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 catalyses 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 patients with prostate cancer who are 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 the urinary tract bacterium Propionimicrobium lymphophilum. Furthermore, 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 androgen-receptor-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.
Nature microbiology. 2025 Apr 21 [Epub]
Taojun Wang, Saeed Ahmad, Angélica Cruz-Lebrón, Sarah E Ernst, Kelly Yovani Olivos Caicedo, Yoon Jeong, Briawna Binion, Pauline Mbuvi, Debapriya Dutta, Francelys V Fernandez-Materan, Adam M Breister, Elizabeth Tang, Jae Won Lee, Jason D Kang, Spencer C Harris, Shigeo Ikegawa, H Rex Gaskins, John W Erdman, Glen Yang, Isaac Cann, Steven L Daniel, Phillip B Hylemon, Karthik Anantharaman, Rafael C Bernardi, João M P Alves, Karen S Sfanos, Joseph Irudayaraj, Jason M Ridlon
Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA., Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL, USA., Departments of Pathology, Oncology, and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Department of Parasitology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Biomedical Research Center, Mills Breast Cancer Institute, Carle Foundation Hospital, Urbana, IL, USA., Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA., Department of Physics, University of Illinois Urbana-Champaign, Urbana, IL, USA., Department of Biotechnology, Sungshin Women's University, Seoul, South Korea., Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA., Genmaikoso Co. Ltd, Hokkaido, Japan., Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA., Department of Urology, Carle Foundation Hospital, Urbana, IL, USA., Department of Physics, Auburn University, Auburn, AL, USA., Departments of Pathology, Oncology, and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA. ., Carl R. Woese Institute for Genomic Biology, Urbana, IL, USA. ., Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, IL, USA. .