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Top-Down Systems Biology Modeling of Host Metabotype−Microbiome Associations in Obese Rodents

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Department of Biomolecular Medicine, SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington SW7 2AZ, United Kingdom, AstraZeneca, Alderley Park, Mereside, Macclesfield, Cheshire SK10 4TF, United Kingdom, and Department of Food Biosciences, Whiteknights, The University of Reading, P.O. Box 226 Reading RG6 6AP, United Kingdom
* To whom correspondence should be addressed. J.K.N.: e-mail, [email protected]; tel, +44 (0)20 7594 3195; fax, +44 (0)20 7594 3226. G.R.G.: e-mail, [email protected]; tel, +44 (0)118 378 8715, fax, +44 (0)118 931 0080.
†Imperial College London.
+Current address: State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Wuhan Centre for Magnetic Resonance, Wuhan Institute of Physics and Mathematics, The Chinese Academy of Sciences, Wuhan, 430071, PR China.
§The University of Reading.
Cite this: J. Proteome Res. 2009, 8, 5, 2361–2375
Publication Date (Web):March 10, 2009
Copyright © 2009 American Chemical Society

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    Covariation in the structural composition of the gut microbiome and the spectroscopically derived metabolic phenotype (metabotype) of a rodent model for obesity were investigated using a range of multivariate statistical tools. Urine and plasma samples from three strains of 10-week-old male Zucker rats (obese (fa/fa, n = 8), lean (fa/−, n = 8) and lean (−/−, n = 8)) were characterized via high-resolution 1H NMR spectroscopy, and in parallel, the fecal microbial composition was investigated using fluorescence in situ hydridization (FISH) and denaturing gradient gel electrophoresis (DGGE) methods. All three Zucker strains had different relative abundances of the dominant members of their intestinal microbiota (FISH), with the novel observation of a Halomonas and a Sphingomonas species being present in the (fa/fa) obese strain on the basis of DGGE data. The two functionally and phenotypically normal Zucker strains (fa/− and −/−) were readily distinguished from the (fa/fa) obese rats on the basis of their metabotypes with relatively lower urinary hippurate and creatinine, relatively higher levels of urinary isoleucine, leucine and acetate and higher plasma LDL and VLDL levels typifying the (fa/fa) obese strain. Collectively, these data suggest a conditional host genetic involvement in selection of the microbial species in each host strain, and that both lean and obese animals could have specific metabolic phenotypes that are linked to their individual microbiomes.

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    Table showing both Pearson correlations and Spearman correlations for important metabolites and bands from the O2PLS analysis; examples of 1H NMR spectra produced from each pulse program from the plasma samples; typical plasma CPMG 1H NMR for each Zucker strain; OPLS coefficient plot comparing the (−/−) lean strain and the (fa/fa) obese strain from the diffusion-edited plasma 1H NMR data; OPLS coefficient plot comparing the (−/−) lean strain and the (fa/fa) obese strain from the DGGE profile. This material is available free of charge via the Internet at

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