Bacteria in the gastrointestinal tract (GI) produce a variety of 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, including a new role in bile acid metabolism by functioning as an amine N-acyl transferase that conjugates amines to form bacterial bile acid amidates (BBAAs). To characterize this new amine N-acyl transferase role for BSH, we used pharmacological inhibition of BSH, heterologous expression of bsh in Escherichia coli, and generated a bsh knockout and knockin in Bacteroides fragilis to demonstrate that BSH is necessary and sufficient for BBAA production. Lastly, we report that BBAAs activate host ligand-activated transcription factors including the farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, and the aryl hydrocarbon receptor. These new findings expand our understanding and appreciation for the important roles that bacteria play in shaping the bile acid metabolic network.
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Posted: 10 October 2022; Biological Sciences
Author information: Bipin Rimal (1), Stephanie L. Collins (2), Edson R. Rocha (3), Megan A. Granda (1), Sumeet Solanki (4),Nushrat Hoque (5), Emily C. Gentry (6,7), Imhoi Koo (8), Tingting Yan(9), Jordan E. Bisanz(2), Kristopher W. Krausz (9), Dhimant Desai (10), Shantu Amin (10), James P. Coleman (3), Yatrik M. Shah (4), Frank J. Gonzalez (9), John P. Vanden Heuvel (1,11), Pieter C. Dorrestein (6,7), Emily E. Weinert (2,5), Andrew D. Patterson (1,2)
(1) Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA
(2) Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA
(3) Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA
(4) Department of Molecular & Integrative Physiology and Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor MI, USA.
(5) Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA
(6) Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, San Diego, CA, USA
(7) Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
(8) Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA
(9) Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
(10) Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USA
(11) INDIGO Biosciences, Inc. 3006 Research Drive, State College, PA, USA