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

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 (<i>fa</i>/<i>fa</i>, <i>n</i> = 8), lean (<i>fa</i>/−, <i>n</i> = 8) and lean (−/−, <i>n</i> = 8)) were characterized <i>via</i> high-resolution <sup>1</sup>H NMR spectroscopy, and in parallel, the fecal microbial composition was investigated using fluorescence <i>in situ</i> 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 <i>Halomonas</i> and a <i>Sphingomonas</i> species being present in the (<i>fa</i>/<i>fa</i>) obese strain on the basis of DGGE data. The two functionally and phenotypically normal Zucker strains (<i>fa</i>/− and −/−) were readily distinguished from the (<i>fa</i>/<i>fa</i>) 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 (<i>fa</i>/<i>fa</i>) 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.