Diet, Genetics, and the Gut Microbiome Drive Dynamic Changes in Plasma Metabolites

TLDR

Diet, genetics, and the gut microbiome shape metabolic status by producing metabolites that influence host physiology. The study aimed to elucidate how these factors interact by performing LC‑MS metabolomic profiling of cecal contents and plasma from multiple mouse strains on chow, high‑fat diet, and antibiotic‑treated high‑fat diet. Functional metagenomic prediction via PICRUSt of 16S data revealed marked differences in microbial metabolic potential, informing the metabolomic analysis. Metabolite profiles differed markedly across diet, antibiotics, host genetics, and microbiome, with 18 plasma metabolites correlating with insulin resistance and over 1,000 unidentified peaks highly regulated, showing that these factors jointly shape plasma metabolites that affect metabolism and insulin resistance.

Abstract

Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the 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 or a 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 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance.