Exploring the Preventive and Therapeutic Mechanisms of Probiotics in Chronic Kidney Disease through the Gut–Kidney Axis

Gut dysbiosis contributes to deterioration of chronic kidney disease (CKD). Probiotics are a potential approach to modulate gut microbiota and gut-derived metabolites to alleviate CKD progression. We aim to provide a comprehensive view of CKD-related gut dysbiosis and a critical perspective on probiotic function in CKD. First, this review addresses gut microbial alterations during CKD progression and the adverse effects associated with the changes in gut-derived metabolites. Second, we conduct a thorough examination of the latest clinical trials involving probiotic intervention to unravel critical pathways via the gut–kidney axis. Finally, we propose our viewpoints on limitations, further considerations, and future research prospects of probiotic adjuvant therapy in alleviating CKD progression. Enhancing our understanding of host–microbe interactions is crucial for gaining precise insights into the mechanisms through which probiotics exert their effects and identifying factors that influence the effectiveness of probiotics in developing strategies to optimize their use and enhance clinical outcomes.


INTRODUCTION
Chronic kidney disease (CKD) is characterized by a substantial loss of kidney function and is associated with consistent exposure to numerous risk factors such as hypertension, diabetes mellitus, and obesity, leading to the irreversible progressive decline of kidney excretory function.The accumulation of uremic toxins in the circulation that are normally excreted by healthy kidneys causes massive damage to the kidney.Typically, kidney fibrosis is involved in CKD development, leading to myofibroblast activation, migration, accumulation of extracellular matrix, and kidney failure. 1 CKD also impacts other organs and tissues, especially the cardiovascular system.Left ventricular hypertrophy is highly prevalent in patients with CKD, which is strongly associated with systolic hypertension and eventually results in heart failure, a leading cause of morbidity and mortality in this population. 2,3he CKD diagnosis is based on kidney function and structure abnormalities that persist for >3 consecutive months.The Kidney Disease Improving Global Outcomes (KDIGO) classifies CKD based on the estimated glomerular filtration rate (eGFR) into five stages: >90 mL/min per 1.73 m 2 (stage 1), 60−89 mL/min per 1.73 m 2 (stage 2), 30−59 mL/min per 1.73 m 2 (stage 3), 15−29 mL/min per 1.73 m 2 (stage 4), and <15 mL/min per 1.73 m 2 (stage 5).The extent of albuminuria is also an additional indicator of end-stage renal disease (ESRD) progression. 4he global CKD prevalence is increasing, affecting over 10% of the global population and accounting for over 843.6 million individuals worldwide. 5Unfortunately, there is no cure for CKD, with treatments, including lifestyle changes, medication, and dialysis, only assisting in relieving symptoms and delaying their progression.A kidney transplant may also be a treatment option for patients suffering from ESRD.However, the limited number of donated kidneys and lengthy waiting periods impede its accessibility.Therefore, CKD is becoming a severe public health issue, requiring a better solution to ameliorate and alleviate its progression. 6−9 Therefore, strategies based on microbiota-based interventions could be considered preventive and therapeutic approaches to modulate gut microbiota and their metabolites to alleviate CKD progression.Probiotics are "live microorganisms that, when administered in adequate amounts, exist a health benefit on the host". 10They are well-recognized for modulating gut microbiota, and research is ongoing regarding their efficacy in preventing and managing CKD.The efficacy of probiotics in decreasing uremic toxin production and improving renal function has been investigated using in vitro models 11,12 and various animal 11,13 and human CKD studies. 14o provide a critical perspective on the potential of probiotics as preventive and therapeutic approaches in CKD, we first systematically delve into gut dysbiosis and its interplay with gut microbiota, associated metabolites, and CKD progression.Subsequently, we evaluate the latest studies examining the efficacy of probiotics in clinical cohorts and comprehensively review their mechanisms of action in CKD through the gut−kidney axis.Finally, we discuss the limitations, further considerations, and future research prospects regarding the utilization of probiotics as adjuvant therapy to enhance outcomes in patients with CKD.

