAL MICE
    SCHAEDLER R W; DUBS R; COSTELLO R
    The Journal of experimental medicine (1965), 122 (), 77-82 ISSN:0022-1007.
    Germfree mice were given food contaminated with pure cultures of various bacterial species isolated from ordinary healthy mice. The cultures were given singly, or in association, or consecutively at weekly intervals. Whatever the technique of administration, the lactobacilli and anaerobic streptococci immediately established themselves throughout the gastrointestinal tract, and became closely associated with the walls of the organs. In contrast, the organisms of the bacteroides group were found in large numbers only in the large intestine. Within a week after exposure, the populations of these three bacterial species reached levels similar to those found in ordinary mice. They remained at these characteristic levels throughout the period of observation (several months). Their presence resulted in a progressive decrease in the size of the cecum which eventually became normal in gross appearance. Coliform bacilli multiplied extensively and persisted at high levels in all parts of the gastrointestinal tract of germfree mice, even after these had become colonized with lactobacilli, anaerobic streptococci and bacteroides. However, the coliform population fell precipitously within a few days after the animals were fed the intestinal contents of healthy pathogen-free mice.
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    Peppercorn, M. A.; Goldman, P. The Role of Intestinal Bacteria in the Metabolism of Salicylazosulfapyridine. Journal of Pharmacology and Experimental Therapeutics 1972, 181, 555– 562
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    Role of intestinal bacteria in the metabolism of salicylazosulfapyridine
    Peppercorn, Mark A.; Goldman, Peter
    Journal of Pharmacology and Experimental Therapeutics (1972), 181 (3), 555-62CODEN: JPETAB; ISSN:0022-3565.
    Following oral administration of salicylazosulfapyridine (I) [599-79-1] to normal rats, sulfapyridine [144-83-2], 5-aminosalicylate [89-57-6], and their N-acetyl derivs. were found in the excreta. No unchanged I was found. Pretreatment of the rats with neomycin [1404-04-2] in order to decrease intestinal microflora resulted in fecal recovery of >50% of the administered dose of I as unchanged I. Intestinal bacteria appear responsible for the initial reaction in I biotransformation and this raises questions concerning the amt. of unchanged I that reaches the presumed site of action in inflammatory disease of the lower intestine.
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    Stark, P. L.; Lee, A. The microbial ecology of the large bowel of breast-fed and formula-fed infants during the first year of life. J. Med. Microbiol. 1982, 15, 189– 203,  DOI: 10.1099/00222615-15-2-189
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    The microbial ecology of the large bowel of breast-fed and formula-fed infants during the first year of life
    Stark P L; Lee A
    Journal of medical microbiology (1982), 15 (2), 189-203 ISSN:0022-2615.
    The succession of bacterial populations in the large bowel of seven breast-fed and seven formula-fed infants was examined during the first year of life. The composition of the intestinal microflora varied according to the infant's diet. During the first week of life breast-fed and formula-fed infants were colonised by enterobacteria and enterococci followed by bifidobacteria, Bacteroides spp., clostridia and anaerobic streptococci. From week 4 until solid foods were given, breast-fed babies had a simple flora consisting of bifidobacteria and relatively few enterobacteria and enterococci. Formula-fed babies during the corresponding period were more often colonised by other anaerobes in addition to bifidobacteria and had higher counts of facultatively anaerobic bacteria. The introduction of solid food to the breast-fed infants caused a major disturbance in the microbial ecology of the large bowel as counts of enterobacteria and enterococci rose sharply and colonisation by Bacteroides spp., clostridia and anaerobic streptococci occurred. This was not observed when formula-fed infants began to take solids; instead, counts of facultative anaerobes remained high while colonisation by anaerobes other than bifidobacteria continued. At 12 months, the anaerobic bacterial populations of the large bowel of breast-fed and formula-fed infants were beginning to resemble those of adults in number and composition and there was a corresponding decrease in the number of facultative anaerobes. These changes are discussed in relation to changes in susceptibility to gastro-intestinal infection.
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    Fleischmann, R. D.; Adams, M. D.; White, O.; Clayton, R. A.; Kirkness, E. F.; Kerlavage, A. R.; Bult, C. J.; Tomb, J. F.; Dougherty, B. A.; Merrick, J. M. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 1995, 269, 496– 512,  DOI: 10.1126/science.7542800
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    Whole-genome random sequencing and assembly of Haemophilus influenzae Rd
    Fleischmann, Robert D.; Adams, Mark D.; White, Owen; Clayton, Rebecca A.; Kirkness, Ewen F.; Kerlavage, Anthony R.; Bult, Carol J.; Tomb, Jean-Francois; Dougherty, Brian A.; et al.
    Science (Washington, D. C.) (1995), 269 (5223), 496-8, 507-12CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    An approach for genome anal. based on sequencing and assembly of unselected pieces of DNA from the whole chromosome has been applied to obtain the complete nucleotide sequence (1,830,137 base pairs) of the genome from the bacterium Haemophilus influenzae Rd. This approach eliminates the need for initial mapping efforts and is therefore applicable to the vast array of microbial species for which genomes maps are unavailable. The H. influenzae Rd genome sequence (Genome Sequence DataBase accession no. L42023) represents the only complete genome sequence from a free-living organism.
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    Wilson, K. H.; Blitchington, R. B. Human colonic biota studied by ribosomal DNA sequence analysis. Appl. Environ. Microbiol. 1996, 62, 2273– 2278,  DOI: 10.1128/aem.62.7.2273-2278.1996
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    Human colonic biota studied by ribosomal DNA sequence analysis
    Wilson, Kenneth H.; Blitchington, Rhonda B.
    Applied and Environmental Microbiology (1996), 62 (7), 2273-2278CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    Human colonic biota is a complex microbial ecosystem that serves as a host defense. Unlike most microbial ecosystems, its compn. has been studied extensively by relatively efficient culture methods. The authors have compared an established culture-based method with direct amplification and partial sequencing of cloned 16S rRNA genes from a human fecal specimen. Nine cycles of PCR were also compared with 35 cycles. Colonies and cloned amplicons were classified by comparing their ribosomal DNA (rDNA; DNA coding for rRNA) sequences with rDNA sequences of known phylogeny. Quant. culture recovered 58% of the microscopic count. The 48 colonies identified gave 21 rDNA sequences; it was estd. that 72% of the rDNA sequences from the total population of culturable cells would match these 21 sampled sequences (72% coverage). Fifty 9-cycle clones gave 27 sequences and 59% coverage of cloned rDNAs. Thirty-nine rDNAs cloned after 35 cycles of PCR gave 13 sequences for 74% coverage. Thus, the representation of the ecosystem after 35 cycles of PCR was distorted and lacked diversity. However, when the no. of temp. cycles was minimized, biodiversity was preserved, and there was good agreement between culturing bacteria and sampling rDNA directly.
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    Guarner, F.; Malagelada, J. R. Gut flora in health and disease. Lancet 2003, 361, 512– 519,  DOI: 10.1016/S0140-6736(03)12489-0
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    Gut flora in health and disease
    Guarner Francisco; Malagelada Juan-R
    Lancet (London, England) (2003), 361 (9356), 512-9 ISSN:0140-6736.
    The human gut is the natural habitat for a large and dynamic bacterial community, but a substantial part of these bacterial populations are still to be described. However, the relevance and effect of resident bacteria on a host's physiology and pathology has been well documented. Major functions of the gut microflora include metabolic activities that result in salvage of energy and absorbable nutrients, important trophic effects on intestinal epithelia and on immune structure and function, and protection of the colonised host against invasion by alien microbes. Gut flora might also be an essential factor in certain pathological disorders, including multisystem organ failure, colon cancer, and inflammatory bowel diseases. Nevertheless, bacteria are also useful in promotion of human health. Probiotics and prebiotics are known to have a role in prevention or treatment of some diseases.
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    Rakoff-Nahoum, S.; Paglino, J.; Eslami-Varzaneh, F.; Edberg, S.; Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 2004, 118, 229– 241,  DOI: 10.1016/j.cell.2004.07.002
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    Recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis
    Rakoff-Nahoum, Seth; Paglino, Justin; Eslami-Varzaneh, Fatima; Edberg, Stephen; Medzhitov, Ruslan
    Cell (Cambridge, MA, United States) (2004), 118 (2), 229-241CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Toll-like receptors (TLRs) play a crucial role in host defense against microbial infection. The microbial ligands recognized by TLRs are not unique to pathogens, however, and are produced by both pathogenic and commensal microorganisms. It is thought that an inflammatory response to commensal bacteria is avoided due to sequestration of microflora by surface epithelia. Here, we show that commensal bacteria are recognized by TLRs under normal steady-state conditions, and this interaction plays a crucial role in the maintenance of intestinal epithelial homeostasis. Furthermore, we find that activation of TLRs by commensal microflora is crit. for the protection against gut injury and assocd. mortality. These findings reveal a novel function of TLRs-control of intestinal epithelial homeostasis and protection from injury-and provide a new perspective on the evolution of host-microbial interactions.
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    Mazmanian, S. K.; Liu, C. H.; Tzianabos, A. O.; Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 2005, 122, 107– 118,  DOI: 10.1016/j.cell.2005.05.007
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    An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system
    Mazmanian, Sarkis K.; Liu, Cui Hua; Tzianabos, Arthur O.; Kasper, Dennis L.
    Cell (Cambridge, MA, United States) (2005), 122 (1), 107-118CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The mammalian gastrointestinal tract harbors a complex ecosystem consisting of countless bacteria in homeostasis with the host immune system. Shaped by evolution, this partnership has potential for symbiotic benefit. However, the identities of bacterial mols. mediating symbiosis remain undefined. Here the authors show that, during colonization of animals with the ubiquitous gut microorganism Bacteroides fragilis, a bacterial polysaccharide (PSA) directs the cellular and phys. maturation of the developing immune system. Comparison with germ-free animals reveals that the immunomodulatory activities of PSA during B. fragilis colonization include correcting systemic T cell deficiencies and TH1/TH2 imbalances and directing lymphoid organogenesis. A PSA mutant of B. fragilis does not restore these immunol. functions. PSA presented by intestinal dendritic cells activates CD4+ T cells and elicits appropriate cytokine prodn. These findings provide a mol. basis for host-bacterial symbiosis and reveal the archetypal mol. of commensal bacteria that mediates development of the host immune system.
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    Turnbaugh, P. J.; Ley, R. E.; Mahowald, M. A.; Magrini, V.; Mardis, E. R.; Gordon, J. I. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006, 444, 1027– 1031,  DOI: 10.1038/nature05414
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    An obesity-associated gut microbiome with increased capacity for energy harvest
    Turnbaugh, Peter J.; Ley, Ruth E.; Mahowald, Michael A.; Magrini, Vincent; Mardis, Elaine R.; Gordon, Jeffrey I.
    Nature (London, United Kingdom) (2006), 444 (7122), 1027-1031CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
    The worldwide obesity epidemic is stimulating efforts to identify host and environmental factors that affect energy balance. Comparisons of the distal gut microbiota of genetically obese mice and their lean littermates, as well as those of obese and lean human volunteers have revealed that obesity is assocd. with changes in the relative abundance of the two dominant bacterial divisions, the Bacteroidetes and the Firmicutes. Here we demonstrate through meta-genomic and biochem. analyses that these changes affect the metabolic potential of the mouse gut microbiota. Our results indicate that the obese microbiome has an increased capacity to harvest energy from the diet. Furthermore, this trait is transmissible: colonization of germ-free mice with an 'obese microbiota' results in a significantly greater increase in total body fat than colonization with a 'lean microbiota'. These results identify the gut microbiota as an addnl. contributing factor to the pathophysiol. of obesity.
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    Routy, B.; Le Chatelier, E.; Derosa, L.; Duong, C. P. M.; Alou, M. T.; Daillère, R.; Fluckiger, A.; Messaoudene, M.; Rauber, C.; Roberti, M. P. Gut microbiome influences efficacy of PD-1&#x2013;based immunotherapy against epithelial tumors. Science 2018, 359, 91– 97,  DOI: 10.1126/science.aan3706
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    Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors
    Routy, Bertrand; Le Chatelier, Emmanuelle; Derosa, Lisa; Duong, Connie P. M.; Alou, Maryam Tidjani; Daillere, Romain; Fluckiger, Aurelie; Messaoudene, Meriem; Rauber, Conrad; Roberti, Maria P.; Fidelle, Marine; Flament, Caroline; Poirier-Colame, Vichnou; Opolon, Paule; Klein, Christophe; Iribarren, Kristina; Mondragon, Laura; Jacquelot, Nicolas; Qu, Bo; Ferrere, Gladys; Clemenson, Celine; Mezquita, Laura; Masip, Jordi Remon; Naltet, Charles; Brosseau, Solenn; Kaderbhai, Coureche; Richard, Corentin; Rizvi, Hira; Levenez, Florence; Galleron, Nathalie; Quinquis, Benoit; Pons, Nicolas; Ryffel, Bernhard; Minard-Colin, Veronique; Gonin, Patrick; Soria, Jean-Charles; Deutsch, Eric; Loriot, Yohann; Ghiringhelli, Francois; Zalcman, Gerard; Goldwasser, Francois; Escudier, Bernard; Hellmann, Matthew D.; Eggermont, Alexander; Raoult, Didier; Albiges, Laurence; Kroemer, Guido; Zitvogel, Laurence
    Science (Washington, DC, United States) (2018), 359 (6371), 91-97CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clin. responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome compn. Antibiotics inhibited the clin. benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clin. responses to ICIs and the relative abundance of Akkermansia muciniphila. Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.
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    Matson, V.; Fessler, J.; Bao, R.; Chongsuwat, T.; Zha, Y.; Alegre, M. L.; Luke, J. J.; Gajewski, T. F. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 2018, 359, 104– 108,  DOI: 10.1126/science.aao3290
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    The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients
    Matson, Vyara; Fessler, Jessica; Bao, Riyue; Chongsuwat, Tara; Zha, Yuanyuan; Alegre, Maria-Luisa; Luke, Jason J.; Gajewski, Thomas F.
    Science (Washington, DC, United States) (2018), 359 (6371), 104-108CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Anti-PD-1-based immunotherapy has had a major impact on cancer treatment but has only benefited a subset of patients. Among the variables that could contribute to interpatient heterogeneity is differential compn. of the patients' microbiome, which has been shown to affect antitumor immunity and immunotherapy efficacy in preclin. mouse models. The authors analyzed baseline stool samples from metastatic melanoma patients before immunotherapy treatment, through an integration of 16S rRNA gene sequencing, metagenomic shotgun sequencing, and quant. polymerase chain reaction for selected bacteria. A significant assocn. was obsd. between commensal microbial compn. and clin. response. Bacterial species more abundant in responders included Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium. Reconstitution of germ-free mice with fecal material from responding patients could lead to improved tumor control, augmented T cell responses, and greater efficacy of anti-PD-L1 therapy. The authors' results suggest that the commensal microbiome may have a mechanistic impact on antitumor immunity in human cancer patients.
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    Belizário, J. E.; Napolitano, M. Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches. Front. Microbiol. 2015, 6, 1050,  DOI: 10.3389/fmicb.2015.01050
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    Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches
    Belizario Jose E; Napolitano Mauro
    Frontiers in microbiology (2015), 6 (), 1050 ISSN:1664-302X.
    The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies.
