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

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.