STRONG LINK BETWEEN CKD AND GUT MICROBIAL DYSBIOSIS
The intestinal microbiota is markedly altered in CKD due to multifactorial causes, including iatrogenic effects and altered physiological conditions. 15,16Antibiotics, phosphate binders, dietary restriction, and low fiber consumption lead to slow intestinal transit, impaired protein assimilation, metabolic acidosis, and constipation. 17CKD-induced adaptive secretion of uric acid by the colon also limits the increase in serum uric acid concentration. 18More undigested protein and urea/uric acid in the colon enrich the proliferation of proteolytic bacteria with urease, uricase, phenol-, and indole-forming enzymes, whereas the short-chain fatty acid-producing bacteria are decreased. 9The increased intestinal pH through the augmented secretion of urea into the gut, along with limited carbohydrate fermentation, favors disruption of the intestinal epithelial barrier, and the production of phenolic and indolic compounds by colonic bacteria. 19This CKD-induced gut dysbiosis increases the production of GDUT and decreases the level of short-chain fatty acid (SCFA) such as butyric acid.The alteration of the gut environment affects the gut barrier by disrupting the colonic epithelial tight junctions, which in turn facilitates the movement of endotoxin, pathogenic microbes, and bacterial fragments into the systemic circulation that triggers inflammation. 20dditionally, the bladder microbiotas also plays a pivotal role in urinary tract infections, interstitial cystitis, urinary incontinence, and kidney stones. 21To date, the literature discussing the relationship between gut microbiota and bladder microbiota is limited.However, kidney function undoubtedly impacts the bladder microbiota, as evidenced by Hrbacek et al.  (2022), who found distinct overall microbial compositions between patients with CKD and healthy individuals. 22urthermore, Kramer et al. (2018) discovered that among patients with CKD, those with better kidney function (higher eGFR) exhibited greater diversity in their urinary microbiota. 23he composition of a patient's urine, which affects the urinary microbiota, can be influenced by kidney function.For instance, a significant decrease in eGFR leads to reduced concentrations of uromodulin (also known as Tamm−Horsfall glycoprotein), produced by renal tubules.Because uromodulin has bacteriostatic properties, its diminished presence affects bacterial growth. 24Therefore, CKD affects the diversity and composition of the bladder/urinary microbiota, subsequently influencing urinary tract symptoms and bladder health.
2.1.Gut-Derived Uremic Toxins Play a Significant Role in CKD Progression.Uremic retention solutes, socalled uremic toxins, are normally excreted by the healthy kidney but accumulate in patients with CKD and contribute to biological dysfunction. 25They can be categorized into three major types: (1) free water-soluble molecules with a molecular weight <500 Da that readily pass the dialysis filter with less toxicity (e.g., trimethylamine, urea, oxalate, creatinine); (2) middle molecules with a molecular weight ≥500 Da that have limited passing capacity due to the dialysis membrane characteristics (e.g., adiponectin, cystatin C, TNF-α); (3) low molecular weight protein-bound molecules which their dialytic removal predominantly depends on the equilibrium between bound and free molecules (e.g., indoxyl sulfate, pcresyl sulfate) (Table 1). 26Uremic toxins can also be classified according to the site of origin, 27 such as GDUT, produced from microbial metabolism.Gut microorganisms can deaminate or decarboxylate amino acids. 28Deamination of aromatic

Journal of Agricultural and Food Chemistry
