An expanded metabolic pathway for androgen production by host-associated bacteria
An expanded metabolic pathway for androgen production by host-associated bacteria
Abstract A growing body of literature implicates host-associated microbiota in the modulation of circulating androgen levels in the host, which could have far-reaching implications for androgen-mediated diseases. However, the microbial genetic pathways involved in androgen production remain unknown. Here, we report the first host-associated microbial gene (desF) encoding an enzyme that catalyzes conversion of androstenedione to epitestosterone (epiT) in the gut bacterium, Clostridium scindens. Despite current dogma that epiT is a nuclear androgen-receptor (AR) antagonist, we demonstrate that epiT is a potent androgen, as assessed by its ability to promote prostate cancer cell growth and expression of prostate specific antigen (PSA). We then quantified the desF gene in fecal samples collected from individuals with advanced prostate cancer (rising blood PSA) undergoing androgen deprivation therapy combined with abiraterone acetate and prednisone (AA/P). Strikingly, fecal desF levels were elevated in a subset of individuals progressing on AA/P versus samples taken during AA/P response (stable). Importantly, we observed that AA does not inhibit the bacterial desmolase enzyme that is analogous to the human drug target of AA. We then determined that bacterial isolates from urine or prostatectomy tissue are capable of androgen production. From these isolates we detected 17β-hydroxysteroid dehydrogenase (17β-HSDH) activity, which has not been previously reported in urinary tract bacteria, and discovered the desG gene in urinary isolates encoding 17β-HSDH that catalyzed conversion of androstenedione to testosterone. Applying advanced artificial intelligence and molecular dynamics, we predict the structures and ligand binding to DesF and DesG. Using a novel bioengineered microencapsulation technique, we demonstrate that urinary androgen-producing bacterial strains can also promote prostate cancer cell growth through steroid metabolism. Taken together, our results are a significant advance for steroid microbiology in humans and suggest that these microbial biotransformations should be further studied in the context of androgen-mediated physiological processes and diseases.
Wang Taojun、Cann Isaac、Lee Jae Won、Ernst Sarah E.、Caicedo Kelly Yovani Olivos、Alves Jo?o M.P.、Irudayaraj Joseph、Gaskins H. Rex、Ikegawa Shigeo、Hylemon Phillip B.、Fernandez-Materan Francelys V.、Harris Spencer C.、Dutta Debapriya、Ahmad Saeed、Binion Briawna、Bernardi Rafael C.、Cruz-Lebr¨?n Ang¨|lica、Erdman John W. Jr.、Yang Glen、Sfanos Karen S.、Daniel Steven L.、Anantharaman Karthik、Ridlon Jason M.、Jeong Yoon、Mbuvi Pauline、Kang Jason D.、Breister Adam M.
Department of Animal Sciences, University of Illinois Urbana-Champaign||Carl R. Woese Institute for Genomic BiologyDepartment of Animal Sciences, University of Illinois Urbana-Champaign||Carl R. Woese Institute for Genomic Biology||Division of Nutritional Sciences, University of Illinois at Urbana-ChampaignDepartment of Biotechnology, Sungshin Women?ˉs UniversityDepartments of Pat hology, Oncology, and Urology, Johns Hopkins University School of MedicineDepartment of Parasitology, Institute of Biomedical Sciences, University of S?o PauloDepartment of Parasitology, Institute of Biomedical Sciences, University of S?o PauloDepartment of Bioengineering, University of Illinois Urbana-Champaign||Biomedical Research Facility, Carle Foundation Hospital||Division of Nutritional Sciences, University of Illinois at Urbana-Champaign||Cancer Center at Illinois, University of Illinois at Urbana-Champaign||Carle-Illinois College of Medicine, University of Illinois Urbana-ChampaignDepartment of Animal Sciences, University of Illinois Urbana-Champaign||Division of Nutritional Sciences, University of Illinois at Urbana-Champaign||Cancer Center at Illinois, University of Illinois at Urbana-ChampaignGenmaikoso Co. LtdStravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University, School of Medicine||Department of Microbiology and Immunology, Virginia Commonwealth University School of MedicineDepartment of Animal Sciences, University of Illinois Urbana-Champaign||Carl R. Woese Institute for Genomic BiologyStravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University, School of MedicineBiomedical Research Facility, Carle Foundation HospitalDepartment of Bioengineering, University of Illinois Urbana-ChampaignDepartment of Animal Sciences, University of Illinois Urbana-Champaign||Carl R. Woese Institute for Genomic BiologyDepartment of Physics, Auburn UniversityDepartments of Pat hology, Oncology, and Urology, Johns Hopkins University School of MedicineDivision of Nutritional Sciences, University of Illinois at Urbana-Champaign||Cancer Center at Illinois, University of Illinois at Urbana-ChampaignDepartment of Urology, Carle Foundation HospitalDepartments of Pat hology, Oncology, and Urology, Johns Hopkins University School of MedicineDepartment of Animal Sciences, University of Illinois Urbana-ChampaignDepartment of Bacteriology, University of Wisconsin-MadisonDepartment of Animal Sciences, University of Illinois Urbana-Champaign||Carl R. Woese Institute for Genomic Biology||Division of Nutritional Sciences, University of Illinois at Urbana-Champaign||Cancer Center at Illinois, University of Illinois at Urbana-Champaign||Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine||Center for Advanced Study, University of Illinois Urbana-ChampaignDepartment of Bioengineering, University of Illinois Urbana-Champaign||Biomedical Research Facility, Carle Foundation HospitalBiomedical Research Facility, Carle Foundation HospitalStravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University, School of MedicineDepartment of Bacteriology, University of Wisconsin-Madison
微生物学肿瘤学分子生物学
Wang Taojun,Cann Isaac,Lee Jae Won,Ernst Sarah E.,Caicedo Kelly Yovani Olivos,Alves Jo?o M.P.,Irudayaraj Joseph,Gaskins H. Rex,Ikegawa Shigeo,Hylemon Phillip B.,Fernandez-Materan Francelys V.,Harris Spencer C.,Dutta Debapriya,Ahmad Saeed,Binion Briawna,Bernardi Rafael C.,Cruz-Lebr¨?n Ang¨|lica,Erdman John W. Jr.,Yang Glen,Sfanos Karen S.,Daniel Steven L.,Anantharaman Karthik,Ridlon Jason M.,Jeong Yoon,Mbuvi Pauline,Kang Jason D.,Breister Adam M..An expanded metabolic pathway for androgen production by host-associated bacteria[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2024.06.09.598130.点此复制
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