Bile salt hydrolase catalyses formation of amine-conjugated bile acids

Bipin Rimal, Stephanie L. Collins, Ceylan E. Tanes, Edson R. Rocha, Megan A. Granda, Sumeet Solanki, Nushrat J. Hoque, Emily C. Gentry, Imhoi Koo, Erin R. Reilly, Fuhua Hao, Devendra Paudel, Vishal Singh, Tingting Yan, Min Soo Kim, Kyle Bittinger, Joseph P. Zackular, Kristopher W. Krausz, Dhimant Desai, Shantu Amin, James P. Coleman, Yatrik M. Shah, Jordan E. Bisanz, Frank J. Gonzalez, John P. Vanden Heuvel, Gary D. Wu, Babette S. Zemel, Pieter C. Dorrestein, Emily E. Weinert and Andrew D. Patterson ()
Additional contact information
Bipin Rimal: Pennsylvania State University
Stephanie L. Collins: Pennsylvania State University
Ceylan E. Tanes: Children’s Hospital of Philadelphia
Edson R. Rocha: East Carolina University
Megan A. Granda: Pennsylvania State University
Sumeet Solanki: University of Michigan
Nushrat J. Hoque: Pennsylvania State University
Emily C. Gentry: University of California San Diego
Imhoi Koo: Pennsylvania State University
Erin R. Reilly: Pennsylvania State University
Fuhua Hao: Pennsylvania State University
Devendra Paudel: Pennsylvania State University
Vishal Singh: Pennsylvania State University
Tingting Yan: National Cancer Institute, National Institutes of Health
Min Soo Kim: Pennsylvania State University
Kyle Bittinger: Children’s Hospital of Philadelphia
Joseph P. Zackular: Children’s Hospital of Philadelphia
Kristopher W. Krausz: National Cancer Institute, National Institutes of Health
Dhimant Desai: Penn State University College of Medicine
Shantu Amin: Penn State University College of Medicine
James P. Coleman: East Carolina University
Yatrik M. Shah: University of Michigan
Jordan E. Bisanz: Pennsylvania State University
Frank J. Gonzalez: National Cancer Institute, National Institutes of Health
John P. Vanden Heuvel: Pennsylvania State University
Gary D. Wu: University of Pennsylvania
Babette S. Zemel: Children’s Hospital of Philadelphia
Pieter C. Dorrestein: University of California San Diego
Emily E. Weinert: Pennsylvania State University
Andrew D. Patterson: Pennsylvania State University

Nature, 2024, vol. 626, issue 8000, 859-863

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41586-023-06990-w

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