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bioRxiv · 10.1101/2024.10.08.617280

Gut Bacteria Metabolize Natural and Synthetic Steroid Hormones via the Reductive OsrABC Pathway

Jacoby, C.·Scorza, K.·Ecker, L.·McMillin, M.·Ramaswamy, R.·Sundararajan, A.·Sidebottom, A. M.·Lin, H.·Dufault-Thompson, K.·Hall, B.·Jiang, X.·Light, S. H.
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Abstract

Steroid hormone metabolism by the gut microbiome affects host physiology, but the underlying microbial pathways remain incompletely understood. Here, we isolate a novel human gut bacterium, Clostridium steroidoreducensT strain HCS.1 that reduces cortisol and related steroid hormones to 3{beta},5{beta}-tetrahydrosteroid products. Through transcriptomics and enzymatic discovery, we establish the C. steroidoreducens OsrABC steroid hormone pathway. OsrA is a 3-oxo-{Delta}1-steroid hormone reductase that targets synthetic glucocorticoids, including prednisolone-- a frontline Crohns disease therapy. OsrB is a 3-oxo-{Delta}4-steroid reductase that converts steroid hormones to 5{beta}-dihydrosteroid intermediates, which OsrC subsequently reduces to 3{beta},5{beta}-tetrahydro products. Homologs of osrA and osrB predict steroid-reducing activity across gut bacteria and are enriched in Crohns disease patient metagenomes. Consistent with a role in modulating drug efficacy, C. steroidoreducens colonization decreases prednisolone bioavailability in gnotobiotic mice. These findings thus define a previously unrecognized pathway for microbial steroid hormone inactivation and establish a mechanistic basis for bacterial interference with anti-inflammatory therapies.

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Jacoby, C., Scorza, K., Ecker, L., McMillin, M., Ramaswamy, R., Sundararajan, A., Sidebottom, A. M., Lin, H., Dufault-Thompson, K., Hall, B., Jiang, X., Light, S. H.. 2024-10-09. Gut Bacteria Metabolize Natural and Synthetic Steroid Hormones via the Reductive OsrABC Pathway. https://doi.org/10.1101/2024.10.08.617280

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