Bile salt hydrolase catalyses formation of amine-conjugated bile acids

• 成果类型: Article
• 署名作者: Rimal, Bipin; Collins, Stephanie L.; Tanes, Ceylan E.; Rocha, Edson R.; Granda, Megan A.; Solanki, Sumeet; Hoque, Nushrat J.; Gentry, Emily C.; Koo, Imhoi; Reilly, Erin R.; Hao, Fuhua; Paudel, Devendra; Singh, Vishal; Yan, Tingting; Kim, Min Soo; Bittinger, Kyle; Zackular, Joseph P.; Krausz, Kristopher W.; Desai, Dhimant; Amin, Shantu; Coleman, James P.; Shah, Yatrik M.; Bisanz, Jordan E.; Gonzalez, Frank J.; Vanden Heuvel, John P.; Wu, Gary D.; Zemel, Babette S.; Dorrestein, Pieter C.; Weinert, Emily E.; Patterson, Andrew D.
• 署名单位: Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of North Carolina; East Carolina University; University of Michigan System; University of Michigan; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of California System; University of California San Diego; University of California System; University of California San Diego; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Penn State Health; University of Pennsylvania; Virginia Polytechnic Institute & State University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4197
• DOI: 10.1038/s41586-023-06990-w
• 发表日期: 2024-02-22
• 关键词: metabolism; cholesterol; enzyme

摘要

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1-6; 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 previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, 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, have a significant role in regulating the bile acid metabolic network. We find that bile salt hydrolase N-acyltransferase activity can form bacterial bile acid amidates that are positively correlated with the colonization of gut bacteria that assist in the regulation of the bile acid metabolic network.