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    Rinninella, E.; Raoul, P.; Cintoni, M.; Franceschi, F.; Miggiano, G. A. D.; Gasbarrini, A.; Mele, M. C. What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases. Microorganisms 2019, 7, 14,  DOI: 10.3390/microorganisms7010014
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    What is the healthy gut microbiota composition? A changing ecosystem across age, environment, diet, and diseases
    Rinninella, Emanuele; Raoul, Pauline; Cintoni, Marco; Franceschi, Francesco; Miggiano, Giacinto Abele Donato; Gasbarrini, Antonio; Mele, Maria Cristina
    Microorganisms (2019), 7 (1), 14CODEN: MICRKN; ISSN:2076-2607. (MDPI AG)
    Each individual is provided with a unique gut microbiota profile that plays many specific functions in host nutrient metab., maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Gut microbiota are composed of different bacteria species taxonomically classified by genus, family, order, and phyla. Each human's gut microbiota are shaped in early life as their compn. depends on infant transitions (birth gestational date, type of delivery, methods of milk feeding, weaning period) and external factors such as antibiotic use. These personal and healthy core native microbiota remain relatively stable in adulthood but differ between individuals due to enterotypes, body mass index (BMI) level, exercise frequency, lifestyle, and cultural and dietary habits. Accordingly, there is not a unique optimal gut microbiota compn. since it is different for each individual. However, a healthy host-microorganism balance must be respected in order to optimally perform metabolic and immune functions and prevent disease development. This review will provide an overview of the studies that focus on gut microbiota balances in the same individual and between individuals and highlight the close mutualistic relationship between gut microbiota variations and diseases. Indeed, dysbiosis of gut microbiota is assocd. not only with intestinal disorders but also with numerous extra-intestinal diseases such as metabolic and neurol. disorders. Understanding the cause or consequence of these gut microbiota balances in health and disease and how to maintain or restore a healthy gut microbiota compn. should be useful in developing promising therapeutic interventions.
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    Cresci, G. A. M.; Izzo, K. Chapter 4 - Gut Microbiome. In Adult Short Bowel Syndrome; Corrigan, M. L., Roberts, K., Steiger, E., Eds.; Academic Press, 2019; pp 45– 54.
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    Kho, Z. Y.; Lal, S. K. The Human Gut Microbiome – A Potential Controller of Wellness and Disease. Front. Microbiol. 2018, 9, 1835,  DOI: 10.3389/fmicb.2018.01835
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    The Human Gut Microbiome - A Potential Controller of Wellness and Disease
    Kho Zhi Y; Lal Sunil K
    Frontiers in microbiology (2018), 9 (), 1835 ISSN:1664-302X.
    Interest toward the human microbiome, particularly gut microbiome has flourished in recent decades owing to the rapidly advancing sequence-based screening and humanized gnotobiotic model in interrogating the dynamic operations of commensal microbiota. Although this field is still at a very preliminary stage, whereby the functional properties of the complex gut microbiome remain less understood, several promising findings have been documented and exhibit great potential toward revolutionizing disease etiology and medical treatments. In this review, the interactions between gut microbiota and the host have been focused on, to provide an overview of the role of gut microbiota and their unique metabolites in conferring host protection against invading pathogen, regulation of diverse host physiological functions including metabolism, development and homeostasis of immunity and the nervous system. We elaborate on how gut microbial imbalance (dysbiosis) may lead to dysfunction of host machineries, thereby contributing to pathogenesis and/or progression toward a broad spectrum of diseases. Some of the most notable diseases namely Clostridium difficile infection (infectious disease), inflammatory bowel disease (intestinal immune-mediated disease), celiac disease (multisystemic autoimmune disorder), obesity (metabolic disease), colorectal cancer, and autism spectrum disorder (neuropsychiatric disorder) have been discussed and delineated along with recent findings. Novel therapies derived from microbiome studies such as fecal microbiota transplantation, probiotic and prebiotics to target associated diseases have been reviewed to introduce the idea of how certain disease symptoms can be ameliorated through dysbiosis correction, thus revealing a new scientific approach toward disease treatment. Toward the end of this review, several research gaps and limitations have been described along with suggested future studies to overcome the current research lacunae. Despite the ongoing debate on whether gut microbiome plays a role in the above-mentioned diseases, we have in this review, gathered evidence showing a potentially far more complex link beyond the unidirectional cause-and-effect relationship between them.
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    Sankar, S. A.; Lagier, J. C.; Pontarotti, P.; Raoult, D.; Fournier, P. E. The human gut microbiome, a taxonomic conundrum. Syst. Appl. Microbiol 2015, 38, 276– 286,  DOI: 10.1016/j.syapm.2015.03.004
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    The human gut microbiome, a taxonomic conundrum
    Sankar, Senthil Alias; Lagier, Jean-Christophe; Pontarotti, Pierre; Raoult, Didier; Fournier, Pierre-Edouard
    Systematic and Applied Microbiology (2015), 38 (4), 276-286CODEN: SAMIDF; ISSN:0723-2020. (Elsevier GmbH)
    From culture to metagenomics, within only 130 years, our knowledge of the human microbiome has considerably improved. With >1000 microbial species identified to date, the gastro-intestinal microbiota is the most complex of human biotas. It is composed of a majority of Bacteroidetes and Firmicutes and, although exhibiting great inter-individual variations according to age, geog. origin, disease or antibiotic uptake, it is stable over time. Metagenomic studies have suggested assocns. between specific gut microbiota compns. and a variety of diseases, including irritable bowel syndrome, Crohn's disease, colon cancer, type 2 diabetes and obesity. However, these data remain method-dependent, as no consensus strategy has been defined to decipher the complexity of the gut microbiota. High-throughput culture-independent techniques have highlighted the limitations of culture by showing the importance of uncultured species, whereas modern culture methods have demonstrated that metagenomics underestimates the microbial diversity by ignoring minor populations. In this review, we highlight the progress and challenges that pave the way to a complete understanding of the human gastrointestinal microbiota and its influence on human health.
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    Kim, D.-H. Gut Microbiota-Mediated Drug-Antibiotic Interactions. Drug Metab. Dispos. 2015, 43, 1581– 1589,  DOI: 10.1124/dmd.115.063867
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    Gut microbiota-mediated drug-antibiotic interactions
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    Drug Metabolism & Disposition (2015), 43 (10), 1581-1589CODEN: DMDSAI; ISSN:1521-009X. (American Society for Pharmacology and Experimental Therapeutics)
    Xenobiotic metab. involves the biochem. modification of drugs and phytochems. in living organisms, including humans and other animals. In the intestine, the gut microbiota catalyzes the conversion of hydrophilic drugs into absorbable, hydrophobic compds. through hydroxyzation and redn. Drugs and phytochems. are transformed into bioactive (sulfasalazine, lovastatin, and ginsenoside Rb1), bioinactive (chloramphenicol, ranitidine, and metronidazole), and toxic metabolites (nitrazepam), thus affecting the pharmacokinetics of the original compds. Antibiotics suppress the activities of drug-metabolizing enzymes by inhibiting the proliferation of gut microbiota. Antibiotic treatment might influence xenobiotic metabs. more extensively and potently than previously recognized and reduce gut microbiotamediated transformation of orally administered drugs, thereby altering the systemic concns. of intact drugs, their metabolites, or both. This review describes the effects of antibiotics on the metab. of drugs and phytochems. by the gut microbiota.
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    Deng, P.; Swanson, K. S. Gut microbiota of humans, dogs and cats: current knowledge and future opportunities and challenges. Br. J. Nutr. 2015, 113 (Suppl), S6– 17,  DOI: 10.1017/S0007114514002943
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    Gut microbiota of humans, dogs and cats: current knowledge and future opportunities and challenges
    Deng, Ping; Swanson, Kelly S.
    British Journal of Nutrition (2015), 113 (S1), S6-S17CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    A review. High-throughput DNA sequencing techniques allow for the identification and characterization of microbes and their genes (microbiome). Using these new techniques, microbial populations in several niches of the human body, including the oral and nasal cavities, skin, urogenital tract and gastrointestinal tract, have been described recently. Very little data on the microbiome of companion animals exist, and most of the data have been derived from the anal. of the faeces of healthy lab. animals. High-throughput assays provide opportunities to study the complex and dense populations of the gut microbiota, including bacteria, archaea, fungi, protozoa and viruses. Our lab. and others have recently described the predominant microbial taxa and genes of healthy dogs and cats and how these respond to dietary interventions. In general, faecal microbial phylogeny (e.g. predominance of Firmicutes, Bacteroidetes, Proteobacteria and Actinobacteria) and functional capacity (e.g. major functional groups related to carbohydrate, protein, DNA and vitamin metab.; virulence factors; and cell wall and capsule) of the canine and feline gut are similar to those of the human gut. Initial sequencing projects have provided a glimpse of the microbial super-organism that exists within the canine and feline gut, but leaves much to be explored and discovered. As DNA provides information only about potential functions, studies that focus on the microbial transcriptome, metabolite profiles, and how microbiome changes affect host physiol. and health are clearly required. Future studies must det. how diet compn., antibiotics and other drug therapies, breed and disease affect or are affected by the gut microbiome and how this information may be used to improve diets, identify disease biomarkers and develop targeted disease therapies.
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    Nardone, G.; Compare, D. The human gastric microbiota: Is it time to rethink the pathogenesis of stomach diseases?. United European Gastroenterol J. 2015, 3, 255– 260,  DOI: 10.1177/2050640614566846
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    The human gastric microbiota: Is it time to rethink the pathogenesis of stomach diseases?
    Nardone, Gerardo; Compare, Debora
    United European Gastroenterology Journal (2015), 3 (3), 255-260CODEN: UEGJAZ; ISSN:2050-6414. (Sage Publications Ltd.)
    Introduction: Although long thought to be a sterile organ, due to its acid prodn., the human stomach holds a core microbiome. Aim: To provide an update of findings related to gastric microbiota and its link with gastric diseases. Methods: We conducted a systematic review of the literature. Results: The development of culture-independent methods facilitated the identification of many bacteria. Five major phyla have been detected in the stomach: Firmicutes, Bacteroidites, Actinobacteria, Fusobacteria and Proteobacteria. At the genera level, the healthy human stomach is dominated by Prevotella, Streptococcus, Veillonella, Rothia and Haemophilus; however, the compn. of the gastric microbiota is dynamic and affected by such factors as diet, drugs and diseases. The interaction between the pre-existing gastric microbiota and Helicobacter pylori infection might influence an individual's risk of gastric disease, including gastric cancer. Conclusions: The maintenance of bacterial homeostasis could be essential for the stomach's health and highlights the chance for therapeutic interventions targeting the gastric microbiota, even if gastric pH, peristalsis and the mucus layer may prevent bacteria colonization; and the definition of gastric microbiota of the healthy stomach is still an ongoing challenging task.
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    Ghosh, S.; Pramanik, S. Structural diversity, functional aspects and future therapeutic applications of human gut microbiome. Arch. Microbiol. 2021, 203, 5281– 5308,  DOI: 10.1007/s00203-021-02516-y
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    Structural diversity, functional aspects and future therapeutic applications of human gut microbiome
    Ghosh, Soma; Pramanik, Sreemanta
    Archives of Microbiology (2021), 203 (9), 5281-5308CODEN: AMICCW; ISSN:0302-8933. (Springer)
    Abstr.: The research on human gut microbiome, regarded as the black box of the human body, is still at the stage of infancy as the functional properties of the complex gut microbiome have not yet been understood. Ongoing metagenomic studies have deciphered that the predominant microbial communities belong to eubacterial phyla Firmicutes, Bacteroidetes, Proteobacteria, Fusobacteria, Cyanobacteria, Verrucomicrobia and archaebacterial phylum Euryarchaeota. The indigenous commensal microbial flora prevents opportunistic pathogenic infection and play undeniable roles in digestion, metabolite and signaling mol. prodn. and controlling host's cellular health, immunity and neuropsychiatric behavior. Besides maintaining intestinal health via short-chain fatty acid (SCFA) prodn., gut microbes also aid in neuro-immuno-endocrine modulatory mol. prodn., immune cell differentiation and glucose and lipid metab. Interdependence of diet and intestinal microbial diversity suggests the effectiveness of pre- and pro-biotics in maintenance of gut and systemic health. Several companies worldwide have started potentially exploiting the microbial contribution to human health and have translated their use in disease management and therapeutic applications. The present review discusses the vast diversity of microorganisms playing intricate roles in human metab. The contribution of the intestinal microbiota to regulate systemic activities including gut-brain-immunity crosstalk has been focused. To the best of our knowledge, this review is the first of its kind to collate and discuss the companies worldwide translating the multi-therapeutic potential of human intestinal microbiota, based on the multi-omics studies, i.e. metagenomics and metabolomics, as ready solns. for several metabolic and systemic disorders. Graphic abstr.: [graphic not available: see fulltext].
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    Leser, T. D.; Mo̷lbak, L. Better living through microbial action: the benefits of the mammalian gastrointestinal microbiota on the host. Environ. Microbiol. 2009, 11, 2194– 2206,  DOI: 10.1111/j.1462-2920.2009.01941.x
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    Better living through microbial action: the benefits of the mammalian gastrointestinal microbiota on the host
    Leser, Thomas D.; Moelbak, Lars
    Environmental Microbiology (2009), 11 (9), 2194-2206CODEN: ENMIFM; ISSN:1462-2912. (Wiley-Blackwell)
    A review. Mammals live in a homeostatic symbiosis with their gastrointestinal microbiota. The mammalian host provides the microbiota with nutrients and a stable environment; whereas the microbiota helps shaping the host's gut mucosa and provides nutritional contributions. Microorganisms start colonizing the gut immediately after birth followed by a succession of populations until a stable, adult microbiota has been established. However, physiol. conditions differ substantially among locations in the gut and det. bacterial d. and diversity. While Firmicutes and Bacteroidetes dominate the gut microbiota in all mammals, the bacterial genera and species diversity is huge and reflects mammalian phylogeny. The main function of the gastrointestinal epithelium is to absorb nutrients and to retain water and electrolytes, yet at the same time it is an efficient barrier against harmful compds. and microorganisms, and is able to neutralize antagonists coincidentally breaching the barrier. These processes are influenced by the microbiota, which modify epithelial expression of genes involved in nutrient uptake and metab., mucosal barrier function, xenobiotic metab., enteric nervous system and motility, hormonal and maturational responses, angiogenesis, cytoskeleton and extracellular matrix, signal transduction, and general cellular functions. Whereas such effects are local at the gut epithelium they may eventually have systemic consequences, e.g. on body wt. and compn.
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    Linares, D. M.; Ross, P.; Stanton, C. Beneficial Microbes: The pharmacy in the gut. Bioengineered 2016, 7, 11– 20,  DOI: 10.1080/21655979.2015.1126015
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    Beneficial Microbes: The pharmacy in the gut
    Linares, Daniel M.; Ross, Paul; Stanton, Catherine
    Bioengineered (2016), 7 (1), 11-20CODEN: BIOEGL; ISSN:2165-5987. (Taylor & Francis, Inc.)
    The scientific evidence supporting the gut microbiome in relation to health maintenance and links with various disease states afflicting humans, from metabolic to mental health, has grown dramatically in the last few years. Strategies addressing the pos. modulation of microbiome functionality assocd. with these disorders offer huge potential to the food and pharmaceutical industries to innovate and provide therapeutic solns. to many of the health issues affecting modern society. Such strategies may involve the use of probiotics and prebiotics as nutritional adjunct therapies. Probiotics are generally recognized to be a good form of therapy to keep harmful, intestinal microorganisms in check, aid digestion and nutrient absorption, and contribute to immune function. Probiotics are reported to improve microbial balance in the intestinal tract and promote the return to a baseline microbial community following a perturbing event (dysbiosis) such as antibiotic therapy. Prebiotics are selectively fermented ingredients that allow specific changes, both in the compn. and/or activity in the gastrointestinal microflora, which confers benefits upon host well-being and health.
