An expanded metabolic pathway for androgen production by commensal bacteria
Wang, Taojun et al.
Commensal bacteria have been implicated in the modulation of steroid hormones, including circulating androgen levels in the host. However, the microbial genetic pathways involved in androgen production have not been fully characterized. Here, we identify a microbial gene encoding an enzyme that catalyzes the conversion of androstenedione to epitestosterone in the gut microbiome member Clostridium scindens, and named this gene desF. We demonstrate that epitestosterone impacts androgen receptor-dependent prostate cancer cell proliferation in vitro. We also demonstrate that stool desF levels are elevated in prostate cancer patients unresponsive to abiraterone/prednisone therapy. Bacterial isolates from urine or prostatectomy tissue produced androgens and 17β-hydroxysteroid dehydrogenase activity encoded by the desG gene was detected in strains of urinary tract bacterium, Propionimicrobium lymphophilum. Further, we demonstrate that urinary androgen-producing bacterial strains can promote prostate cancer cell growth through metabolism of cortisol and prednisone. Abiraterone, which targets host desmolase (CYP17A1), a rate limiting enzyme in adrenal steroidogenesis, does not inhibit bacterial desmolase (DesAB), whereas the conversion of prednisone to androgens by DesAB, DesF, and DesG drives AR-dependent prostate cancer cell line proliferation in vitro. Our results are a significant advance in steroid microbiology and highlight a potentially important role for gut and urinary tract bacteria in host endocrine function and drug metabolism.
