Bile salt hydrolase catalyses formation of amine-conjugated bile acids.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Acyltransferases*/metabolism ; Amidohydrolases*/metabolism ; Amines*/chemistry ; Amines*/metabolism ; Bile Acids and Salts*/chemistry ; Bile Acids and Salts*/metabolism ; Biocatalysis* ; Gastrointestinal Microbiome*/physiology; Humans ; Bacteroides fragilis/enzymology ; Bacteroides fragilis/genetics ; Bacteroides fragilis/metabolism ; Cohort Studies ; Escherichia coli/enzymology ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Ligands ; Pregnane X Receptor/metabolism ; Receptors, Aryl Hydrocarbon/metabolism ; Transcription Factors/metabolism ; Infant ; Cell Culture Techniques

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.
(© 2024. The Author(s).)

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R00 AI147165 United States AI NIAID NIH HHS; U01 DK119702 United States DK NIDDK NIH HHS; P30 DK050306 United States DK NIDDK NIH HHS; S10 OD021750 United States OD NIH HHS; T32 DK120509 United States DK NIDDK NIH HHS; R35 GM138369 United States GM NIGMS NIH HHS; T32 GM102057 United States GM NIGMS NIH HHS; R35 GM151045 United States GM NIGMS NIH HHS; R35 ES035027 United States ES NIEHS NIH HHS

EC 2.3.- (Acyltransferases)
EC 3.5.- (Amidohydrolases)
0 (Amines)
0 (Bile Acids and Salts)
EC 3.5.1.24 (choloylglycine hydrolase)
0 (Ligands)
0 (Pregnane X Receptor)
0 (Receptors, Aryl Hydrocarbon)
0 (Transcription Factors)

Date Created: 20240207 Date Completed: 20240223 Latest Revision: 20240607

20240607

PMC10881385

10.1038/s41586-023-06990-w

38326609