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    Shah, H. N.; Olsen, I.; Bernard, K.; Finegold, S. M.; Gharbia, S.; Gupta, R. S. Approaches to the study of the systematics of anaerobic, Gram-negative, non-sporeforming rods: Current status and perspectives. Anaerobe 2009, 15, 179– 194,  DOI: 10.1016/j.anaerobe.2009.08.003
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    Approaches to the study of the systematics of anaerobic, Gram-negative, non-spore forming rods: Current status and perspectives
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    Anaerobe (2009), 15 (5), 179-194CODEN: ANAEF8; ISSN:1075-9964. (Elsevier Ltd.)
    A review. The present article gives an overview of recent taxonomic changes among the Gram-neg., anaerobic rods, briefly highlighting areas where the biol. and ecol. have a bearing on recent nomenclatorial changes. The focus is among the genera Bacteroides, Prevotella, Porphyromonas, Leptotrichia, Dysgonomonas, Fusobacterium and the Synergistes group and addnl. demonstrates the value of conserved indels and group-specific proteins for identifying and circumscribing many of these taxa and the Bacteroidetes-Chlorobi species in general.
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    Thomas, F.; Hehemann, J.-H.; Rebuffet, E.; Czjzek, M.; Michel, G. Environmental and Gut Bacteroidetes: The Food Connection. Front. Microbiol. 2011, 2, 93,  DOI: 10.3389/fmicb.2011.00093
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    Environmental and gut bacteroidetes: the food connection
    Thomas Francois; Hehemann Jan-Hendrik; Rebuffet Etienne; Czjzek Mirjam; Michel Gurvan
    Frontiers in microbiology (2011), 2 (), 93 ISSN:.
    Members of the diverse bacterial phylum Bacteroidetes have colonized virtually all types of habitats on Earth. They are among the major members of the microbiota of animals, especially in the gastrointestinal tract, can act as pathogens and are frequently found in soils, oceans and freshwater. In these contrasting ecological niches, Bacteroidetes are increasingly regarded as specialists for the degradation of high molecular weight organic matter, i.e., proteins and carbohydrates. This review presents the current knowledge on the role and mechanisms of polysaccharide degradation by Bacteroidetes in their respective habitats. The recent sequencing of Bacteroidetes genomes confirms the presence of numerous carbohydrate-active enzymes covering a large spectrum of substrates from plant, algal, and animal origin. Comparative genomics reveal specific Polysaccharide Utilization Loci shared between distantly related members of the phylum, either in environmental or gut-associated species. Moreover, Bacteroidetes genomes appear to be highly plastic and frequently reorganized through genetic rearrangements, gene duplications and lateral gene transfers (LGT), a feature that could have driven their adaptation to distinct ecological niches. Evidence is accumulating that the nature of the diet shapes the composition of the intestinal microbiota. We address the potential links between gut and environmental bacteria through food consumption. LGT can provide gut bacteria with original sets of utensils to degrade otherwise refractory substrates found in the diet. A more complete understanding of the genetic gateways between food-associated environmental species and intestinal microbial communities sheds new light on the origin and evolution of Bacteroidetes as animals' symbionts. It also raises the question as to how the consumption of increasingly hygienic and processed food deprives our microbiota from useful environmental genes and possibly affects our health.
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    McKee, L. S.; La Rosa, S. L.; Westereng, B.; Eijsink, V. G.; Pope, P. B.; Larsbrink, J. Polysaccharide degradation by the Bacteroidetes: mechanisms and nomenclature. Environ. Microbiol. Rep. 2021, 13, 559– 581,  DOI: 10.1111/1758-2229.12980
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    Polysaccharide degradation by the Bacteroidetes: mechanisms and nomenclature
    McKee, Lauren S.; La Rosa, Sabina Leanti; Westereng, Bjoerge; Eijsink, Vincent G.; Pope, Phillip B.; Larsbrink, Johan
    Environmental Microbiology Reports (2021), 13 (5), 559-581CODEN: EMRNAG; ISSN:1758-2229. (Wiley-Blackwell)
    The Bacteroidetes phylum is renowned for its ability to degrade a wide range of complex carbohydrates, a trait that has enabled its dominance in many diverse environments. The best studied species inhabit the human gut microbiome and use polysaccharide utilization loci (PULs), discrete genetic structures that encode proteins involved in the sensing, binding, deconstruction, and import of target glycans. In many environmental species, polysaccharide degrdn. is tightly coupled to the phylum-exclusive type IX secretion system (T9SS), which is used for the secretion of certain enzymes and is linked to gliding motility. In addn., within specific species these two adaptive systems (PULs and T9SS) are intertwined, with PUL-encoded enzymes being secreted by the T9SS. Here, we discuss the most noteworthy PUL and non-PUL mechanisms that confer specific and rapid polysaccharide degrdn. capabilities to the Bacteroidetes in a range of environments. We also acknowledge that the literature showcasing examples of PULs is rapidly expanding and developing a set of assumptions that can be hard to track back to original findings. Therefore, we present a simple universal description of conserved PUL functions and how they are detd., while proposing a common nomenclature describing PULs and their components, to simplify discussion and understanding of PUL systems.
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    Ludwig, W.; Schleifer, K.-H.; Whitman, W. B. Revised road map to the phylum Firmicutes. In Bergey’s Manual of Systematic Bacteriology: Vol. Three The Firmicutes; De Vos, P., Garrity, G. M., Jones, D., Krieg, N. R., Ludwig, W., Rainey, F. A., Schleifer, K.-H., Whitman, W. B., Eds.; Springer New York: New York, 2009; pp 1– 13.
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    Yang, M.; Gu, Y.; Li, L.; Liu, T.; Song, X.; Sun, Y.; Cao, X.; Wang, B.; Jiang, K.; Cao, H. Bile Acid–Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside. Nutrients 2021, 13, 3143,  DOI: 10.3390/nu13093143
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    Bile Acid-Gut Microbiota Axis in Inflammatory Bowel Disease: From Bench to Bedside
    Yang, Min; Gu, Yu; Li, Lingfeng; Liu, Tianyu; Song, Xueli; Sun, Yue; Cao, Xiaocang; Wang, Bangmao; Jiang, Kui; Cao, Hailong
    Nutrients (2021), 13 (9), 3143CODEN: NUTRHU; ISSN:2072-6643. (MDPI AG)
    A review. Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the gastrointestinal tract, with increasing prevalence, and its pathogenesis remains unclear. Accumulating evidence suggested that gut microbiota and bile acids play pivotal roles in intestinal homeostasis and inflammation. Patients with IBD exhibit decreased microbial diversity and abnormal microbial compn. marked by the depletion of phylum Firmicutes (including bacteria involved in bile acid metab.) and the enrichment of phylum Proteobacteria. Dysbiosis leads to blocked bile acid transformation. Thus, the concn. of primary and conjugated bile acids is elevated at the expense of secondary bile acids in IBD. In turn, bile acids could modulate the microbial community. Gut dysbiosis and disturbed bile acids impair the gut barrier and immunity. Several therapies, such as diets, probiotics, prebiotics, engineered bacteria, fecal microbiota transplantation and ursodeoxycholic acid, may alleviate IBD by restoring gut microbiota and bile acids. Thus, the bile acid-gut microbiota axis is closely connected with IBD pathogenesis. Regulation of this axis may be a novel option for treating IBD.
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  99. 99
    Barka, E. A.; Vatsa, P.; Sanchez, L.; Gaveau-Vaillant, N.; Jacquard, C.; Klenk, H.-P.; Clément, C.; Ouhdouch, Y.; Wezel, G. P. v. Taxonomy, Physiology, and Natural Products of Actinobacteria. Microbiology and Molecular Biology Reviews 2016, 80, 1– 43,  DOI: 10.1128/MMBR.00019-15
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    Taxonomy, Physiology, and Natural Products of Actinobacteria
    Barka Essaid Ait; Vatsa Parul; Sanchez Lisa; Gaveau-Vaillant Nathalie; Jacquard Cedric; Clement Christophe; Meier-Kolthoff Jan P; Klenk Hans-Peter; Ouhdouch Yder; van Wezel Gilles P
    Microbiology and molecular biology reviews : MMBR (2016), 80 (1), 1-43 ISSN:.
    Actinobacteria are Gram-positive bacteria with high G+C DNA content that constitute one of the largest bacterial phyla, and they are ubiquitously distributed in both aquatic and terrestrial ecosystems. Many Actinobacteria have a mycelial lifestyle and undergo complex morphological differentiation. They also have an extensive secondary metabolism and produce about two-thirds of all naturally derived antibiotics in current clinical use, as well as many anticancer, anthelmintic, and antifungal compounds. Consequently, these bacteria are of major importance for biotechnology, medicine, and agriculture. Actinobacteria play diverse roles in their associations with various higher organisms, since their members have adopted different lifestyles, and the phylum includes pathogens (notably, species of Corynebacterium, Mycobacterium, Nocardia, Propionibacterium, and Tropheryma), soil inhabitants (e.g., Micromonospora and Streptomyces species), plant commensals (e.g., Frankia spp.), and gastrointestinal commensals (Bifidobacterium spp.). Actinobacteria also play an important role as symbionts and as pathogens in plant-associated microbial communities. This review presents an update on the biology of this important bacterial phylum.
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    Hidalgo-Cantabrana, C.; Delgado, S.; Ruiz, L.; Ruas-Madiedo, P.; Sánchez, B.; Margolles, A. Bifidobacteria and Their Health-Promoting Effects. Microbiol Spectr 2017, 5, 5.3.21,  DOI: 10.1128/microbiolspec.BAD-0010-2016
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    Stackebrandt, E.; Murray, R. G. E.; Trüper, H. G. Proteobacteria classis nov., a Name for the Phylogenetic Taxon That Includes the “Purple Bacteria and Their Relatives. International Journal of Systematic and Evolutionary Microbiology 1988, 38, 321– 325,  DOI: 10.1099/00207713-38-3-321
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    Rizzatti, G.; Lopetuso, L. R.; Gibiino, G.; Binda, C.; Gasbarrini, A. Proteobacteria: A Common Factor in Human Diseases. BioMed. Research International 2017, 2017, 9351507,  DOI: 10.1155/2017/9351507
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    Proteobacteria: A Common Factor in Human Diseases
    Rizzatti G; Lopetuso L R; Gibiino G; Binda C; Gasbarrini A
    BioMed research international (2017), 2017 (), 9351507 ISSN:.
    Microbiota represents the entire microbial community present in the gut host. It serves several functions establishing a mutualistic relation with the host. Latest years have seen a burst in the number of studies focusing on this topic, in particular on intestinal diseases. In this scenario, Proteobacteria are one of the most abundant phyla, comprising several known human pathogens. This review highlights the latest findings on the role of Proteobacteria not only in intestinal but also in extraintestinal diseases. Indeed, an increasing amount of data identifies Proteobacteria as a possible microbial signature of disease. Several studies demonstrate an increased abundance of members belonging to this phylum in such conditions. Major evidences currently involve metabolic disorders and inflammatory bowel disease. However, more recent studies suggest a role also in lung diseases, such as asthma and chronic obstructive pulmonary disease, but evidences are still scant. Notably, all these conditions are sustained by various degree of inflammation, which thus represents a core aspect of Proteobacteria-related diseases.
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  103. 103
    Lee, K.-C.; Webb, R. I.; Janssen, P. H.; Sangwan, P.; Romeo, T.; Staley, J. T.; Fuerst, J. A. Phylum Verrucomicrobia representatives share a compartmentalized cell plan with members of bacterial phylum Planctomycetes. BMC Microbiol. 2009, 9, 5,  DOI: 10.1186/1471-2180-9-5
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    103
    Phylum Verrucomicrobia representatives share a compartmentalized cell plan with members of bacterial phylum Planctomycetes
    Lee Kuo-Chang; Webb Richard I; Janssen Peter H; Sangwan Parveen; Romeo Tony; Staley James T; Fuerst John A
    BMC microbiology (2009), 9 (), 5 ISSN:.
    BACKGROUND: The phylum Verrucomicrobia is a divergent phylum within domain Bacteria including members of the microbial communities of soil and fresh and marine waters; recently extremely acidophilic members from hot springs have been found to oxidize methane. At least one genus, Prosthecobacter, includes species with genes homologous to those encoding eukaryotic tubulins. A significant superphylum relationship of Verrucomicrobia with members of phylum Planctomycetes possessing a unique compartmentalized cell plan, and members of the phylum Chlamydiae including human pathogens with a complex intracellular life cycle, has been proposed. Based on the postulated superphylum relationship, we hypothesized that members of the two separate phyla Planctomycetes and Verrucomicrobia might share a similar ultrastructure plan differing from classical prokaryote organization. RESULTS: The ultrastructure of cells of four members of phylum Verrucomicrobia - Verrucomicrobium spinosum, Prosthecobacter dejongeii, Chthoniobacter flavus, and strain Ellin514 - was examined using electron microscopy incorporating high-pressure freezing and cryosubstitution. These four members of phylum Verrucomicrobia, representing 3 class-level subdivisions within the phylum, were found to possess a compartmentalized cell plan analogous to that found in phylum Planctomycetes. Like all planctomycetes investigated, they possess a major pirellulosome compartment containing a condensed nucleoid and ribosomes surrounded by an intracytoplasmic membrane (ICM), as well as a ribosome-free paryphoplasm compartment between the ICM and cytoplasmic membrane. CONCLUSION: A unique compartmentalized cell plan so far found among Domain Bacteria only within phylum Planctomycetes, and challenging our concept of prokaryote cell plans, has now been found in a second phylum of the Domain Bacteria, in members of phylum Verrucomicrobia. The planctomycete cell plan thus occurs in at least two distinct phyla of the Bacteria, phyla which have been suggested from other evidence to be related phylogenetically in the proposed PVC (Planctomycetes-Verrucomicrobia-Chlamydiae) superphylum. This planctomycete cell plan is present in at least 3 of 6 subdivisions of Verrucomicrobia, suggesting that the common ancestor of the verrucomicrobial phylum was also compartmentalized and possessed such a plan. The presence of this compartmentalized cell plan in both phylum Planctomycetes and phylum Verrucomicrobia suggest that the last common ancestor of these phyla was also compartmentalized.
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    Rappé, M. S.; Giovannoni, S. J. The Uncultured Microbial Majority. Annu. Rev. Microbiol. 2003, 57, 369– 394,  DOI: 10.1146/annurev.micro.57.030502.090759
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    The uncultured microbial majority
    Rappe, Michael S.; Giovannoni, Stephen J.
    Annual Review of Microbiology (2003), 57 (), 369-394CODEN: ARMIAZ; ISSN:0066-4227. (Annual Reviews Inc.)
    A review. Since the delineation of 12 bacterial phyla by comparative phylogenetic analyses of 16S rRNA in 1987, knowledge of microbial diversity has expanded dramatically owing to the sequencing of rRNA genes cloned from environmental DNA. Currently, only 26 of the approx. 52 identifiable major lineages, or phyla, within the domain Bacteria have cultivated representatives. Evidence from field studies indicates that many of the uncultivated phyla are found in diverse habitats, and some are extraordinarily abundant. In some important environments, including seawater, freshwater, and soil, many biol. and geochem. important organisms are at best only remotely related to any strain that has been characterized by phenotype or by genome sequencing. Genome sequence information that would allow rRNA gene trees to be related to broader patterns in microbial genome evolution is scant, and therefore microbial diversity remains largely unexplored territory.