amino acids (tyrosine, tryptophan, and phenylalanine) leads to the formation of phenolic compounds (indole, p-cresol, and phenol).Consequently, gut microbial dysbiosis could increase the production of GDUT precursors and generate more uremic toxins. 29DUTs have recently gained attention for their role in CKD as they cause detrimental effects on renal, vascular, cardiac, and other tissues and organs. 30−33 Dietary protein is the source of IS, IAA, PCS, and PAG, whereas IS and IAA are protein-bound uremic toxins generated from dietary tryptophan.Indole, a precursor of IS, is a product of tryptophan produced by intestinal microorganisms, which is converted into an IS through sulfation in the liver after intestinal absorption.IAA biosynthesis is linked to the metabolism of tryptophan and involves the elimination of amino and carboxyl groups from tryptophan α-carbon via intermediates such as indolepyruvate, indoleacetamide, or indoleacetonitrile. 34PCS and PAG are derived from tyrosine and phenylalanine, which are metabolized and converted into p-cresol by intestinal proteolytic microorganisms in the colon, then absorbed into the circulation and subsequently undergo oxidization and sulfation by the liver to produce PCS. 35PAG biosynthesis is also involved in phenylalanine metabolism.Gut microbiota fermented unabsorbed phenylalanine to produce phenylacetate and conjugate with glutamine to generate PAG in the liver. 36Trimethylamine (TMA), a precursor of TMAO, is produced by bacterial metabolism of quaternary amines such as choline, phosphatidylcholine, betaine, and L-carnitine.TMA is subsequently absorbed and oxidized by the hepatic enzyme flavin monooxygenase isoform 3 (FMO3) to form TMAO in the liver. 3S, IAA, PCS, and PAG are the protein-bound molecules with high binding affinity for albumin. 37These albumin complexes are transported to proximal renal tubular cells and excreted via organic anion transporter (OAT) 1 and OAT3, located on the basolateral membrane of tubular cells. 38OATs are inhibited by high levels of GDUTs as kidney function declines. 39Accumulation of IS, IAA, PCS, and PAG in circulation is toxic due to the limited dialytic clearance by conventional hemodialysis and their adverse health impact, resulting in cardiovascular complications and mortality in patients with CKD. 40Additionally, IS and PCS increase oxidative stress in renal tubular cells associated with CKD progression and its comorbidities. 41TMAO is efficiently removed by dialysis, but it is a risk factor for CKD and cardiovascular disease (CVD). 42A clinical trial of 4007 patients concluded that elevated plasma TMAO levels are associated with an increased risk of incident major adverse cardiovascular events such as death, myocardial infarction, or stroke during three years of follow-up. 43

Gut Microbial Alternation in Patients with CKD is a Potential Biomarker for the Detection of Kidney
Disease.Numerous studies have reported CKD-associated changes in the human gut microbiome composition, indicating strong links between CKD and gut microbial dysbiosis (Table 2).Based on previous studies with more than 75% consistent findings, patients with kidney disease have a higher relative abundance of Proteobacteria, Enterobacteriaceae, Streptococcaceae, Streptococcus, Bilophila, Desulfovibrio, Klebsiella, Escher-ichia-Shigella, and lower abundance of Firmicutes, Prevotellaceae, Prevotella, Prevotella 9, Alcaligenaceae, Roseburia, Faecalibacterium, and Faecalibacterium prausnitzii in comparison to healthy subjects. 44Immunoglobulin A (IgA) nephropathy patients have increased Ruminococcaceae, Lachnospiraceae, Eubacteriaceae, and Streptococcaeae in Firmicutes, while Bif idobacterium and species of Clostridium, Enterococcus, and Lactobacillus were decreased compared to healthy controls. 45en et al. investigated differences in the microbial structure based on different CKD stages.Linear discriminant analysis (LDA) indicated that Tenericutes and Mollicutes were enhanced in CKD stages 1−2, Parasutterella was enriched in CKD stages 3−4, and Akkermansia, Blautia, and Verrucomicrobia were augmented in CKD stage 5. 46 Alphaproteobacteria, Streptococcaceae, and Streptococcus were more abundant in adults receiving hemodialysis or peritoneal dialysis than in controls. 44uirong et al. evaluated the gut microbiota composition of kidney transplant (KT) recipients reporting that their gut microbial profiles were similar to patients with CKD stages 3− 4, with increased Bacteroidetes, Proteobacteria, Clostridiales, and Enterobacteriaceae but decreased Firmicutes, Lachnospiraceae, Ruminococcaceae, and Faecalibacterium compared to healthy controls. 47hese differences in bacterial phyla and genera between patients with CKD and healthy controls suggest that the alterations in bacterial taxa may offer valuable insights into predicting CKD progression.Akkermansia (the area under the receiver operating characteristic curve (AUC) = 0.753), 48 Lactobacillus (AUC = 0.792), 48 Ruminococcus (AUC = 0.771), 49 and Roseburia (AUC = 0.803) 49 51 Other families, such as Bif idobacteriaceae, Coriobacteriaceae, Enterobacteriaceae, Propionibacteriaceae, and Rikenellaceae, are involved in indole production. 