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

Steroid hormones, critical regulators of various physiological processes, are metabolized by both the host and gut bacteria, with profound implications for mammalian health. Due to their diverse effects, many natural and synthetic steroids are widely used to treat autoimmune diseases, inflammatory disorders, hormone deficiencies, and cancer. In this study, we isolated a novel gut bacterium, Clostridium steroidoreducens strain HCS.1, and identified a unique steroid metabolism pathway, OsrABC, capable of reducing a broad range of steroid hormones, including glucocorticoids, mineralocorticoids, androgens, and progestins.¹ The OsrABC pathway consists of three key enzymes: OsrA, a 3-oxo-Δ1-steroid reductase that targets synthetic corticosteroids; OsrB, a versatile 3-oxo-Δ4-steroid reductase that produces 5β-dihydrosteroid intermediates; and OsrC, which further reduces these intermediates to 3β,5β-tetrahydrosteroid products. Our results suggest that this pathway may contribute to chronic inflammation by potentially interfering with glucocorticoid therapies and affecting drug bioavailability. Notably, osrA and osrB homologs were found to be highly enriched in active Crohn's disease patients, particularly in microbes such as Clostridium tertium, Clostridium_AQ innocuum, and Ruminococcus_B gnavus, the latter two of which have previously been associated with the disease. These microbes may exploit steroid metabolism to thrive in an inflamed environment, further perpetuating inflammation. In conclusion, our study highlights how microbial metabolism may influence the efficacy of steroid-based therapies in patients with inflammatory diseases, underscoring the need for personalized treatment approaches.

Jacoby, C. et al. Gut Bacteria Metabolize Natural and Synthetic Steroid Hormones via the Reductive OsrABC Pathway. bioRxiv 2024.10.08.617280 (2024) doi:10.1101/2024.10.08.617280.