ESPE Yearbook of Paediatric Endocrinology

Nat Microbiol. 2025;10(5):1084-98. doi: 10.1038/s41564-025-01979-9

Brief Summary: This in vitro and ex vivo study combined microbial genetics, in vitro cancer cell assays, and an observational cohort study of 69 patients with hormone-sensitive prostate cancer (HSPC). It elucidated a novel bacterial pathway for androgen biosynthesis from host-derived glucocorticoids, identifying microbial 17α and 17β-hydroxysteroid dehydrogenases (DesF and DesG) that produce active androgens, including epitestosterone (epiT) and testosterone (T). The authors demonstrate that these microbial metabolites can activate androgen receptor (AR) signaling and promote prostate cancer cell proliferation, even in the presence of androgen deprivation therapy (ADT) and abiraterone. They also show that these genes are enriched in the gut and urinary microbiota of patients with advanced prostate cancer, suggesting a potential microbial contribution to disease progression and therapy resistance.

The conversion of glucocorticoid derivatives to androgens by microbial strains was confirmed using liquid chromatography-mass spectrometry and nuclear magnetic resonance. Comparative genomics and RNA-seq analysis identified the bacterial genes desF and desG as encoding enzymes responsible for the synthesis of epiT and 11β-hydroxy-testosterone, respectively. Challenging the long-held standing dogma that epiT is an inactive androgen, epiT is shown here to be produced by gut bacteria from commonly used glucocorticoids and to promote proliferation of androgen-sensitive prostate cancer cells while sustaining AR target gene expression. Elevated desF levels associated with HSPC progression suggest that gut microbiota-mediated androgen synthesis may undermine the efficacy of ADT therapy. Notably, the alternative bacterial androgen biosynthesis pathway seems to be not inhibited by abiraterone, a drug that blocks human androgen production, highlighting a potentially targetable mechanism for overcoming abiraterone resistance.

Overall, this study underscores the growing importance of the microbiome in cancer therapy. The findings warrant further investigation into whether long-term colonization of the urinary tract or gut by androgen-producing bacteria may be associated with cancer risk, disease progression in certain individuals, or contribute to other endocrine-related conditions. If confirmed, these insights could open new avenues for microbiome-targeted therapies in hormone-driven cancers.