51A high abundance of bacterial families with urease, uricase, and indole and p-cresol-forming enzymes could accelerate CKD progression by affecting the synthesis of uremic toxins. 9.3.2.Bacterial Families Possessing the Ability to Synthesize SCFA.Lactobacillaceae and Prevotellaceae are butyrate-producing bacteria with phosphotransbutyrylase and butyrate kinase activity, which are reduced in ESRD patients.9 Butyrate exerts the most biological activity in SCFA and stimulates mucin synthesis to protect intestinal homeostasis and intact antibacterial barrier.52 Integration of the intestinal epithelium is crucial to prevent the systemic translocation of microbial toxins and pathogens into the systemic circulation with widespread damage throughout the body.53 Gryp et al. revealed a lower abundance of SCFA-producing bacteria, Bif idobacterium spp., and Streptococcus spp. in patients with CKD.51 Similarly, Wang et al. reported a decrease in SCFAproducing bacteria in the CKD group, including Ruminococcaceae, Eubacteriaceae, Oscillospiraceae, Lachnospiraceae, Clostridiaceae, Oscillospiraceae, Veillonellaceae, Rikenellaceae, Bif idobacteriaceae, and Lactobacillaceae.7 2.3.3. Bterial Families Possessing/Producing Lipopolysaccharide (LPS).LPS constitutes the outer membranes of most Gram-negative bacteria. 54Gram-negative bacterial families, such as Corynebacteriaceae, Pseudomonadaceae, and Enterobacteriaceae, are enriched in the CKD population.8,9 LPS activates the NF-κB pathway and mTOR signaling in macrophages to stimulate the production of proinflammatory cytokines (IL-β1, TGF-β1, MCP-1, and TNF-α), leading to the CKD progression with kidney inflammatory injuries and fibrosis.55,56 2.4. Th Causal Relationship Between CKD and Gut Dysbiosis Remains Unclear.Clinical studies have highlighted microbial composition and its bidirectional relationship with CKD, contributing to disease progression.57 However, the causality between CKD progression and gut dysbiosis has not been fully elucidated; therefore, further exploration of the causal relationship between gut dysbiosis and CKD is required to clarify the potential pathogenesis of CKD progression.Xu et al. transferred fecal microbiota from patients with CKD and healthy controls into antibiotic-treated C57BL/6 mice, showing that the CKD fecal samples resulted in significantly higher plasma TMAO levels in mice with increased Clostridium and Parabacteroides, along with decreased Ruminococcaceae and Megamonas compared to the group that received healthy fecal microbes.8 Wang et al. revealed that ESRD-specific gut microbiota induced systemic inflammation and colonic epithelial barrier defects in germ-free rats with a significant increase in fecal phenol and phenol-producing bacteria (Bacteroides and Escherichia), suggesting that gut microbiota from ESRD patients led to gut barrier defects by excessive phenol production.58 Until now, manipulating gut microbiota via fecal microbiota transplantation (FMT) from patients with ESRD or CKD into germ-free animals has not provided convincing evidence to illustrate the detrimental effect on renal function.The parameters of FMT operation, including frequency, dosage of fecal microbiota, and duration, should be considered in future investigations to establish the causative relationship between gut dysbiosis and CKD. Hoever, several studies demonstrated that the gut microbiota significantly aggravate or alleviate CKD progression.Fecal microbiota from CKD rats transplanted into 5/6 nephrectomy rats increased proteinbound uremic toxins and a decline in renal function compared to the nontransplanted 5/6 nephrectomy rats.However, these adverse effects were significantly mitigated when fecal microbiota from healthy recipients was transplanted.59 Similarly, CKD mice that underwent FMT from healthy mice demonstrated a noticeable improvement in gut microbiota disturbance and a reduction in PCS accumulation.60 Collectively, these studies showed that manipulating the gut microbiota in CKD is a potential approach to alleviate disease progression.

