Diet, genetics and gut microbiome drive dynamic changes in plasma metabolites

Diet, genetics and the gut microbiome are determinants of metabolic status, in part through production of metabolites by gut microbiota. To understand mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ and 129S6/SvEvTac mice on chow, high-fat diet (HFD), and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 as-of-yet-unidentified metabolite peaks were also highly regulated by diet, antibiotics and genetic background. Thus diet, host genetics and gut microbiota interact to create unique responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance.