A biosynthetic pathway for the selective sulfonation of steroidal metabolites by human gut bacteria.

Autor: Yao L; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., D'Agostino GD; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Park J; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Hang S; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Adhikari AA; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Zhang Y; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Li W; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Avila-Pacheco J; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bae S; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Clish CB; Broad Institute of MIT and Harvard, Cambridge, MA, USA., Franzosa EA; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Huttenhower C; Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Huh JR; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA., Devlin AS; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. sloan_devlin@hms.harvard.edu.
Jazyk: angličtina
Zdroj: Nature microbiology [Nat Microbiol] 2022 Sep; Vol. 7 (9), pp. 1404-1418. Date of Electronic Publication: 2022 Aug 18.
DOI: 10.1038/s41564-022-01176-y
Abstrakt: Members of the human gut microbiome enzymatically process many bioactive molecules in the gastrointestinal tract. Most gut bacterial modifications characterized so far are hydrolytic or reductive in nature. Here we report that abundant human gut bacteria from the phylum Bacteroidetes perform conjugative modifications by selectively sulfonating steroidal metabolites. While sulfonation is a ubiquitous biochemical modification, this activity has not yet been characterized in gut microbes. Using genetic and biochemical approaches, we identify a widespread biosynthetic gene cluster that encodes both a sulfotransferase (BtSULT, BT0416) and enzymes that synthesize the sulfonate donor adenosine 3'-phosphate-5'-phosphosulfate (PAPS), including an APS kinase (CysC, BT0413) and an ATP sulfurylase (CysD and CysN, BT0414-BT0415). BtSULT selectively sulfonates steroidal metabolites with a flat A/B ring fusion, including cholesterol. Germ-free mice monocolonized with Bacteroides thetaiotaomicron ΔBT0416 exhibited reduced gastrointestinal levels of cholesterol sulfate (Ch-S) compared with wild-type B. thetaiotaomicron-colonized mice. The presence of BtSULT and BtSULT homologues in bacteria inhibited leucocyte migration in vitro and in vivo, and abundances of cluster genes were significantly reduced in patients with inflammatory bowel disease. Together, these data provide a mechanism by which gut bacteria sulfonate steroidal metabolites and suggest that these compounds can modulate immune cell trafficking in the host.
(© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
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