ALLEVIATING EFFECTS OF PROBIOTICS ON CKD VIA THE GUT−KIDNEY AXIS
The strong linkage between CKD and gut microbial dysbiosis suggests that modifying the gut microbiota could potentially diminish uremic toxin levels and associated adverse effects.Probiotics, defined as "live microorganisms that, when administered in adequate amounts, exist a health benefit on the host" 10 exert a positive impact on CKD alleviation by attenuating gut microbiome disturbances.

3.1.
In Vitro Preselection Platforms with in Vivo Verification are Feasible Strategies for Potential CKD-Alleviating Probiotic Screening.Preselection of suitable probiotic strains based on their beneficial attributes is crucial because their physiological functions are highly strainspecific. 61However, most studies have not elucidated the probiotic selection in detail, so the development of an in vitro screening platform is essential for providing an opportunity to mass-screen potential microorganisms. 11A previous study created a probiotic screening platform based on gut-derived uremic toxin-reducing probiotics and successfully preselected three probiotic strains, Lactobacillus paracasei subsp.paracasei BCRC 12188, Streptococcus salivarius subsp.thermophiles BCRC 13869, and Lactobacillus plantarum subsp.plantarum BCRC 12251 due to their ability to reduce IS in vitro. 12In vivo, oral administration of a combination of the three strains (Pm1) significantly suppressed IS accumulation in the serum, kidneys, and liver in a cisplatin-induced acute kidney injury mouse model. 12A cisplatin-induced minipig model also demonstrated a lower incidence of lesions, including atrophy, mononuclear inflammation, cell infiltration, and interstitial fibrosis in renal tubules in the high-dosage Pm1 group. 62A significant reduction of blood urea nitrogen (BUN) and creatinine (CRE) was also observed compared with the cisplatin group.The possible mechanism involves the downregulation of inflammatory cytokine production and the upregulation of plasma superoxide dismutase activity.The modulation of gut microbiota was also observed after Pm1 intervention, with a decreasing abundance of Gram-negative bacteria contributing to reduced inflammation and apoptosis in the kidney, preventing CKD progression. 62 recent study preselected two potential strains (Lactobacillus plantarum subsp.plantarum MFM 30−3 and Lactobacillus paracasei subsp.paracasei MFM 18) using a modified screening platform to determine the ability to remove uremic toxin precursors in simulated intestinal juice. 11Furthermore, an in vivo study in an adenine-induced renal injury mouse model demonstrated that the renal dysfunction features, including high levels of BUN, CRE, IS, and PCS in plasma, interstitial fibrosis, and kidney injuries, were reduced by intervention with the preselected probiotics, which was accompanied by improvement of gut dysbiosis and prevention of intestinal barrier disruption via modulation of metabolite production. 11eveloping an in vitro screening platform to identify strains that can reduce uremic toxin levels with further in vivo verification is a feasible strategy for potential CKD-alleviating probiotic screening.However, the speed of removal of a toxic compound is strain-specific and affected by the physiological state of the strain, pH, and nutrients. 63Other selection criteria, including decreasing indole production by Escherichia coli, 64 antipathogenic, 64,65 antioxidant, 66,67 anti-inflammatory, 68,69 and gut barrier protection 70,71 are highly recommended to increase the therapeutic potentials for CKD.Bif idobacterium infantis: 1 × 10 9 Bif idobacterium longum: 1 × 10 9 Lactobacillus acidophilus: 1 × 10 9 Lactobacillus (Ligilactobacillus) salivarius: 1 ×    3 summarizes the clinical trials examining the use of probiotics in patients with CKD.A total of 12 trials each were conducted for both dialysis patients and nondialyzed patients with stage 2−5 CKD.One trial was conducted on kidney transplantation patients.The sample size ranged between 9 and 70 patients, and the study duration varied from 2 to 24 weeks.Probiotic agent dosages ranged from 1.1 × 10 7 to 2.0 × 10 12 CFU.The probiotic agents were in various forms, including sachets, powders, and capsule.