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    Geerlings, S. Y.; Ouwerkerk, J. P.; Koehorst, J. J.; Ritari, J.; Aalvink, S.; Stecher, B.; Schaap, P. J.; Paulin, L.; de Vos, W. M.; Belzer, C. Genomic convergence between Akkermansia muciniphila in different mammalian hosts. BMC Microbiol. 2021, 21, 298,  DOI: 10.1186/s12866-021-02360-6
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    Genomic convergence between Akkermansia muciniphila in different mammalian hosts
    Geerlings, Sharon Y.; Ouwerkerk, Janneke P.; Koehorst, Jasper J.; Ritari, Jarmo; Aalvink, Steven; Stecher, Baerbel; Schaap, Peter J.; Paulin, Lars; de Vos, Willem M.; Belzer, Clara
    BMC Microbiology (2021), 21 (1), 298CODEN: BMMIBC; ISSN:1471-2180. (BioMed Central Ltd.)
    Akkermansia muciniphila is a member of the human gut microbiota where it resides in the mucus layer and uses mucin as the sole carbon, nitrogen and energy source. A. muciniphila is the only representative of the Verrucomicrobia phylum in the human gut. However, A. muciniphila 16S rRNA gene sequences have also been found in the intestines of many vertebrates. We detected A. muciniphila-like bacteria in the intestines of animals belonging to 15 out of 16 mammalian orders. In addn., other species belonging to the Verrucomicrobia phylum were detected in fecal samples. We isolated 10 new A. muciniphila strains from the feces of chimpanzee, siamang, mouse, pig, reindeer, horse and elephant. The physiol. and genome of these strains were highly similar in comparison to the type strain A. muciniphila MucT. Overall, the genomes of the new strains showed high av. nucleotide identity (93.9 to 99.7%). In these genomes, we detected considerable conservation of at least 75 of the 78 mucin degrdn. genes that were previously detected in the genome of the type strain MucT. The low genomic divergence obsd. in the new strains may indicate that A. muciniphila favors mucosal colonization independent of the differences in hosts. In addn., the conserved mucus degrdn. capability points towards a similar beneficial role of the new strains in regulating host metabolic health.
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    Liu, M.-J.; Yang, J.-Y.; Yan, Z.-H.; Hu, S.; Li, J.-Q.; Xu, Z.-X.; Jian, Y.-P. Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases. Clin. Nutr. 2022, 41, 2333– 2344,  DOI: 10.1016/j.clnu.2022.08.029
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    Recent findings in Akkermansia muciniphila-regulated metabolism and its role in intestinal diseases
    Liu, Meng-Jie; Yang, Jing-Yu; Yan, Zhen-Hua; Hu, Shuang; Li, Jun-Qi; Xu, Zhi-Xiang; Jian, Yong-Ping
    Clinical Nutrition (2022), 41 (10), 2333-2344CODEN: CLNUDP; ISSN:0261-5614. (Elsevier Ltd.)
    A review. The mammalian gastrointestinal tract is colonized with a majority of gut microbes, affecting host metab. and homeostasis. Gut microbiota plays a vital role in nutrient exchange, signaling transduction between intestinal epithelial cells, and resistance to pathogen invasion. Gut microbiota is divided into mucus layer bacteria and intestinal lumen bacteria based on the colonization distribution. Akkermansia muciniphila (A. muciniphila) prefers to colonize in the intestinal mucus layer, and specifically degrades mucins to produce short-chain fatty acids, providing energy for the host and promoting colonization of the bacterium itself. Degrdn. of mucins prompts the host to compensate for the prodn. of more mucins, thereby maintaining the dynamics of these proteins. In the intestinal micro-ecosystem, A. muciniphila is non-pathogenic, and its colonization with suitable abundance contributes to the development of immune system, thus promoting intestinal health. The mechanisms by which A. muciniphila bears a protective role in the host intestine are currently unclear. We summarize the microenvironment for the colonization of A. muciniphila, physiol. characteristics and pathophysiol. impact of A. muciniphila on intestinal diseases, such as irritable bowel syndrome, inflammatory bowel diseases, and intestinal tumors. We also provided updates for current studies on signals that A. muciniphila enhances intestinal barrier integrity and regulates immune response. Together, we conclude that A. muciniphila is a promising probiotic, which could be a microbial target for the treatment of multiple intestinal diseases.
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    Gupta, R. S.; Sethi, M. Phylogeny and molecular signatures for the phylum Fusobacteria and its distinct subclades. Anaerobe 2014, 28, 182– 198,  DOI: 10.1016/j.anaerobe.2014.06.007
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    Phylogeny and molecular signatures for the phylum Fusobacteria and its distinct subclades
    Gupta, Radhey S.; Sethi, Mohit
    Anaerobe (2014), 28 (), 182-198CODEN: ANAEF8; ISSN:1075-9964. (Elsevier Ltd.)
    The members of the phylum Fusobacteria and its two families, Fusobacteriaceae and Leptotrichiaceae, are distinguished at present mainly on the basis of their branching in the 16S rRNA gene trees and anal. of the internal transcribed spacer sequences in the 16S-23S rDNA. However, no biochem. or mol. characteristics are known that are uniquely shared by all of most members of these groups of bacteria. We report here detailed phylogenetic and comparative analyses on 45 sequenced Fusobacteria genomes to examine their evolutionary relationships and to identify mol. markers that are specific for the members of this phylum. In phylogenetic trees based on 16S rRNA gene sequences or concatenated sequences for 17 conserved proteins, members of the families Fusobacteriaceae and Leptotrichiaceae formed strongly supported clades and were clearly distinguished. In these trees, the species from the genus Fusobacterium also formed a no. of well-supported clades. In parallel, comparative analyses on Fusobacteria genomes have identified 44 conserved signature indels (CSIs) in proteins involved in a broad range of functions that are either specific for the phylum Fusobacteria or a no. of distinct subclades within this phylum. Seven of these CSIs in important proteins are uniquely present in the protein homologs of all sequenced Fusobacteria and they provide potential mol. markers for this phylum. Six and three other CSIs in other protein sequences are specific for members of the families Fusobacteriaceae and Leptotrichiaceae, resp., and they provide novel mol. means for distinguishing members of these two families. Fourteen addnl. CSIs in different proteins, which are specific for either members of the genera Fusobacterium or Leptotrichia, or a no. of other well-supported clades of Fusobacteria at multiple phylogenetic levels, provide mol. markers for these groups and information regarding the evolutionary relationships among the members of this phylum. Lastly, the present work has also identified 14 CSIs in divergent proteins that are specific for three specific subclades of Fusobacterium species, which are also indicated to be distinct by phylogenetic analyses. The members of these three Fusobacterium subclades also differ significantly from each other in their whole genome av. nucleotide identities values, suggesting that they are possible candidates for recognition as different genera. The mol. markers reported here provide novel means for the identification of members of the phylum Fusobacteria and for their classification.
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    Madhogaria, B.; Bhowmik, P.; Kundu, A. Correlation between human gut microbiome and diseases. Infectious Medicine 2022, 1, 180– 191,  DOI: 10.1016/j.imj.2022.08.004
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    Bull, M. J.; Plummer, N. T. Part 1: The Human Gut Microbiome in Health and Disease. Integr. Med. 2014, 13, 17– 22
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    Part 1: The Human Gut Microbiome in Health and Disease
    Bull Matthew J; Plummer Nigel T
    Integrative medicine (Encinitas, Calif.) (2014), 13 (6), 17-22 ISSN:1546-993X.
    The bacterial cells harbored within the human gastrointestinal tract (GIT) outnumber the host's cells by a factor of 10 and the genes encoded by the bacteria resident within the GIT outnumber their host's genes by more than 100 times. These human digestive-tract associated microbes are referred to as the gut microbiome. The human gut microbiome and its role in both health and disease has been the subject of extensive research, establishing its involvement in human metabolism, nutrition, physiology, and immune function. Imbalance of the normal gut microbiota have been linked with gastrointestinal conditions such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), and wider systemic manifestations of disease such as obesity, type 2 diabetes, and atopy. In the first part of this review, we evaluate our evolving knowledge of the development, complexity, and functionality of the healthy gut microbiota, and the ways in which the microbial community is perturbed in dysbiotic disease states; the second part of this review covers the role of interventions that have been shown to modulate and stabilize the gut microbiota and also to restore it to its healthy composition from the dysbiotic states seen in IBS, IBD, obesity, type 2 diabetes, and atopy.
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    Vijay, A.; Valdes, A. M. Role of the gut microbiome in chronic diseases: a narrative review. Eur. J. Clin. Nutr. 2022, 76, 489– 501,  DOI: 10.1038/s41430-021-00991-6
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    Role of the gut microbiome in chronic diseases: a narrative review
    Vijay, Amrita; Valdes, Ana M.
    European Journal of Clinical Nutrition (2022), 76 (4), 489-501CODEN: EJCNEQ; ISSN:0954-3007. (Nature Portfolio)
    A review. The gut microbiome, i.e., the community of bacteria and other microorganisms living in the human gut, has been implicated both directly and indirectly (mediating the effects of diet) on human health. The assocns. between gut microbiome compn. and disease status have been widely reported, while recent studies have demonstrated a role for the gut microbiome in influencing remote organs, mucosal, and immune function. This review details the role of the gut microbiome in chronic diseases and ways it can be modulated for the management or prevention of chronic conditions. The aim of this narrative review is to describe the assocns. between gut microbiome compn. and various types of chronic diseases and to discuss the links to habitual diet and dietary components. Discussed here is the gut microbiome compn. and its assocn. with autoimmune diseases, gut inflammation/bowel disorders, cardiometabolic diseases, chronic kidney disease (CKD). Finally, the gut microbiome is studied as a therapeutic target in the treatment of chronic diseases.
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    Baquero, F.; Nombela, C. The microbiome as a human organ. Clin Microbiol Infect 2012, 18 (Suppl 4), 2– 4,  DOI: 10.1111/j.1469-0691.2012.03916.x
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    The microbiome as a human organ
    Baquero, F.; Nombela, C.
    Clinical Microbiology and Infection (2012), 18 (Suppl. 4), 2-4CODEN: CMINFM; ISSN:1198-743X. (Wiley-Blackwell)
    A review. The human organism is a complex structure composed of cells belonging to all three domains of life on Earth, Eukarya, Bacteria and Archaea, as well as their viruses. Bacterial cells of more than a thousand taxonomic units are condensed in a particular functional collective domain, the intestinal microbiome. The microbiome constitutes the last human organ under active research. Like other organs, and despite its intrinsic complexity, the microbiome is readily inherited, in a process probably involving 'small world' power law dynamics of construction in newborns. Like any other organ, the microbiome has physiol. and pathol., and the individual (and collective) health might be damaged when its collective population structure is altered. The diagnostic of microbiomic diseases involves metagenomic studies. The therapeutics of microbiome-induced pathol. include microbiota transplantation, a technique increasingly available. Perhaps a new medical specialty, microbiomol., is being born.
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    Evans, J. M.; Morris, L. S.; Marchesi, J. R. The gut microbiome: the role of a virtual organ in the endocrinology of the host. J. Endocrinol. 2013, 218, R37– R47,  DOI: 10.1530/JOE-13-0131
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    The gut microbiome: the role of a virtual organ in the endocrinology of the host
    Evans, James M.; Morris, Laura S.; Marchesi, Julian R.
    Journal of Endocrinology (2013), 218 (3), R37-R47CODEN: JOENAK; ISSN:0022-0795. (BioScientifica Ltd.)
    A review. The human microbiome contains a vast array of microbes and genes that show greater complexity than the host's own karyome; the functions of many of these microbes are beneficial and show co-evolution with the host, while others are detrimental. The microbiota that colonises the gut is now being considered as a virtual organ or emergent system, with properties that need to be integrated into host biol. and physiol. Unlike other organs, the functions that the gut microbiota plays in the host are as yet not fully understood and can be quite easily disrupted by antibiotics, diet or surgery. In this review, we look at some of the best-characterised functions that only the gut microbiota plays and how it interacts with the host's endocrine system and we try to make it clear that the 21st-century biol. cannot afford to ignore this facet of biol., if it wants to fully understand what makes us human.
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    Haseeb, A.; Shahzad, I.; Ghulam, H.; Muhammad Naeem, F.; Humaira, M.; Imtiaz, M.; Imran, M.; Saima, M.; Muhammad Irfan, U. Gut Microbiome: A New Organ System in Body. In Parasitology and Microbiology Research; Gilberto Antonio Bastidas, P., Asghar Ali, K., Eds.; IntechOpen: Rijeka, Croatia, 2019.
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    Cani, P. D. Human gut microbiome: hopes, threats and promises. Gut 2018, 67, 1716– 1725,  DOI: 10.1136/gutjnl-2018-316723
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    Human gut microbiome: hopes, threats and promises
    Cani, Patrice D.
    Gut (2018), 67 (9), 1716-1725CODEN: GUTTAK; ISSN:0017-5749. (BMJ Publishing Group)
    A review. The microbiome has received increasing attention over the last 15 years. Although gut microbes have been explored for several decades, investigations of the role of microorganisms that reside in the human gut has attracted much attention beyond classical infectious diseases. For example, numerous studies have reported changes in the gut microbiota during not only obesity, diabetes, and liver diseases but also cancer and even neurodegenerative diseases. The human gut microbiota is viewed as a potential source of novel therapeutics. Between 2013 and 2017, the no. of publications focusing on the gut microbiota was, remarkably, 12 900, which represents four-fifths of the total no. of publications over the last 40 years that investigated this topic. This review discusses recent evidence of the impact of the gut microbiota on metabolic disorders and focus on selected key mechanisms. This review also aims to provide a crit. anal. of the current knowledge in this field, identify putative key issues or problems and discuss misinterpretations. The abundance of metagenomic data generated on comparing diseased and healthy subjects can lead to the erroneous claim that a bacterium is causally linked with the protection or the onset of a disease. In fact, environmental factors such as dietary habits, drug treatments, intestinal motility and stool frequency and consistency are all factors that influence the compn. of the microbiota and should be considered. The cases of the bacteria Prevotella copri and Akkermansia muciniphila will be discussed as key examples.
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    Lloyd-Price, J.; Arze, C.; Ananthakrishnan, A. N.; Schirmer, M.; Avila-Pacheco, J.; Poon, T. W.; Andrews, E.; Ajami, N. J.; Bonham, K. S.; Brislawn, C. J. Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases. Nature 2019, 569, 655– 662,  DOI: 10.1038/s41586-019-1237-9
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    Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases
    Lloyd-Price, Jason; Arze, Cesar; Ananthakrishnan, Ashwin N.; Schirmer, Melanie; Avila-Pacheco, Julian; Poon, Tiffany W.; Andrews, Elizabeth; Ajami, Nadim J.; Bonham, Kevin S.; Brislawn, Colin J.; Casero, David; Courtney, Holly; Gonzalez, Antonio; Graeber, Thomas G.; Hall, A. Brantley; Lake, Kathleen; Landers, Carol J.; Mallick, Himel; Plichta, Damian R.; Prasad, Mahadev; Rahnavard, Gholamali; Sauk, Jenny; Shungin, Dmitry; Vazquez-Baeza, Yoshiki; White, Richard A., III; Braun, Jonathan; Denson, Lee A.; Jansson, Janet K.; Knight, Rob; Kugathasan, Subra; McGovern, Dermot P. B.; Petrosino, Joseph F.; Stappenbeck, Thaddeus S.; Winter, Harland S.; Clish, Clary B.; Franzosa, Eric A.; Vlamakis, Hera; Xavier, Ramnik J.; Huttenhower, Curtis
    Nature (London, United Kingdom) (2019), 569 (7758), 655-662CODEN: NATUAS; ISSN:0028-0836. (Nature Research)
    Inflammatory bowel diseases, which include Crohn's disease and ulcerative colitis, affect several million individuals worldwide. Crohn's disease and ulcerative colitis are complex diseases that are heterogeneous at the clin., immunol., mol., genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal mol. profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as mol. disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochem. shifts. Finally, integrative anal. identified microbial, biochem., and host factors central to this dysregulation. The study's infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi'omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.
