Bile, sulphur and carbohydrate metabolic variation co-occur with host adiposity in mice colonized with primate microbiota.

Although mechanistic links between the microbiome and chronic disease are increasingly well defined, how microbiomes facilitate normal variation in host metabolism remains less clear. Building on our recent demonstration that pooled faecal inocula from different primate species can cause relative differences in mouse host adiposity, we define potential mechanisms by which this could occur. Using existing samples from germ-free mice inoculated with faecal samples from humans (Homo sapiens), rhesus macaques (Macaca mulatta) and squirrel monkeys (Saimiri boliviensis), we integrate shotgun metagenomics of caecal contents, liquid chromatography-MS-MS metabolomics of serum and caecal contents and hepatic RNA-sequencing. Our multi-omic analysis reveals that the relative increase in adiposity previously observed in macaque-donor mice is associated with differences in hepatic cysteine catabolism and bile metabolism pathway features. These data suggest that bile and sulphur co-metabolic variation may mediate increased bile pool hydrophobicity. We also observed variation in caecal microbiome composition as well as host hepatic retinol signalling and lipid metabolism between treatments. When considered together with the observation that macaque-donor mice consumed less food than the other treatment groups, our results support the hypothesis that increased bile pool hydrophobicity results in increased dietary energy extraction. Our findings provide a foundation for future mechanistic testing of new hypotheses for understanding how the intestinal microbiomes of different primate species regulate lipid homeostasis in a mouse host.