The Positive Effects on CKD Alleviation after Probiotics Intervention. Table
The various probiotic strains evaluated were within nine genera (Bifidobacterium, Enterococcus, Lacticaseibacillus, Lactiplantibacillus, Lactobacillus, Lactococcus, Ligilactobacillus, Saccharomyces, and Streptococcus) according to new Lactobacillus taxonomy. 72−92 It is worth noting that intervention with multiple probiotic strains in human trials is preferred (20 of 25 studies) due to a broader range of health-promoting effects and synergistic mechanisms of action, 93 suggesting a higher opportunity for success. 94owever, insufficient evidence supports a better healthpromoting effect when using multistrain probiotics than single-strain probiotics. 95Therefore, the selection of probiotic strains for human trials must be based on in vitro and in vivo scientific evidence.
−83,85,86,89−91 However, only seven trials 14,64,77,78,87,88,92 observed an improved renal function index, including reduced BUN and CRE, and slowing eGFR decline.The primary function of specific probiotics is an adjuvant strategy used to restore microbial balance and suppress circulating levels of uremic toxins, 96 so improved renal function indicators may not be observed at this stage.Additionally, BUN and CRE levels are influenced by dietary and physiologic conditions unrelated to renal function, 97 which might affect the statistical significance of clinical studies.3][74][75]14,86,99,100 Inflammatory biomarkers were evaluated in seven studies, with decreased inflammatory cytokines (TNF-α, IL-5, IL-6, IL-18), CRP, and LPS in serum compared to controls after probiotics intervention.
Synbiotic supplementation also positively affected renal function and gut microbiota in patients with CKD. 14,78,89,98ynbiotic therapy significantly reduced serum IS and PCS in patients with CKD, with the enrichment of Bif idobacterium and Lactobacillus and depletion of Ruminococcaceae.Moreover, a significant negative correlation was observed between changes in the relative abundance of Bifidobacterium and serum PCS and IS concentrations. 89ttempts to restore the desired microbiome by introducing favorable microorganisms seem feasible for CKD alleviation.However, the limited size of the study cohorts and the relatively short follow-up period hinder a comprehensive understanding of probiotics' efficacy in treating individuals with CKD.Therefore, further long-term basic and clinical studies are needed in the future.
3.3.The Gut−Kidney Axis Plays a Vital Role in the Preventive/Therapeutic Mechanisms of Probiotics in CKD.The probiotics' potential efficacy in managing CKD is through the gut−kidney axis by modulating gut microbial composition and improving gut dysbiosis, which further reduces uremic toxins, increases SCFA, enhances gut barrier integrity, ameliorates gastrointestinal symptoms, and decreases the inflammatory response, contributing to alleviating CKD progression.