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  116. 116
    Mars, R. A. T.; Yang, Y.; Ward, T.; Houtti, M.; Priya, S.; Lekatz, H. R.; Tang, X.; Sun, Z.; Kalari, K. R.; Korem, T. Longitudinal Multi-omics Reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome. Cell 2020, 182, 1460– 1473.e17,  DOI: 10.1016/j.cell.2020.08.007
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    116
    Longitudinal multi-omics reveals Subset-Specific Mechanisms Underlying Irritable Bowel Syndrome
    Mars, Ruben A. T.; Yang, Yi; Ward, Tonya; Houtti, Mo; Priya, Sambhawa; Lekatz, Heather R.; Tang, Xiaojia; Sun, Zhifu; Kalari, Krishna R.; Korem, Tal; Bhattarai, Yogesh; Zheng, Tenghao; Bar, Noam; Frost, Gary; Johnson, Abigail J.; van Treuren, Will; Han, Shuo; Ordog, Tamas; Grover, Madhusudan; Sonnenburg, Justin; D'Amato, Mauro; Camilleri, Michael; Elinav, Eran; Segal, Eran; Blekhman, Ran; Farrugia, Gianrico; Swann, Jonathan R.; Knights, Dan; Kashyap, Purna C.
    Cell (Cambridge, MA, United States) (2020), 182 (6), 1460-1473.e17CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Detg. its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiol. changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiol. We identified IBS subtype-specific and symptom-related variation in microbial compn. and function. A subset of identified changes in microbial metabolites correspond to host physiol. mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metab. as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases.
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  117. 117
    Rinttilä, T.; Lyra, A.; Krogius-Kurikka, L.; Palva, A. Real-time PCR analysis of enteric pathogens from fecal samples of irritable bowel syndrome subjects. Gut Pathog. 2011, 3, 6,  DOI: 10.1186/1757-4749-3-6
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    Real-time PCR analysis of enteric pathogens from fecal samples of irritable bowel syndrome subjects
    Rinttila, Teemu; Lyra, Anna; Krogius-Kurikka, Lotta; Palva, Airi
    Gut Pathogens (2011), 3 (), 6CODEN: GPUAB2; ISSN:1757-4749. (BioMed Central Ltd.)
    Growing amt. of scientific evidence suggests that microbes are involved in the pathophysiol. of irritable bowel syndrome (IBS). The predominant fecal microbiota compn. of IBS subjects has been widely studied with DNA-based techniques but less research has been focused on the intestinal pathogens in this disorder. Here, we optimized a highly sensitive panel of 12 quant. real-time PCR (qPCR) assays to shed light on the putative presence of intestinal pathogens in IBS sufferers. The panel was used to screen fecal samples from 96 IBS subjects and 23 healthy controls. Fifteen IBS samples (17%) tested pos. for Staphylococcus aureus with a thermonuclease (nuc) gene-targeting qPCR assay, whereas none of the healthy controls were pos. for S. aureus (p < 0.05). The S. aureus-pos. IBS samples were confirmed by sequencing of the PCR amplicons. Clostridium perfringens was detected from IBS and control groups with a similar frequency (13% and 17%, resp.) with α-toxin (plc) gene-targeting qPCR assay while none of the samples tested pos. for the Cl. perfringens enterotoxin-encoding gene (cpe). The qPCR panel consisting of 12 assays for an extensive set of pathogenic microorganisms provides an efficient alternative to the conventional detection of gastrointestinal pathogens and could accelerate the initiation of targeted antibiotic therapy reducing the risk of post-infectious IBS (PI-IBS). S. aureus has not been previously reported to be assocd. with the onset of IBS. Although we discovered significant differences in the prevalence of S. aureus between the study groups, its importance in giving rise to IBS symptoms requires further studies.
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  118. 118
    Mayer, E. A.; Nance, K.; Chen, S. The Gut-Brain Axis. Annu. Rev. Med. 2022, 73, 439– 453,  DOI: 10.1146/annurev-med-042320-014032
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    118
    The Gut-Brain Axis
    Mayer Emeran A; Nance Karina; Chen Shelley
    Annual review of medicine (2022), 73 (), 439-453 ISSN:.
    Preclinical evidence has firmly established bidirectional interactions among the brain, the gut, and the gut microbiome. Candidate signaling molecules and at least three communication channels have been identified. Communication within this system is nonlinear, is bidirectional with multiple feedback loops, and likely involves interactions between different channels. Alterations in gut-brain-microbiome interactions have been identified in rodent models of several digestive, psychiatric, and neurological disorders. While alterations in gut-brain interactions have clearly been established in irritable bowel syndrome, a causative role of the microbiome in irritable bowel syndrome remains to be determined. In the absence of specific microbial targets for more effective therapies, current approaches are limited to dietary interventions and centrally targeted pharmacological and behavioral approaches. A more comprehensive understanding of causative influences within the gut-brain-microbiome system and well-designed randomized controlled trials are needed to translate these exciting preclinical findings into effective therapies.
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  119. 119
    Zhang, T.; Zhang, C.; Zhang, J.; Sun, F.; Duan, L. Efficacy of Probiotics for Irritable Bowel Syndrome: A Systematic Review and Network Meta-Analysis. Front Cell Infect Microbiol 2022, 12, 859967,  DOI: 10.3389/fcimb.2022.859967
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    Efficacy of Probiotics for Irritable Bowel Syndrome: A Systematic Review and Network Meta-Analysis
    Zhang Tao; Zhang Cunzheng; Zhang Jindong; Duan Liping; Sun Feng; Sun Feng
    Frontiers in cellular and infection microbiology (2022), 12 (), 859967 ISSN:.
    Background: Irritable bowel syndrome (IBS) is a common gastrointestinal condition. Studies regarding the treatment of IBS with probiotics have not yielded consistent results, and the best probiotics has not yet been confirmed. Therefore, we performed a network meta-analysis (NMA) to assess the relative rank order of different probiotics for IBS. Method: We searched for RCTs on the efficacy of probiotics for IBS until August 25, 2021. The primary outcome was the symptom relief rate, as well as global symptoms, abdominal pain, bloating, and straining scores. The NMA was conducted using Stata 15.0. We also used meta-regression to explore whether the treatment length and dose influenced the efficacy. Results: Forty-three RCTs, with 5,531 IBS patients, were included in this analysis. Firstly, we compared the efficacy of different probiotic species. B.coagulans exhibited the highest probability to be the optimal probiotic specie in improving IBS symptom relief rate, as well as global symptom, abdominal pain, bloating, and straining scores. In regard to the secondary outcomes, L.plantarum ranked first in ameliorating the QOL of IBS patients, but without any significant differences compared with other probiotic species in standardized mean differences (SMD) estimates. Moreover, patients received L.acidophilus had lowest incidence of adverse events. The meta-regression revealed that no significant differences were found between participants using different doses of probiotics in all outcomes, while the treatment length, as a confounder, can significantly influence the efficacy of probiotics in ameliorating abdominal pain (Coef = -2.30; p = 0.035) and straining (Coef = -3.15; p = 0.020) in IBS patients. Thus, we performed the subgroup analysis on treatment length subsequently in these two outcomes, which showed that efficacy of B.coagulans using 8 weeks ranked first both in improving the abdominal pain and straining scores. Additionally, B. coagulans still had significant efficacy compared to different types of probiotic combinations in present study. Conclusions: The findings of this NMA suggested that B.coagulans had prominent efficacy in treating IBS patients, and incorporating B.coagulans into a probiotic combination, or genetically engineering it to amplify its biological function may be a future research target to treat IBS patients. With few direct comparisons available between individual therapies today, this NMA may have utility in forming treatment guideline for IBS with probiotics.
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    Ponnusamy, K.; Choi, J. N.; Kim, J.; Lee, S. Y.; Lee, C. H. Microbial community and metabolomic comparison of irritable bowel syndrome faeces. J. Med. Microbiol. 2011, 60, 817– 827,  DOI: 10.1099/jmm.0.028126-0
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    120
    Microbial community and metabolomic comparison of irritable bowel syndrome faeces
    Ponnusamy, Kannan; Choi, Jung Nam; Kim, Jiyoung; Lee, Sun-Young; Lee, Choong Hwan
    Journal of Medical Microbiology (2011), 60 (6), 817-827CODEN: JMMIAV; ISSN:0022-2615. (Society for General Microbiology)
    Human health relies on the compn. of microbiota in an individual's gut and the synthesized metabolites that may alter the gut environment. Gut microbiota and fecal metabolites are involved in several gastrointestinal diseases. In this study, 16S rRNA-specific denaturing gradient gel electrophoresis and quant. PCR anal. showed that the mean similarity of total bacteria was significantly different (P<0.001) in fecal samples from patients with irritable bowel syndrome (IBS; n=11) and from non-IBS (nIBS) patients (n=8). IBS subjects had a significantly higher diversity of total bacteria, as measured by the Shannon index (H') (3.36<H'<4.37, P=0.004), Bacteroidetes and lactobacilli; however, less diversity was obsd. for Bifidobacter (1.7< H'<3.08, P<0.05) and Clostridium coccoides (0.9< H'<2.98, P=0.007). In this study, no significant difference was found in total bacterial quantity (P>0.05). GC/MS-based multi-variate anal. delineated the fecal metabolites of IBS from nIBS samples. Elevated levels of amino acids (alanine and pyroglutamic acid) and phenolic compds. (hydroxyphenyl acetate and hydroxyphenyl propionate) were found in IBS. These results were highly correlated with the abundance of lactobacilli and Clostridium, which indicates an altered metab. rate assocd. with these gut microorganisms. A higher diversity of Bacteroidetes and Lactobacillus groups in IBS fecal samples also correlated with the resp. total quantity. In addn., these changes altered protein and carbohydrate energy metab. in the gut.
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    Rajilić-Stojanović, M.; Biagi, E.; Heilig, H. G.; Kajander, K.; Kekkonen, R. A.; Tims, S.; de Vos, W. M. Global and deep molecular analysis of microbiota signatures in fecal samples from patients with irritable bowel syndrome. Gastroenterology 2011, 141, 1792– 1801,  DOI: 10.1053/j.gastro.2011.07.043
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    Global and Deep Molecular Analysis of Microbiota Signatures in Fecal Samples From Patients With Irritable Bowel Syndrome
    Rajilic-Stojanovic, Mirjana; Biagi, Elena; Heilig, Hans G. H. J.; Kajander, Kajsa; Kekkonen, Riina A.; Tims, Sebastian; de Vos, Willem M.
    Gastroenterology (2011), 141 (5), 1792-1801CODEN: GASTAB; ISSN:0016-5085. (Elsevier)
    Background & Aims: Irritable bowel syndrome (IBS) has been assocd. with disruptions to the intestinal microbiota, but studies have had limited power, coverage, and depth of anal. We aimed to define microbial populations that can be used discriminate the fecal microbiota of patients with IBS from that of healthy subjects and correlate these with IBS intestinal symptom scores. Methods: The microbiota compn. was assessed by global and deep mol. anal. of fecal samples from 62 patients with IBS patients and 46 healthy individuals (controls). We used a comprehensive and highly reproducible phylogenetic microarray in combination with quant. polymerase chain reaction. Results: The intestinal microbiota of IBS patients differed significantly (P = .0005) from that of controls. The microbiota of patients, compared with controls, had a 2-fold increased ratio of the Firmicutes to Bacteroidetes (P = .0002). This resulted from an approx. 1.5-fold increase in nos. of Dorea, Ruminococcus, and Clostridium spp (P < .005); a 2-fold decrease in the no. of Bacteroidetes (P < .0001); a 1.5-fold decrease in nos. of Bifidobacterium and Faecalibacterium spp (P < .05); and, when present, a 4-fold lower av. no. of methanogens (3.50 × 107 vs 8.74 × 106 cells/g feces; P = .003). Correlation anal. of the microbial groups and IBS symptom scores indicated the involvement of several groups of Firmicutes and Proteobacteria in the pathogenesis of IBS. Conclusions: Global and deep mol. anal. of fecal samples indicates that patients with IBS have a different compn. of microbiota. This information might be used to develop better diagnostics and ultimately treatments for IBS.
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  122. 122
    Pittayanon, R.; Lau, J. T.; Yuan, Y.; Leontiadis, G. I.; Tse, F.; Surette, M.; Moayyedi, P. Gut Microbiota in Patients With Irritable Bowel Syndrome-A Systematic Review. Gastroenterology 2019, 157, 97– 108,  DOI: 10.1053/j.gastro.2019.03.049
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    122
    Gut Microbiota in Patients With Irritable Bowel Syndrome-A Systematic Review
    Pittayanon Rapat; Lau Jennifer T; Yuan Yuhong; Leontiadis Grigorios I; Tse Frances; Surette Michael; Moayyedi Paul
    Gastroenterology (2019), 157 (1), 97-108 ISSN:.
    BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is common but difficult to treat. Altering the gut microbiota has been proposed as a strategy for treatment of IBS, but the association between the gut microbiome and IBS symptoms has not been well established. We performed a systematic review to explore evidence for this association. METHODS: We searched databases, including MEDLINE, EMBASE, Cochrane CDSR, and CENTRAL, through April 2, 2018 for case-control studies comparing the fecal or colon microbiomes of adult or pediatric patients with IBS with microbiomes of healthy individuals (controls). The primary outcome was differences in specific gut microbes between patients with IBS and controls. RESULTS: The search identified 2631 citations; 24 studies from 22 articles were included. Most studies evaluated adults presenting with various IBS subtypes. Family Enterobacteriaceae (phylum Proteobacteria), family Lactobacillaceae, and genus Bacteroides were increased in patients with IBS compared with controls, whereas uncultured Clostridiales I, genus Faecalibacterium (including Faecalibacterium prausnitzii), and genus Bifidobacterium were decreased in patients with IBS. The diversity of the microbiota was either decreased or not different in IBS patients compared with controls. More than 40% of included studies did not state whether cases and controls were comparable (did not describe sex and/or age characteristics). CONCLUSIONS: In a systematic review, we identified specific bacteria associated with microbiomes of patients with IBS vs controls. Studies are needed to determine whether these microbes are a product or cause of IBS.
