Bile salt hydrolase catalyses formation of amine-conjugated bile acids PMID: 38326609

ADC Targets in Oncology

2026-04-10

Bile salt hydrolase catalyses formation of amine-conjugated bile acids

Nature. 2024 Feb;626(8000):859-863. doi: 10.1038/s41586-023-06990-w.

Bipin Rimal ^# ¹ , Stephanie L Collins ^# ² , Ceylan E Tanes ³ , Edson R Rocha ⁴ , Megan A Granda ¹ , Sumeet Solanki ⁵ , Nushrat J Hoque ⁶ , Emily C Gentry ⁷ ⁸ ⁹ , Imhoi Koo ¹⁰ , Erin R Reilly ² , Fuhua Hao ¹ , Devendra Paudel ¹¹ , Vishal Singh ¹¹ , Tingting Yan ¹² , Min Soo Kim ² , Kyle Bittinger ³ , Joseph P Zackular ¹³ ¹⁴ , Kristopher W Krausz ¹² , Dhimant Desai ¹⁵ , Shantu Amin ¹⁵ , James P Coleman ⁴ , Yatrik M Shah ⁵ , Jordan E Bisanz ² ¹⁶ , Frank J Gonzalez ¹² , John P Vanden Heuvel ¹ ¹⁷ , Gary D Wu ¹⁸ , Babette S Zemel ³ , Pieter C Dorrestein ⁷ ⁸ , Emily E Weinert ² ⁶ , Andrew D Patterson ¹⁹ ²⁰ ²¹

Affiliations

1. Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, USA.
2. Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA.
3. Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
4. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
5. Department of Molecular & Integrative Physiology and Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA.
6. Department of Chemistry, Pennsylvania State University, University Park, PA, USA.
7. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA.
8. Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, San Diego, CA, USA.
9. Department of Chemistry, Virginia Tech, Blacksburg, VA, USA.
10. Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA.
11. Department of Nutritional Sciences, Pennsylvania State University, University Park, PA, USA.
12. Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
13. Division of Protective Immunity, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
14. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
15. Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA.
16. One Health Microbiome Center, Huck Life Sciences Institute, University Park, PA, USA.
17. INDIGO Biosciences, Inc., State College, PA, USA.
18. Division of Gastroenterology and Hepatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
19. Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, USA. [email protected].
20. Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA, USA. [email protected].
21. One Health Microbiome Center, Huck Life Sciences Institute, University Park, PA, USA. [email protected].
# Contributed equally.

Abstract

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes^1-6; 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.