3.3.1.Modulating Gut Microbial Composition and Improving Gut Dysbiosis.Numerous studies reveal that orally administered probiotics in animal models slow the progression of kidney disease by correcting the intestinal microbial imbalance. 11,13,101Six clinical studies analyzed gut microbiota after probiotics intervention in patients with CKD using high throughput sequencing, and the results support the importance of the gut−kidney axis in alleviating CKD. 14,64,73,83,89,92In a single-center double-blind, randomized, placebo-controlled study, administration of Bifco capsules, which is a mixture of viable bacteria (Enterococcus faecalis, Bifdobacterium longum, and Lactobacillus acidophilus), for six months induced microbial composition changes and reduced the relative abundance of Ruminococcaceae, Halomonadaceae, Peptostreptococcaceae, and Erysipelotrichacease and elevated Bacteroidaceae and Enterococcaceae in nondiabetic hemodialysis patients. 83In another 6-month single-arm pilot study, the dominant genera of the intestinal microbiome changed during the probiotic intervention. 64In a double-blind, randomized, placebocontrolled trial, intervention with synbiotic pills (Lactobacillus acidophilus CBT LA1, Lacticaseibacillus casei CBT LC5, Bif idobacterium lactis CBT BL3, and inulin), the relative abundance of Bif idobacterium, Lactobacillus, and Subdoligranulum significantly increased compared to the placebo group. 14n a small-scale study with a probiotics intervention (mixture of Bif idobacterium bif idum BGN4 and Bif idobacterium longum BORI) for three months, the population of Prevotella, Enterococcus, Alistipes, Clostridia, Escherichia-Shigella, Klebsiella, and Bif idobacterium increased while Bacteroides, Faecalibacterium, Eubacterium siraeum, Tyzzerella, Sutterella, and Akkermansia reduced. 73hrough analyzing the microbial composition based on the reviewed clinical studies, the CKD alleviating effect of probiotics on modulating gut microbiota involves: 3.3.1.1.Upregulating the Beneficial Bacterial Genus Bif idobacterium.Among the clinical trials, six studies noted significant increases in Bif idobacterium, which parallels other fecal microbial analyses in patients with CKD using culturedependent, qPCR quantification or next-generation sequencing approaches. 14,64,73,89,90,98Bif idobacterium, decreased in patients with CKD, 45 has been reported to promote colon health by increasing the production of microbial metabolites, such as SCFA, 102 and the slow CKD progression positively relates to the eGFR improvement. 14,51.3.1.2.Upregulating Bacterial Families Possessing the Enzymes to Synthesize SCFA.Other bacterial genera possessing enzymes to synthesize SCFA are enriched after probiotic intervention, such as Lactobacillus and Subdoligranulum.14,103 These bacteria convert dietary fiber in the gut into monosaccharides through a series of reactions mediated by specific enzymes.104 A reduction in Bif idobacterium, Lactobacillus, and SCFA producers, such as Prevotella spp., Clostridium spp., Roseburia spp., Enbacterium spp., Coprococcus spp., and Faecalibacterium prausnitzii have been observed in the patients with CKD.9,45,105−107 Furthermore, SCFA producers (Butyricicoccus spp., F. prausnitzii, Roseburia spp., and Bif idobacterium spp.) showed an inverse correlation with the severity of CKD progression and increased with higher eGFR.51 Additionally, SCFAs produced by gut bacteria and delivered to the kidney through the peripheral circulation could protect tubular cells from oxidative cellular stress, mitigate renal ischemiareperfusion injury, reduce inflammation, lower the infiltration of immune cells, and diminish apoptotic cells in injured kidneys.108 Thus, increased SCFA-producing bacteria in the gut after probiotic intervention could improve gut health and positively affect CKD.109,110 3.3.1.3.Downregulating the Bacterial Families Possessing the Enzymes to Synthesize Uremic Toxins. A highabundance of gut bacterial families with enzymes to synthesize uremic toxins could accelerate CKD progression.Indole, phenol, and p-cresol are aromatic compounds produced by intestinal bacteria via aromatic amino acids (tryptophan and tyrosine).9,51,110 Upregulating nonphenol-producing bacteria, such as Subdoligranulum, genera of the Ruminococcaceae family, 14 and downregulating indole-producing bacteria, such as Escherichia spp., 64 were observed in patients with CKD after the probiotic intervention.Reducing the Ruminococcaceae family was also reported in HD patients supplemented with probiotics. 83 ome bacteria from Ruminococcaceae can ferment tyrosine to p-cresol, 110 and modulation of Ruminococcaceae appears to correlate with a healthier gut environment in CKD patients.
3.3.1.4.Downregulating the Bacterial Families Associated with Inflammation.Reduction of endotoxin-producing Gramnegative bacteria, such as Megamonas, Escherichia-Shigella, and Halomonadaceae, in patients with CKD with probiotic intervention indicates decreasing chronic immune responses associated with inflammation in the human gut.Both studies show a reduction in the serum levels of endotoxin. 64,75,83everal reports found more Halomonadaceae in ESRD patients. 9,111The observed decline in these bacteria suggests that probiotics may potentially restrain their overgrowth in CKD patients.

