Bile Acids Are Substrates for Amine N-Acyl Transferase Activity by Bile Salt Hydrolase

Bacteria in the gastrointestinal tract (GI) produce amino acid bile acid amidates that impact host-mediated metabolic processes; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a new role for BSH as an amine N-acyl transferase that conjugates amines to bile acids thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyl transferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli, and a bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further demonstrate in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, play a significant role in regulating the bile acid metabolic network.