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  123. 123
    El-Salhy, M.; Hatlebakk, J. G.; Gilja, O. H.; Bråthen Kristoffersen, A.; Hausken, T. Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study. Gut 2020, 69, 859– 867,  DOI: 10.1136/gutjnl-2019-319630
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    Efficacy of faecal microbiota transplantation for patients with irritable bowel syndrome in a randomised, double-blind, placebo-controlled study
    El-Salhy, Magdy; Hatlebakk, Jan Gunnar; Gilja, Odd Helge; Kristoffersen, Anja Braathen; Hausken, Trygve
    Gut (2020), 69 (5), 859-867CODEN: GUTTAK; ISSN:0017-5749. (BMJ)
    Objective Faecal microbiota transplantation (FMT) from healthy donors to patients with irritable bowel syndrome (IBS) has been attempted in two previous double-blind, placebo-controlled studies. While one of those studies found improvement of the IBS symptoms, the other found no effect. The present study was conducted to clarify these contradictory findings. Design This randomised, double-blind, placebo-controlled study randomised 165 patients with IBS to placebo (own faeces), 30 g FMT or 60 g FMT at a ratio of 1:1:1. The material for FMT was obtained from one healthy, well-characterised donor, frozen and administered via gastroscope. The primary outcome was a redn. in the IBS symptoms at 3 mo after FMT (response). A response was defined as a decrease of 50 or more points in the total IBS symptom score. The secondary outcome was a redn. in the dysbiosis index (DI) and a change in the intestinal bacterial profile, analyzed by 16S rRNA gene sequencing, at 1 mo following FMT. Results Responses occurred in 23.6%, 76.9% (p < 0.0001) and 89.1% (p < 00.0001) of the patients who received placebo, 30 g FMT and 60 g FMT, resp. These were accompanied by significant improvements in fatigue and the quality of life in patients who received FMT. The intestinal bacterial profiles changed also significantly in the groups received FMT. The FMT adverse events were mild self-limiting gastrointestinal symptoms. Conclusions FMT is an effective treatment for patients with IBS. Utilizing a well-defined donor with a normal DI and favorable specific microbial signature is essential for successful FMT. The response to FMT increases with the dose.
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    Wilson, B.; Rossi, M.; Kanno, T.; Parkes, G. C.; Anderson, S.; Mason, A. J.; Irving, P. M.; Lomer, M. C.; Whelan, K. β-Galactooligosaccharide in Conjunction With Low FODMAP Diet Improves Irritable Bowel Syndrome Symptoms but Reduces Fecal Bifidobacteria. Am. J. Gastroenterol. 2020, 115, 906– 915,  DOI: 10.14309/ajg.0000000000000641
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    β-Galactooligosaccharide in Conjunction With Low FODMAP Diet Improves Irritable Bowel Syndrome Symptoms but Reduces Fecal Bifidobacteria
    Wilson Bridgette; Rossi Megan; Lomer Miranda C; Whelan Kevin; Wilson Bridgette; Lomer Miranda C; Kanno Tokuwa; Mason A James; Parkes Gareth C; Anderson Simon; Irving Peter M
    The American journal of gastroenterology (2020), 115 (6), 906-915 ISSN:.
    INTRODUCTION: The low FODMAP diet (LFD) reduces symptoms and bifidobacteria in irritable bowel syndrome (IBS). β-galactooligosaccharides (B-GOS) may reduce the symptoms and increase bifidobacteria in IBS. We investigated whether B-GOS supplementation alongside the LFD improves IBS symptoms while preventing the decline in bifidobacteria. METHODS: We performed a randomized, placebo-controlled, 3-arm trial of 69 Rome III adult patients with IBS from secondary care in the United Kingdom. Patients were randomized to a sham diet with placebo supplement (control) or LFD supplemented with either placebo (LFD) or 1.4 g/d B-GOS (LFD/B-GOS) for 4 weeks. Gastrointestinal symptoms, fecal microbiota (fluorescent in situ hybridization and 16S rRNA sequencing), fecal short-chain fatty acids (gas-liquid chromatography) and pH (probe), and urine metabolites (H NMR) were analyzed. RESULTS: At 4 weeks, adequate symptom relief was higher in the LFD/B-GOS group (16/24, 67%) than in the control group (7/23, 30%) (odds ratio 4.6, 95% confidence interval: 1.3-15.6; P = 0.015); Bifidobacterium concentrations (log10 cells/g dry weight) were not different between LFD and LFD/B-GOS but were lower in the LFD/B-GOS (9.49 [0.73]) than in the control (9.77 [0.41], P = 0.018). A proportion of Actinobacteria was lower in LFD (1.9%, P = 0.003) and LFD/B-GOS (1.8%, P < 0.001) groups than in the control group (4.2%). Fecal butyrate was lower in the LFD (387.3, P = 0.028) and LFD/B-GOS (346.0, P = 0.007) groups than in the control group (609.2). DISCUSSION: The LFD combined with B-GOS prebiotic produced a greater symptom response than the sham diet plus placebo, but addition of 1.4 g/d B-GOS did not prevent the reduction of bifidobacteria. The LFD reduces fecal Actinobacteria and butyrate thus strict long-term use should not be advised.
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    Vasant, D. H.; Paine, P. A.; Black, C. J.; Houghton, L. A.; Everitt, H. A.; Corsetti, M.; Agrawal, A.; Aziz, I.; Farmer, A. D.; Eugenicos, M. P. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut 2021, 70, 1214– 1240,  DOI: 10.1136/gutjnl-2021-324598
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    British Society of Gastroenterology guidelines on the management of irritable bowel syndrome
    Vasant Dipesh H; Vasant Dipesh H; Paine Peter A; Paine Peter A; Black Christopher J; Ford Alexander C; Black Christopher J; Houghton Lesley A; Ford Alexander C; Houghton Lesley A; Everitt Hazel A; Corsetti Maura; Agrawal Anurag; Aziz Imran; Aziz Imran; Farmer Adam D; Farmer Adam D; Eugenicos Maria P; Moss-Morris Rona; Yiannakou Yan
    Gut (2021), 70 (7), 1214-1240 ISSN:.
    Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care. Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based management of patients. One of the strengths of this guideline is that the recommendations for treatment are based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of trial-based and network meta-analyses assessing the efficacy of dietary, pharmacological and psychological therapies in treating IBS. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system, summarising both the strength of the recommendations and the overall quality of evidence. Finally, this guideline identifies novel treatments that are in development, as well as highlighting areas of unmet need for future research.
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  126. 126
    Moayyedi, P.; Andrews, C. N.; MacQueen, G.; Korownyk, C.; Marsiglio, M.; Graff, L.; Kvern, B.; Lazarescu, A.; Liu, L.; Paterson, W. G. Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS). J. Can. Assoc Gastroenterol 2019, 2, 6– 29,  DOI: 10.1093/jcag/gwy071
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    126
    Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Irritable Bowel Syndrome (IBS)
    Moayyedi Paul; Sidani Sacha; Andrews Christopher N; MacQueen Glenda; Korownyk Christina; Marsiglio Megan; Graff Lesley; Kvern Brent; Lazarescu Adriana; Liu Louis; Paterson William G; Vanner Stephen
    Journal of the Canadian Association of Gastroenterology (2019), 2 (1), 6-29 ISSN:.
    BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is one of the most common gastrointestinal (GI) disorders, affecting about 10% of the general population globally. The aim of this consensus was to develop guidelines for the management of IBS. METHODS: A systematic literature search identified studies on the management of IBS. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a multidisciplinary group of clinicians and a patient. RESULTS: Consensus was reached on 28 of 31 statements. Irritable bowel syndrome is diagnosed based on symptoms; serological testing is suggested to exclude celiac disease, but routine testing for C-reactive protein (CRP), fecal calprotectin or food allergies is not recommended. A trial of a low fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAP) diet is suggested, while a gluten-free diet is not. Psyllium, but not wheat bran, supplementation may help reduce symptoms. Alternative therapies such as peppermint oil and probiotics are suggested, while herbal therapies and acupuncture are not. Cognitive behavioural therapy and hypnotherapy are suggested psychological therapies. Among the suggested or recommended pharmacological therapies are antispasmodics, certain antidepressants, eluxadoline, lubiprostone, and linaclotide. Loperamide, cholestyramine and osmotic laxatives are not recommended for overall IBS symptoms. The nature of the IBS symptoms (diarrhea-predominant or constipation-predominant) should be considered in the choice of pharmacological treatments. CONCLUSIONS: Patients with IBS may benefit from a multipronged, individualized approach to treatment, including dietary modifications, psychological and pharmacological therapies.
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  127. 127
    Fukudo, S.; Okumura, T.; Inamori, M.; Okuyama, Y.; Kanazawa, M.; Kamiya, T.; Sato, K.; Shiotani, A.; Naito, Y.; Fujikawa, Y. Evidence-based clinical practice guidelines for irritable bowel syndrome 2020. J. Gastroenterol. 2021, 56, 193– 217,  DOI: 10.1007/s00535-020-01746-z
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    127
    Evidence-based clinical practice guidelines for irritable bowel syndrome 2020
    Fukudo Shin; Okumura Toshikatsu; Inamori Masahiko; Okuyama Yusuke; Kanazawa Motoyori; Kamiya Takeshi; Sato Ken; Shiotani Akiko; Naito Yuji; Fujikawa Yoshiko; Hokari Ryota; Masaoka Tastuhiro; Fujimoto Kazuma; Kaneko Hiroshi; Torii Akira; Matsueda Kei; Miwa Hiroto; Enomoto Nobuyuki; Shimosegawa Tooru; Koike Kazuhiko; Fukudo Shin
    Journal of gastroenterology (2021), 56 (3), 193-217 ISSN:.
    Managing irritable bowel syndrome (IBS) has attracted international attention because single-agent therapy rarely relieves bothersome symptoms for all patients. The Japanese Society of Gastroenterology (JSGE) published the first edition of evidence-based clinical practice guidelines for IBS in 2015. Much more evidence has accumulated since then, and new pharmacological agents and non-pharmacological methods have been developed. Here, we report the second edition of the JSGE-IBS guidelines comprising 41 questions including 12 background questions on epidemiology, pathophysiology, and diagnostic criteria, 26 clinical questions on diagnosis and treatment, and 3 questions on future research. For each question, statements with or without recommendations and/or evidence level are given and updated diagnostic and therapeutic algorithms are provided based on new evidence. Algorithms for diagnosis are requisite for patients with chronic abdominal pain or associated symptoms and/or abnormal bowel movement. Colonoscopy is indicated for patients with one or more alarm symptoms/signs, risk factors, and/or abnormal routine examination results. The diagnosis is based on the Rome IV criteria. Step 1 therapy consists of diet therapy, behavioral modification, and gut-targeted pharmacotherapy for 4 weeks. For non-responders, management proceeds to step 2 therapy, which includes a combination of different mechanistic gut-targeted agents and/or psychopharmacological agents and basic psychotherapy for 4 weeks. Step 3 therapy is for non-responders to step 2 and comprises a combination of gut-targeted pharmacotherapy, psychopharmacological treatments, and/or specific psychotherapy. These updated JSGE-IBS guidelines present best practice strategies for IBS patients in Japan and we believe these core strategies can be useful for IBS diagnosis and treatment globally.
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  128. 128
    Lacy, B. E.; Pimentel, M.; Brenner, D. M.; Chey, W. D.; Keefer, L. A.; Long, M. D.; Moshiree, B. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am. J. Gastroenterol. 2021, 116, 17,  DOI: 10.14309/ajg.0000000000001036
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    ACG clinical guideline: management of irritable bowel syndrome
    Lacy, Brian E.; Pimentel, Mark; Brenner, Darren M.; Chey, William D.; Keefer, Laurie A.; Long, Millie D.; Moshiree, Baha
    American Journal of Gastroenterology (2021), 116 (1), 17-44CODEN: AJGAAR; ISSN:1572-0241. (Wolters Kluwer)
    Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterol. clin. guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodol. Twenty-five clin. important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodol., we endorse the following: We suggest that a pos. diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serol. testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Addnl. statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.
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  129. 129
    Ford, A. C.; Harris, L. A.; Lacy, B. E.; Quigley, E. M. M.; Moayyedi, P. Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome. Aliment. Pharmacol. Ther. 2018, 48, 1044– 1060,  DOI: 10.1111/apt.15001
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    129
    Systematic review with meta-analysis: the efficacy of prebiotics, probiotics, synbiotics and antibiotics in irritable bowel syndrome
    Ford Alexander C; Ford Alexander C; Harris Lucinda A; Lacy Brian E; Quigley Eamonn M M; Moayyedi Paul
    Alimentary pharmacology & therapeutics (2018), 48 (10), 1044-1060 ISSN:.
    BACKGROUND: Irritable bowel syndrome (IBS) is a chronic functional bowel disorder. Disturbances in the gastrointestinal microbiome may be involved in its aetiology. AIM: To perform a systematic review and meta-analysis to examine the efficacy of prebiotics, probiotics, synbiotics and antibiotics in IBS. METHODS: MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to July 2017). Randomised controlled trials (RCTs) recruiting adults with IBS, comparing prebiotics, probiotics, synbiotics or antibiotics with placebo or no therapy were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). Continuous data were pooled using a standardised mean difference with a 95% CI. RESULTS: The search identified 4017 citations. Data for prebiotics and synbiotics were sparse. Fifty-three RCTs of probiotics, involving 5545 patients, were eligible. Particular combinations of probiotics, or specific species and strains, appeared to have beneficial effects on global IBS symptoms and abdominal pain, but it was not possible to draw definitive conclusions about their efficacy. There were five trials of similar design that used rifaximin in non-constipated IBS patients, which was more effective than placebo (RR of symptoms persisting = 0.84; 95% CI 0.79-0.90). Adverse events were no more common with probiotics or antibiotics. CONCLUSIONS: Which particular combination, species or strains of probiotics are effective for IBS remains, for the most part, unclear. Rifaximin has modest efficacy in improving symptoms in non-constipated IBS.
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    Caruso, R.; Lo, B. C.; Núñez, G. Host-microbiota interactions in inflammatory bowel disease. Nat. Rev. Immunol. 2020, 20, 411– 426,  DOI: 10.1038/s41577-019-0268-7
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    130
    Host-microbiota interactions in inflammatory bowel disease
    Caruso, Roberta; Lo, Bernard C.; Nunez, Gabriel
    Nature Reviews Immunology (2020), 20 (7), 411-426CODEN: NRIABX; ISSN:1474-1733. (Nature Research)
    Abstr.: The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. The presence of large nos. of symbionts near the epithelial surface of the intestine poses an enormous challenge to the host because it must avoid the activation of harmful inflammatory responses to the microorganisms while preserving its ability to mount robust immune responses to invading pathogens. In patients with inflammatory bowel disease, there is a breakdown of the multiple strategies that the immune system has evolved to promote the sepn. between symbiotic microorganisms and the intestinal epithelium and the effective killing of penetrant microorganisms, while suppressing the activation of inappropriate T cell responses to resident microorganisms. Understanding the complex interactions between intestinal microorganisms and the host may provide crucial insight into the pathogenesis of inflammatory bowel disease as well as new avenues to prevent and treat the disease.