Reducing Inflammation, Oxidative Stress, and Intestinal Barrier Injury via Reducing Serum Uremic
Toxins/Endotoxin and Increasing SCFAs.SCFAs produced by the intestinal microbiome can reduce inflammation and oxidative stress.The mechanisms involved in the antiinflammatory response include decreasing the proliferation of immune cells and cytokine levels, inhibiting NF-κB, reducing neutrophil recruitment, 113 and a direct effect on T cells through binding to specific receptors (GPR41, GPR43, and GPR109A). 104SCFAs can modulate the Keap1-Nrf2-dependent cellular signaling pathway to maintain redox homeostasis. 114,115Detrimental effects of GDUTs, including oxidative stress, inflammation, fibrosis, kidney failure, and insulin resistance, have been well documented,.Thus, by downregulating GDUTs and upregulating SCFAs, probiotics reduce inflammation, oxidative stress, and intestinal barrier injury in patients with CKD.Probiotics have been shown to decrease serum proinflammatory cytokines, 64,73,75 increase T regulatory cytokines, 75 reduce small intestinal permeability, 76 increase fecal SCFAs, 73 and reduce serum GDUTs 14,76,81−83,86,89−91 and endotoxins 64,75 in patients with CKD.These findings verify that the gut−kidney axis significantly impacts the preventive/therapeutic mechanisms of probiotics in CKD.

FURTHER CONSIDERATIONS AND CONCLUDING REMARKS
Gut dysbiosis contributes to deteriorating CKD progression; thus, probiotics are a potential strategy to restore the desired microbiome and treat CKD.Clinical studies have revealed the various physiological functions of probiotics in patients with CKD including reduction of uremic toxins and related precursors, modulation of gut microbiota, regulation of immune capacity, protection of the gastrointestinal tract, and improvement of gastrointestinal symptoms.However, only approximately 25% of human cohorts have shown a positive effect on renal function, which is the most critical outcome demonstrating the efficacy of probiotics in improving CKD.
The considerable heterogeneity in the responses to probiotic treatment in CKD may be due to individual factors such as diet, age, physiological condition, immune response, and indigenous gut microbiota, 116 as well as differing expression of mucosal immune-related genes in gastrointestinal organs, leading to personalized colonization patterns. 117onetheless, a strong relationship exists between CKDrelated specific gut microbial profiles and metabolites and their interplay with probiotics.Thus, it is necessary to investigate alterations in the bacterial communities and bacterial-related metabolic functions to select appropriate probiotics to treat CKD and understand their underlying mechanisms of action.Human clinical studies should involve the integrated analysis of microbial configurations and metabolite profiles during probiotics intervention using a combination of multiomic technologies, such as metagenomics, metabolomics, and transcriptomics, which could provide more precise insights into the mechanisms of probiotics function.
CKD severity shapes varying statuses of gut dysbiosis, indicating a descending trend of gut diversity and abundance with CKD progression. 7,118Clinical studies are usually conducted with specific CKD populations, which make it interesting whether disease severity influences gut modulation and subsequent probiotics effects.Such investigations could help suggest favorable timing of probiotic interventions for better outcomes.A large-scale prospective longitudinal clinical study of varying levels of impaired kidney function and a long follow-up period should be conducted to comprehensively understand probiotics' efficacy in treating CKD.In addition, it is recommended that commensal bacteria be identified as novel microbiota-based biomarkers to monitor disease progression and facilitate the development of next-generation probiotics or precision probiotics to prevent CKD progression.
In conclusion, although several clinical studies have demonstrated the positive impacts of probiotics on various outcomes in patients with CKD, their effectiveness in CKD treatment remains a subject of debate and requires further verification.It is anticipated that future large-scale, long-term studies will confirm the potential benefits of utilizing probiotics as an adjuvant therapy in CKD.

Table 2 .
Summary of the Current Literature Supporting Gut Dysbiosis in Patients with Chronic Kidney Disease a

Table 3 .
Summary of Clinical Trials Examining the Use of Probiotics in Patients with Chronic Kidney Disease a