4.5 Article

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

Journal

NATURE MICROBIOLOGY
Volume 7, Issue 9, Pages 1404-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41564-022-01176-y

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Funding

  1. Massachusetts Host-Microbiome Center [P30DK034854]
  2. National Institutes of Health [MIRA R35 GM128618, R01 DK110559, U54DE023798, R24DK110499]
  3. Harvard Medical School Dean's Innovation Grant in the Basic and Social Sciences
  4. John and Virginia Kaneb Fellowship
  5. Harvard Medical School Christopher Walsh Fellowship
  6. Wellington Postdoctoral Fellowship
  7. FAS Division of Science Research Computing Group at Harvard University

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This study characterizes a biosynthetic pathway in gut bacteria that sulfonates steroidal metabolites, potentially impacting immune cell trafficking and inflammatory bowel disease.
Characterization of a biosynthetic pathway for the sulfonation of steroidal metabolites, such as cholesterol, by gut bacteria may have implications for immune cell trafficking and inflammatory bowel disease. 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 Delta BT0416 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.

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