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  131. 131
    Federici, S.; Kredo-Russo, S.; Valdés-Mas, R.; Kviatcovsky, D.; Weinstock, E.; Matiuhin, Y.; Silberberg, Y.; Atarashi, K.; Furuichi, M.; Oka, A. Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation. Cell 2022, 185, 2879– 2898.e24,  DOI: 10.1016/j.cell.2022.07.003
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    131
    Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation
    Federici, Sara; Kredo-Russo, Sharon; Valdes-Mas, Rafael; Kviatcovsky, Denise; Weinstock, Eyal; Matiuhin, Yulia; Silberberg, Yael; Atarashi, Koji; Furuichi, Munehiro; Oka, Akihiko; Liu, Bo; Fibelman, Morine; Weiner, Iddo Nadav; Khabra, Efrat; Cullin, Nyssa; Ben-Yishai, Noa; Inbar, Dana; Ben-David, Hava; Nicenboim, Julian; Kowalsman, Noga; Lieb, Wolfgang; Kario, Edith; Cohen, Tal; Geffen, Yael Friedman; Zelcbuch, Lior; Cohen, Ariel; Rappo, Urania; Gahali-Sass, Inbar; Golembo, Myriam; Lev, Vered; Dori-Bachash, Mally; Shapiro, Hagit; Moresi, Claudia; Cuevas-Sierra, Amanda; Mohapatra, Gayatree; Kern, Lara; Zheng, Danping; Nobs, Samuel Philip; Suez, Jotham; Stettner, Noa; Harmelin, Alon; Zak, Naomi; Puttagunta, Sailaja; Bassan, Merav; Honda, Kenya; Sokol, Harry; Bang, Corinna; Franke, Andre; Schramm, Christoph; Maharshak, Nitsan; Sartor, Ryan Balfour; Sorek, Rotem; Elinav, Eran
    Cell (Cambridge, MA, United States) (2022), 185 (16), 2879-2898.e24CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geog. distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly assocd. with disease exacerbation and severity. Transfer of clin. IBD-assocd. Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-assocd. Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.
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    Nagalingam, N. A.; Lynch, S. V. Role of the microbiota in inflammatory bowel diseases. Inflamm. Bowel Dis. 2012, 18, 968– 984,  DOI: 10.1002/ibd.21866
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    132
    Role of the microbiota in inflammatory bowel diseases
    Nagalingam Nabeetha A; Lynch Susan V
    Inflammatory bowel diseases (2012), 18 (5), 968-84 ISSN:.
    Studying the role of the human microbiome as it relates to human health status has revolutionized our view of microbial community contributions to a large number of diseases, particularly chronic inflammatory disorders. The lower gastrointestinal (GI) tract houses trillions of microbial cells representing a large diversity of species in relatively well-defined phylogenetic ratios that are associated with maintenance of key aspects of host physiology and immune homeostasis. It is not surprising, therefore, that many GI inflammatory diseases, including inflammatory bowel disease (IBD), are associated with substantial changes in the composition of these microbial assemblages, either as a cause or consequence of host inflammatory response. Here we review current knowledge in the emerging field of human microbiome research as it relates to IBD, specifically focusing on Crohn's disease (CD) and ulcerative colitis (UC). We discuss bacteriotherapeutic efforts to restore GI microbial assemblage integrity via probiotic supplementation of IBD patients, and speculate on future directions for the field.
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    Barcenilla, A.; Pryde, S. E.; Martin, J. C.; Duncan, S. H.; Stewart, C. S.; Henderson, C.; Flint, H. J. Phylogenetic relationships of butyrate-producing bacteria from the human gut. Appl. Environ. Microbiol. 2000, 66, 1654– 1661,  DOI: 10.1128/AEM.66.4.1654-1661.2000
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    Phylogenetic relationships of butyrate-producing bacteria from the human gut
    Barcenilla, Adela; Pryde, Susan E.; Martin, Jennifer C.; Duncan, Sylvia H.; Stewart, Colin S.; Henderson, Colin; Flint, Harry J.
    Applied and Environmental Microbiology (2000), 66 (4), 1654-1661CODEN: AEMIDF; ISSN:0099-2240. (American Society for Microbiology)
    Butyrate is a preferred energy source for colonic epithelial cells and is thought to play an important role in maintaining colonic health in humans. In order to investigate the diversity and stability of butyrate-producing organisms of the colonic flora, anaerobic butyrate-producing bacteria were isolated from freshly voided human fecal samples from 3 healthy individuals: an infant, an adult omnivore, and an adult vegetarian. A 2nd isolation was performed on the same 3 individuals 1 yr later. Of a total of 313 bacterial isolates, 74 produced more than 2 mM butyrate in vitro. Butyrate-producing isolates were grouped by 16S ribosomal DNA (rDNA) PCR-restriction fragment length polymorphism anal. The results indicate very little overlap between the predominant ribotypes of the 3 subjects; furthermore, the flora of each individual changed significantly between the 2 isolations. Complete sequences of 16S rDNAs were detd. for 24 representative strains and subjected to phylogenetic anal. Eighty percent of the butyrate-producing isolates fell within the XIVa cluster of gram-pos. bacteria as defined by M. D. Collins et al. and A. Willems et al., with the most abundant group (10 of 24 or 42%) clustering with Eubacterium rectale, Eubacterium ramulus, and Roseburia cecicola. Fifty percent of the butyrate-producing isolates were net acetate consumers during growth, suggesting that they employ the butyryl CoA-acetyl CoA transferase pathway for butyrate prodn. In contrast, only 1% of the 239 non-butyrate-producing isolates consumed acetate.
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    Halfvarson, J.; Brislawn, C. J.; Lamendella, R.; Vázquez-Baeza, Y.; Walters, W. A.; Bramer, L. M.; D’Amato, M.; Bonfiglio, F.; McDonald, D.; Gonzalez, A. Dynamics of the human gut microbiome in inflammatory bowel disease. Nat. Microbiol 2017, 2, 17004,  DOI: 10.1038/nmicrobiol.2017.4
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    Dynamics of the human gut microbiome in inflammatory bowel disease
    Halfvarson, Jonas; Brislawn, Colin J.; Lamendella, Regina; Vazquez-Baeza, Yoshiki; Walters, William A.; Bramer, Lisa M.; D'Amato, Mauro; Bonfiglio, Ferdinando; McDonald, Daniel; Gonzalez, Antonio; McClure, Erin E.; Dunklebarger, Mitchell F.; Knight, Rob; Jansson, Janet K.
    Nature Microbiology (2017), 2 (1), 17004CODEN: NMAICH; ISSN:2058-5276. (Nature Publishing Group)
    Inflammatory bowel disease (IBD) is characterized by flares of inflammation with a periodic need for increased medication and sometimes even surgery. The etiology of IBD is partly attributed to a deregulated immune response to gut microbiome dysbiosis. Cross-sectional studies have revealed microbial signatures for different IBD subtypes, including ulcerative colitis, colonic Crohn's disease and ileal Crohn's disease. Although IBD is dynamic, microbiome studies have primarily focused on single time points or a few individuals. Here, we dissect the long-term dynamic behavior of the gut microbiome in IBD and differentiate this from normal variation. Microbiomes of IBD subjects fluctuate more than those of healthy individuals, based on deviation from a newly defined healthy plane (HP). Ileal Crohn's disease subjects deviated most from the HP, esp. subjects with surgical resection. Intriguingly, the microbiomes of some IBD subjects periodically visited the HP then deviated away from it. Inflammation was not directly correlated with distance to the healthy plane, but there was some correlation between obsd. dramatic fluctuations in the gut microbiome and intensified medication due to a flare of the disease. These results will help guide therapies that will redirect the gut microbiome towards a healthy state and maintain remission in IBD.
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    Mottawea, W.; Chiang, C.-K.; Mühlbauer, M.; Starr, A. E.; Butcher, J.; Abujamel, T.; Deeke, S. A.; Brandel, A.; Zhou, H.; Shokralla, S. Altered intestinal microbiota–host mitochondria crosstalk in new onset Crohn’s disease. Nat. Commun. 2016, 7, 13419,  DOI: 10.1038/ncomms13419
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    Altered intestinal microbiota-host mitochondria crosstalk in new onset Crohn's disease
    Mottawea, Walid; Chiang, Cheng-Kang; Muhlbauer, Marcus; Starr, Amanda E.; Butcher, James; Abujamel, Turki; Deeke, Shelley A.; Brandel, Annette; Zhou, Hu; Shokralla, Shadi; Hajibabaei, Mehrdad; Singleton, Ruth; Benchimol, Eric I.; Jobin, Christian; Mack, David R.; Figeys, Daniel; Stintzi, Alain
    Nature Communications (2016), 7 (), 13419CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    Intestinal microbial dysbiosis is assocd. with Crohn's disease (CD). However, the mechanisms leading to the chronic mucosal inflammation that characterizes this disease remain unclear. In this report, we use systems-level approaches to study the interactions between the gut microbiota and host in new-onset paediatric patients to evaluate causality and mechanisms of disease. We report an altered host proteome in CD patients indicative of impaired mitochondrial functions. In particular, mitochondrial proteins implicated in H2S detoxification are downregulated, while the relative abundance of H2S microbial producers is increased. Network correlation anal. reveals that Atopobium parvulum controls the central hub of H2S producers. A. parvulum induces pancolitis in colitis-susceptible interleukin-10-deficient mice and this phenotype requires the presence of the intestinal microbiota. Administrating the H2S scavenger bismuth mitigates A. parvulum-induced colitis in vivo. This study reveals that host-microbiota interactions are disturbed in CD and thus provides mechanistic insights into CD pathogenesis.
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    Marchesi, J. R.; Holmes, E.; Khan, F.; Kochhar, S.; Scanlan, P.; Shanahan, F.; Wilson, I. D.; Wang, Y. Rapid and noninvasive metabonomic characterization of inflammatory bowel disease. J. Proteome Res. 2007, 6, 546– 551,  DOI: 10.1021/pr060470d
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    Rapid and Noninvasive Metabonomic Characterization of Inflammatory Bowel Disease
    Marchesi, Julian R.; Holmes, Elaine; Khan, Fatima; Kochhar, Sunil; Scanlan, Pauline; Shanahan, Fergus; Wilson, Ian D.; Wang, Yulan
    Journal of Proteome Research (2007), 6 (2), 546-551CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
    Inflammatory bowel diseases (IBD) including Crohn's disease (CD) and ulcerative colitis (UC) have a major impact on the health of individuals and populations. Accurate diagnosis of inflammatory bowel disease (IBD) at an early stage, and correct differentiation between Crohn's disease (CD) and ulcerative colitis (UC), is important for optimum treatment and prognosis. The authors present here the first characterization of fecal exts. obtained from patients with CD and UC by employing a noninvasive metabonomics approach, which combines high resoln. 1H NMR spectroscopy and multivariate pattern recognition techniques. The fecal exts. of both CD and UC patients were characterized by reduced levels of butyrate, acetate, methylamine, and trimethylamine in comparison with a control population, suggesting changes in the gut microbial community. Also, elevated quantities of amino acids were present in the feces from both disease groups, implying malabsorption caused by the inflammatory disease or an element of protein losing enteropathy. Metabolic differences in fecal profiles were more marked in the CD group in comparison with the control group, indicating that the inflammation caused by CD is more extensive in comparison with UC and involves the whole intestine. Furthermore, glycerol resonances were a dominant feature of fecal spectra from patients with CD but were present in much lower intensity in the control and UC groups. This work illustrates the potential of metabonomics to generate novel noninvasive diagnostics for gastrointestinal diseases and may further our understanding of disease mechanisms.
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    Van Immerseel, F.; Ducatelle, R.; De Vos, M.; Boon, N.; Van De Wiele, T.; Verbeke, K.; Rutgeerts, P.; Sas, B.; Louis, P.; Flint, H. J. Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease. J. Med. Microbiol. 2010, 59, 141– 143,  DOI: 10.1099/jmm.0.017541-0
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    Butyric acid-producing anaerobic bacteria as a novel probiotic treatment approach for inflammatory bowel disease
    Van Immerseel Filip; Ducatelle Richard; De Vos Martine; Boon Nico; Van De Wiele Tom; Verbeke Kristin; Rutgeerts Paul; Sas Benedikt; Louis Petra; Flint Harry J
    Journal of medical microbiology (2010), 59 (Pt 2), 141-143 ISSN:.
    There is no expanded citation for this reference.
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    Miquel, S.; Martín, R.; Rossi, O.; Bermúdez-Humarán, L. G.; Chatel, J. M.; Sokol, H.; Thomas, M.; Wells, J. M.; Langella, P. Faecalibacterium prausnitzii and human intestinal health. Curr. Opin. Microbiol. 2013, 16, 255– 261,  DOI: 10.1016/j.mib.2013.06.003
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    Faecalibacterium prausnitzii and human intestinal health
    Miquel, S.; Martin, R.; Rossi, O.; Bermudez-Humaran, L. G.; Chatel, J. M.; Sokol, H.; Thomas, M.; Wells, J. M.; Langella, P.
    Current Opinion in Microbiology (2013), 16 (3), 255-261CODEN: COMIF7; ISSN:1369-5274. (Elsevier Ltd.)
    A review. Faecalibacterium prausnitzii is the most abundant bacterium in the human intestinal microbiota of healthy adults, representing more than 5% of the total bacterial population. Over the past five years, an increasing no. of studies have clearly described the importance of this highly metabolically active commensal bacterium as a component of the healthy human microbiota. Changes in the abundance of F. prausnitzii have been linked to dysbiosis in several human disorders. Administration of F. prausnitzii strain A2-165 and its culture supernatant have been shown to protect against 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in mice. Here, we discuss the role of F. prausnitzii in balancing immunity in the intestine and the mechanisms involved.
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    Tamanai-Shacoori, Z.; Smida, I.; Bousarghin, L.; Loreal, O.; Meuric, V.; Fong, S. B.; Bonnaure-Mallet, M.; Jolivet-Gougeon, A. Roseburia spp.: a marker of health?. Future Microbiol. 2017, 12, 157– 170,  DOI: 10.2217/fmb-2016-0130
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    Roseburia spp.: a marker of health?
    Tamanai-Shacoori, Zohreh; Smida, Imen; Bousarghin, Latifa; Loreal, Olivier; Meuric, Vincent; Fong, Shao Bing; Bonnaure-Mallet, Martine; Jolivet-Gougeon, Anne
    Future Microbiology (2017), 12 (2), 157-170CODEN: FMUIAR; ISSN:1746-0913. (Future Medicine Ltd.)
    A review. The genus Roseburia consists of obligate Gram-pos. anaerobic bacteria that are slightly curved, rod-shaped and motile by means of multiple subterminal flagella. It includes five species: Roseburia intestinalis, R. hominis, R. inulinivorans, R. faecis and R. cecicola. Gut Roseburia spp. metabolize dietary components that stimulate their proliferation and metabolic activities. They are part of commensal bacteria producing short-chain fatty acids, esp. butyrate, affecting colonic motility, immunity maintenance and anti-inflammatory properties. Modification in Roseburia spp. representation may affect various metabolic pathways and is assocd. with several diseases (including irritable bowel syndrome, obesity, Type 2 diabetes, nervous system conditions and allergies). Roseburia spp. could also serve as biomarkers for symptomatic pathologies (e.g., gallstone formation) or as probiotics for restoration of beneficial flora.
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    Li, Y.; Xia, S.; Jiang, X.; Feng, C.; Gong, S.; Ma, J.; Fang, Z.; Yin, J.; Yin, Y. Gut Microbiota and Diarrhea: An Updated Review. Microbiology 2021, 11, 625210,  DOI: 10.3389/fcimb.2021.625210
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    Gut Microbiota and Diarrhea: An Updated Review
    Li Yunxia; Xia Siting; Jiang Xiaohan; Feng Can; Gong Saiming; Ma Jie; Yin Jie; Yin Yulong; Fang Zhengfeng; Yin Yulong
    Frontiers in cellular and infection microbiology (2021), 11 (), 625210 ISSN:.
