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.

胃肠道（GI）内的细菌可产生影响宿主代谢过程的氨基酸胆汁酸酰胺化物，但目前负责合成这类物质的细菌基因仍未明确。本研究证实，胆汁盐水解酶（bile salt hydrolase）在胆汁酸代谢中具有双重功能。具体而言，我们发现了该酶的全新功能：作为胺N-酰基转移酶（amine N-acyl transferase），可将胺类与胆汁酸结合，进而生成细菌源性胆汁酸酰胺化物（bacterial bile acid amidates，BBAA）。为表征BSH的该胺N-酰基转移酶活性，我们通过对BSH实施药理学抑制、在大肠杆菌（Escherichia coli）中异源表达bsh基因及其突变体，以及在脆弱拟杆菌（Bacteroides fragilis）中构建bsh基因敲除与互补菌株，证实了BSH可催化生成BBAA。我们进一步在人类婴儿队列中发现，BBAA的生成量与表达bsh基因的细菌定植水平呈正相关。最后，本研究证实BBAA可激活宿主配体激活型转录因子，包括孕烷X受体（pregnane X receptor）和芳香烃受体（aryl hydrocarbon receptor）。上述研究结果加深了我们对肠道细菌如何通过BSH的多效性作用，在调控胆汁酸代谢网络中发挥重要作用的理解。