Gut bacteria metabolize natural and synthetic steroid hormones via the reductive OsrABC pathway

Steroid hormone metabolism by the gut microbiome affects host physiology, however, the underlying microbial pathways remain incompletely understood. Here, we isolate a gut bacterial species, which we designate Clostridium steroidoreducens, that reduces cortisol and related steroid hormones to 3β,5β-tetrahydrosteroid products. Through transcriptomics and enzymatic discovery, we establish the C. steroidoreducens OsrABC steroid hormone pathway. OsrA is a 3-oxo-Δ¹-steroid hormone reductase that targets synthetic glucocorticoids, including prednisolone-a frontline Crohn's disease therapy. OsrB is a 3-oxo-Δ⁴-steroid reductase that converts steroid hormones to 5β-dihydrosteroid intermediates, which OsrC subsequently reduces to 3β,5β-tetrahydro products. Homologs of osrA and osrB predict steroid-reducing activity across gut bacteria and are enriched in metagenomes of Crohn's disease patients. 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.