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

Steroid hormone metabolism by the gut microbiome has multiple implications for mammalian physiology, but the underlying mechanisms and broader significance of this activity remains largely unknown. Here, we isolate a novel human gut bacterium, strain HCS.1, that reduces cortisol, progesterone, testosterone, and related steroid hormones to 3β,5β-tetrahydrosteroid products. Through transcriptomics and heterologous enzyme profiling, we identify and biochemically characterize the OsrABC reductive steroid hormone pathway. OsrA is a 3-oxo-Δ-steroid hormone reductase that selectively targets the Δ-bond present in synthetic steroid hormones, including the anti-inflammatory corticosteroids prednisolone and dexamethasone. OsrB is a promiscuous 3-oxo-Δ-steroid hormone reductase that converts steroid hormones to 5β-dihydrosteroid intermediates. OsrC is a 3-oxo-5β-steroid hormone oxidoreductase that reduces 5β-intermediates to 3β,5β-tetrahydro products. We find that and homologs predict steroid hormone reductase activity in diverse gut bacteria and are enriched in Crohn's disease fecal metagenomes. These studies thus identify the basis of reductive steroid hormone metabolism in the gut and establish a link between inflammatory disease and microbial enzymes that deplete anti-inflammatory corticosteroids.