    Diarrhea is a common problem to the whole world and the occurrence of diarrhea is highly associated with gut microbiota, such as bacteria, fungi, and viruses. Generally, diarrheal patients or animals are characterized by gut microbiota dysbiosis and pathogen infections may lead to diarrheal phenotypes. Of relevance, reprograming gut microbiota communities by dietary probiotics or fecal bacteria transplantation are widely introduced to treat or prevent diarrhea. In this review, we discussed the influence of the gut microbiota in the infection of diarrhea pathogens, and updated the research of reshaping the gut microbiota to prevent or treat diarrhea for the past few years. Together, gut microbiota manipulation is of great significance to the prevention and treatment of diarrhea, and further insight into the function of the gut microbiota will help to discover more anti-diarrhea probiotics.
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    Infectious diarrhea: Cellular and molecular mechanisms
    Hodges Kim; Gill Ravinder
    Gut microbes (2010), 1 (1), 4-21 ISSN:.
    Diarrhea caused by enteric infections is a major factor in morbidity and mortality worldwide. An estimated 2-4 billion episodes of infectious diarrhea occur each year and are especially prevalent in infants. This review highlights the cellular and molecular mechanisms underlying diarrhea associated with the three classes of infectious agents, i.e., bacteria, viruses and parasites. Several bacterial pathogens have been chosen as model organisms, including Vibrio cholerae as a classical example of secretory diarrhea, Clostridium difficile and Shigella species as agents of inflammatory diarrhea and selected strains of pathogenic Escherichia coli (E. coli) to discuss the recent advances in alteration of epithelial ion absorption. Many of the recent studies addressing epithelial ion transport and barrier function have been carried out using viruses and parasites. Here, we focus on the rapidly developing field of viral diarrhea including rotavirus, norovirus and astrovirus infections. Finally we discuss Giardia lamblia and Entamoeba histolytica as examples of parasitic diarrhea. Parasites have a greater complexity than the other pathogens and are capable of creating molecules similar to those produced by the host, such as serotonin and PGE(2). The underlying mechanisms of infectious diarrhea discussed include alterations in ion transport and tight junctions as well as the virulence factors, which alter these processes either through direct effects or indirectly through inflammation and neurotransmitters.
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    Levine, M. M. Escherichia coli that cause diarrhea: enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic, and enteroadherent. J. Infect. Dis. 1987, 155, 377– 389,  DOI: 10.1093/infdis/155.3.377
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    Escherichia coli that cause diarrhea: enterotoxigenic, enteropathogenic, enteroinvasive, enterohemorrhagic, and enteroadherent
    Levine M M
    The Journal of infectious diseases (1987), 155 (3), 377-89 ISSN:0022-1899.
    There are four major categories of diarrheagenic Escherichia coli: enterotoxigenic (a major cause of travelers' diarrhea and infant diarrhea in less-developed countries), enteroinvasive (a cause of dysentery), enteropathogenic (an important cause of infant diarrhea), and enterohemorrhagic (a cause of hemorrhagic colitis and hemolytic uremic syndrome). Besides manifesting distinct clinical patterns, these categories of E. coli differ in their epidemiology and pathogenesis and in their O:H serotypes. Common features (albeit distinct for each category) include plasmid-encoded virulence properties, characteristic interactions with intestinal mucosa, and elaboration of various types of enterotoxins or cytotoxins. A less-well-defined fifth category of diarrheagenic E. coli is that of enteroadherent E. coli, so far identifiable only by their pattern of adherence to Hep-2 cells in tissue culture.
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    Gallo, A.; Passaro, G.; Gasbarrini, A.; Landolfi, R.; Montalto, M. Modulation of microbiota as treatment for intestinal inflammatory disorders: An uptodate. World J. Gastroenterol. 2016, 22, 7186– 7202,  DOI: 10.3748/wjg.v22.i32.7186
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    Modulation of microbiota as treatment for intestinal inflammatory disorders: An uptodate
    Gallo Antonella; Passaro Giovanna; Gasbarrini Antonio; Landolfi Raffaele; Montalto Massimo
    World journal of gastroenterology (2016), 22 (32), 7186-202 ISSN:.
    Alterations of intestinal microflora may significantly contribute to the pathogenesis of different inflammatory and autoimmune disorders. There is emerging interest on the role of selective modulation of microflora in inducing benefits in inflammatory intestinal disorders, by as probiotics, prebiotics, synbiotics, antibiotics, and fecal microbiota transplantation (FMT). To summarize recent evidences on microflora modulation in main intestinal inflammatory disorders, PubMed was searched using terms microbiota, intestinal flora, probiotics, prebiotics, fecal transplantation. More than three hundred articles published up to 2015 were selected and reviewed. Randomized placebo-controlled trials and meta-analysis were firstly included, mainly for probiotics. A meta-analysis was not performed because of the heterogeneity of these studies. Most of relevant data derived from studies on probiotics, reporting some efficacy in ulcerative colitis and in pouchitis, while disappointing results are available for Crohn's disease. Probiotic supplementation may significantly reduce rates of rotavirus diarrhea. Efficacy of probiotics in NSAID enteropathy and irritable bowel syndrome is still controversial. Finally, FMT has been recently recognized as an efficacious treatment for recurrent Clostridium difficile infection. Modulation of intestinal flora represents a very interesting therapeutic target, although it still deserves some doubts and limitations. Future studies should be encouraged to provide new understanding about its therapeutical role.
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    Bron, P. A.; Kleerebezem, M.; Brummer, R. J.; Cani, P. D.; Mercenier, A.; MacDonald, T. T.; Garcia-Ródenas, C. L.; Wells, J. M. Can probiotics modulate human disease by impacting intestinal barrier function?. Br. J. Nutr. 2017, 117, 93– 107,  DOI: 10.1017/S0007114516004037
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    Can probiotics modulate human disease by impacting intestinal barrier function?
    Bron, Peter A.; Kleerebezem, Michiel; Brummer, Robert-Jan; Cani, Patrice D.; Mercenier, Annick; MacDonald, Thomas T.; Garcia-Rodenas, Clara L.; Wells, Jerry M.
    British Journal of Nutrition (2017), 117 (1), 93-107CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    Intestinal barrier integrity is a prerequisite for homeostasis of mucosal function, which is balanced to maximise absorptive capacity, while maintaining efficient defensive reactions against chem. and microbial challenges. Evidence is mounting that disruption of epithelial barrier integrity is one of the major etiol. factors assocd. with several gastrointestinal diseases, including infection by pathogens, obesity and diabetes, necrotising enterocolitis, irritable bowel syndrome and inflammatory bowel disease. The notion that specific probiotic bacterial strains can affect barrier integrity fuelled research in which in vitro cell lines, animal models and clin. trials are used to assess whether probiotics can revert the diseased state back to homeostasis and health. This review catalogues and categorises the lines of evidence available in literature for the role of probiotics in epithelial integrity and, consequently, their beneficial effect for the redn. of gastrointestinal disease symptoms.
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    Zhang, S.; Wang, R.; Li, D.; Zhao, L.; Zhu, L. Role of gut microbiota in functional constipation. Gastroenterol. Rep. 2021, 9, 392– 401,  DOI: 10.1093/gastro/goab035
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    Role of gut microbiota in functional constipation
    Zhang Shengsheng; Wang Ruixin; Li Danyan; Zhao Luqing; Zhu Lixin
    Gastroenterology report (2021), 9 (5), 392-401 ISSN:2052-0034.
    Functional constipation (FC) is common, yet the etiology is not clear. Accumulating evidence suggests an association between FC and abnormal gut microbiota. The relationship between the gut microbiota and the gut transit is likely bidirectional. This review summarizes the current evidence regarding the impact of gut microbiota on the pathogenesis of FC. By modulating the colonic motility, secretion, and absorption, gut microbiota may contribute to the development of FC through microbial metabolic activities involving bile acids, short-chain fatty acids, 5-hydroxytryptamine, and methane. In support of the key roles of the gut microbiota in FC, treatment with probiotics, prebiotics, synbiotics, and traditional Chinese medicine often result in compositional and functional changes in the gut microbiota. Further studies on the pathogenesis of FC and the therapeutic mechanism of microecological agents will provide a knowledge base for better management of FC.
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    Zoppi, G.; Cinquetti, M.; Luciano, A.; Benini, A.; Muner, A.; Bertazzoni Minelli, E. The intestinal ecosystem in chronic functional constipation. Acta Paediatr. 1998, 87, 836– 841,  DOI: 10.1111/j.1651-2227.1998.tb01547.x
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    The intestinal ecosystem in chronic functional constipation
    Zoppi G; Cinquetti M; Luciano A; Benini A; Muner A; Bertazzoni Minelli E
    Acta paediatrica (Oslo, Norway : 1992) (1998), 87 (8), 836-41 ISSN:0803-5253.
    Chronic functional constipation is common in infants, and the bacterial composition of stools in this condition is not known. The study aims were to: (i) investigate the composition of the intestinal ecosystem in chronic functional constipation; (ii) establish whether the addition of the water-holding agent calcium polycarbophil to the diet induces an improvement in constipation; and (iii) determine the composition of the intestinal ecosystem after the use of this agent. In total, 42 children (20F, 22M; mean age: 8.6 +/- 2.9 y) were studied. Twenty-eight children with functional chronic constipation without anatomical disorders were treated double-blind in random sequence for 1 month with an oral preparation of calcium polycarbophil (0.62 g/twice daily) or placebo. Intestinal flora composition was evaluated by standard microbiological methods and biochemical assays on faecal samples collected before and after treatment. Fourteen healthy children were studied as controls. The results show that (i) the constipated children presented a significant increase in clostridia and bifidobacteria in faeces compared to healthy subjects--different species of clostridia and enterobacteriaceae were frequently isolated; no generalized overgrowth was observed; Clostridia outnumbered bacteroides and E. coli mean counts by 2-3log, while bacteroides and E. coli counts were similar (5-6 log10/g fresh faeces); these intestinal disturbances could be defined as a dysbiosis, i.e. a quantitative alteration in the relative proportions of certain intestinal bacterial species. (ii) Clinical resolution of constipation was achieved only in 43% of treated children and an improvement in 21% (one bowel movement every 2 d). (iii) Calcium polycarbophil treatment induced no significant changes in the composition of the intestinal ecosystem, nor in blood chemistry parameters.
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    Khalif, I. L.; Quigley, E. M.; Konovitch, E. A.; Maximova, I. D. Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation. Dig. Liver Dis. 2005, 37, 838– 849,  DOI: 10.1016/j.dld.2005.06.008
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    Alterations in the colonic flora and intestinal permeability and evidence of immune activation in chronic constipation
    Khalif I L; Quigley E M M; Konovitch E A; Maximova I D
    Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver (2005), 37 (11), 838-49 ISSN:1590-8658.
    BACKGROUND: Disturbances in bowel function in chronic constipation could result in changes in the colonic flora and lead to disordered immunity and to decreased resistance to pathogenic flora. AIM: To investigate systemic immunity, the faecal flora and intestinal permeability in patients with chronic constipation, under basal conditions and following therapy with the laxative Bisacodyl. METHODS: Intestinal permeability, faecal flora analysis, T- and B-lymphocyte numbers, T-cell subpopulations, lymphocyte proliferation, phagocytosis, intracellular killing of Staphylococcus aureus by neutrophils, as well as circulating levels of immunoglobulins, immune complexes and antibacterial antibodies were assessed in 57 patients with functional constipation. In 12 patients with severely delayed transit, investigations were repeated following therapy with Bisacodyl. RESULTS: Ovalbumin concentrations, in serum, were higher in constipated patients (28.2+/-4.1 ng/ml versus 1.0+/-0.4 ng/ml, p < 0.05). Elevated counts of CD3+, CD4+, CD25+ cells, increased spontaneous proliferation of lymphocytes, elevated titres of antibodies to Escherichia coli and S. aureus, diminished counts of CD72+ B cells, diminished lymphocyte proliferation under phytohemagglutinin (PHA) stimulation and a diminished phagocytic index for both neutrophils and monocytes were found in the constipated patients. Concentrations of Bifidobacterium and Lactobacillus were significantly lower in constipated patients; potentially pathogenic bacteria and/or fungi were increased. Therapy with Bisacodyl resulted in normalisation of the faecal flora, a reduction in ovalbumin concentration and return towards normal for certain immunologic parameters. CONCLUSION: Constipation is associated with striking changes in the faecal flora, intestinal permeability and the systemic immune response. Relief of constipation tends to normalise these findings suggesting that these changes are secondary to, rather than a cause of, constipation.
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    Kim, S. E.; Choi, S. C.; Park, K. S.; Park, M. I.; Shin, J. E.; Lee, T. H.; Jung, K. W.; Koo, H. S.; Myung, S. J. Change of Fecal Flora and Effectiveness of the Short-term VSL#3 Probiotic Treatment in Patients With Functional Constipation. J. Neurogastroenterol. Motil. 2015, 21, 111– 120,  DOI: 10.5056/jnm14048
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    Change of Fecal Flora and Effectiveness of the Short-term VSL#3 Probiotic Treatment in Patients With Functional Constipation
    Kim Seong-Eun; Choi Suck Chei; Park Kyung Sik; Park Moo In; Shin Jeong Eun; Lee Tae Hee; Jung Kee Wook; Myung Seung-Jae; Koo Hoon Sup
    Journal of neurogastroenterology and motility (2015), 21 (1), 111-20 ISSN:2093-0879.
    BACKGROUND/AIMS: We investigated gut flora characteristics in patients with functional constipation (FC) and influences of short-term treatment with VSL#3 probiotic on flora and symptom improvement. METHODS: Thirty patients fulfilling Rome III criteria for FC and 30 controls were enrolled. Fecal samples were obtained before and after VSL#3 intake (one sachet twice daily for 2 weeks) and flora were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Symptom changes were also investigated. RESULTS: The fold differences in Bifidobacterium and Bacteroides species were significantly lower in feces from FC, compared to in controls (P = 0.030 and P = 0.021). After taking VSL#3, the fold differences in Lactobacillus, Bifidobacterium and Bacteroides species increased in controls (P = 0.022, P = 0.018, and P = 0.076), but not in FC. Mean Bristol scores and complete spontaneous bowel movements (CSBMs)/week increased significantly in FC after ingesting VSL#3 (both P < 0.001). Relief of subjective CSBM frequency, stool consistency and abdominal bloating were reported in 70%, 60%, and 47% of patients. After VSL#3 cessation, 44.4% of patients with symptom improvement experienced constipation recurrence mostly within one month. CONCLUSIONS: Bifidobacterium and Bacteroides species might be quantitatively altered in FC. A short-term VSL#3 treatment can improve clinical symptoms of FC. Further studies are needed to investigate VSL#3's additional effects beyond altering gut flora to allevate constipation.
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    Zhu, L.; Liu, W.; Alkhouri, R.; Baker, R. D.; Bard, J. E.; Quigley, E. M.; Baker, S. S. Structural changes in the gut microbiome of constipated patients. Physiol. Genomics 2014, 46, 679– 686,  DOI: 10.1152/physiolgenomics.00082.2014
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    Structural changes in the gut microbiome of constipated patients
    Zhu, Lixin; Liu, Wensheng; Alkhouri, Razan; Baker, Robert D.; Bard, Jonathan E.; Quigley, Eamonn M.; Baker, Susan S.
    Physiological Genomics (2014), 46 (18), 679-686CODEN: PHGEFP; ISSN:1094-8341. (American Physiological Society)
    Previous studies using culture-based methods suggested an assocn. between constipation and altered abundance of certain taxa of the colonic microbiome. We aim to examine the global changes in gut microbial compn. of constipated patients. A cross-sectional pilot study using 16S rRNA gene pyrosequencing was performed to compare stool microbial compn. of eight constipated patients and 14 nonconstipated controls. Only obes