Bacterial Modification of Bile Acids Alters Host Metabolism

Bile acids are steroidal metabolites that play crucial roles in host metabolism by acting both as detergents that aid in digestion and as ligands for host receptors, including nuclear hormone receptors and GPCRs. In the colon, bacteria chemically modify host-produced primary bile acids, generating a group of approximately 50 metabolites called secondary bile acids. While imbalances in this bile acid pool have been correlated with metabolic disorders, it is unclear which bile acids exert beneficial or harmful effects on host metabolism. My lab can now control the in vivo pool of bile acids in mice by inhibiting the keystone enzyme of bacterial bile acid metabolism, bile salt hydrolases (BSHs), using both genetic and chemical tools. We find that knocking out a selective BSH in monocolonized mice results in altered host metabolism, including reduced weight gain, reduced respiratory exchange ratios, and altered transcriptional profiles in the gut and liver. These results indicate that the deletion of a single bacterial gene can profoundly alter host physiology. In ongoing work, we have developed a small molecule inhibitor of BSHs, and we are using this compound as a chemical tool to probe the effects of bacterial bile acid modifications on host metabolism in fully colonized animals.