Bile salt hydrolase catalyses formation of amine-conjugated bile acids

• Published in: Nature (London) Vol. 626; no. 8000; pp. 859 - 863
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.02.2024; Nature Publishing Group
• Subjects: 13; 13/106; 14; 38; 38/22; 38/23; 38/39; 38/47; 42; 45; 45/77; 45/91; 59; 631/326/2565/2134; 631/45/607/1164; 631/45/607/1172; 64; 64/60; 82; 82/29; Acyltransferase; Acyltransferases - metabolism; Amidohydrolases - metabolism; Amines; Amines - chemistry; Amines - metabolism; Amino acids; Bacteria; Bacteroides fragilis - enzymology; Bacteroides fragilis - genetics; Bacteroides fragilis - metabolism; Bile; Bile acids; Bile Acids and Salts - chemistry; Bile Acids and Salts - metabolism; Bile salts; Biocatalysis; Cell culture; Cell Culture Techniques; Cohort Studies; Complementation; E coli; Enzymes; Escherichia coli - enzymology; Escherichia coli - genetics; Escherichia coli - metabolism; Gastrointestinal Microbiome - physiology; Gastrointestinal system; Gastrointestinal tract; Genes; Humanities and Social Sciences; Humans; Hydrocarbons; Infant; Ligands; Metabolic networks; Metabolism; Microbiota; multidisciplinary; Pregnane X Receptor - metabolism; Pregnane X receptors; Receptors; Receptors, Aryl Hydrocarbon - metabolism; Science; Science (multidisciplinary); Transcription factors; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-023-06990-w

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. 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.