Commensal bacteria promote endocrine-resistance in prostate cancer via androgen biosynthesis

The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. While there is evidence that an altered prostate microbiota is implicated in prostate carcinogenesis, the contribution of the gut microbiota to prostate cancer progression and, in particular, to the emergence of castration-resistant prostate cancer (CRPC) has not been addressed yet. Here, we found that androgen-deprivation in mice and humans promotes the expansion of a defined commensal microbiota capable of synthesizing androgens and contributing to the onset of castration-resistance in mice. Specifically, the intestinal microbial community of CRPC mice and patients was enriched for Bacteroides and Ruminococcus species. Ablation of the gut microbiota delayed the onset of CRPC by regulating the androgen pathway without halting the tumor immune response. Fecal microbiota transplantation (FMT) from CRPC and patients rendered these mice resistant to castration. In contrast FMT from uncastrated mice and castration sensitive (CS) patients controlled tumour growth as compared to CRPC FMT. Taken together, these results reveal that the commensal gut microbiota contributes to CRPC by providing an alternative source of androgens. Thus, FMT or probiotic therapy may be administered to CS prostate cancer patients in order to delay the onset of CRPC.