Deciphering microbial contribution to androgen bioavailability in castration resistant prostate cancer patients

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PROJECT SUMMARY An emerging role of microbiome in cancer is the capacity of microorganisms to impact treatment, drug efficacy and metabolism. For example, we recently showed that the gut microbiome plays an important role in castration resistant prostate cancer (CRPC) through microbial-derived androgen synthesis (Pernigoni et al. Science. 2021;374(6564):216-224). In that study, we found that androgen deprivation in both mice and humans promotes the expansion of specific gut bacteria capable of converting testosterone precursors into active testosterone, through bacterial CYP17A1-like enzymes (Ruminococcus gnavus, Ruminococcus sp. and Bacteroides acidifaciens), thus increasing its levels in patients and mice with CRPC and preventing complete suppression of testosterone during androgen deprivation therapy. In addition to the biosynthetic route, testosterone bioavailability could represent an additional means to regulate therapeutic responses. Androgens are glucuronidated in the liver for elimination and a fraction of these glucuronidated androgens reaches the gut through the bile and are targeted by bacterial β-glucuronidases (GUS) (Ruminococcus gnavus, Ruminococcus sp., Bacteroides acidifaciens and Clostridium scindens) for “reactivation” and potentially reabsorption. In fact, androgen concentration is higher in the intestine than in serum of human males. Another route by which gut microbiota contribute to the bioavailability of androgens is through cortisol to 11β-Hydroxyandrostenedione conversion by bacterial steroid-17,20-desmolases (Clostridium scindens desABCD operon). In turn, 11β- Hydroxyandrostenedione is converted to 11-oxyandrogen, which contribute to the tumor androgen pool. It is unclear how much each of these different routes contribute to the pool of circulating androgens. Our central hypothesis is that gut microbiome contributes to the production and bioavailability of androgens through a combination of biosynthetic and bioavailability routes. The objective of this project is to computationally identify androgen-related bacterial enzymes (CYP17A1-like, GUS, desA and desB) in CRPC patients gut microbiome and to isolate bacterial species harboring those enzymes for functional analysis. The rationale for the proposed research is that the outcomes will provide targets for future development and evaluation of interventions in CRPC patients that minimize or prevent the bioavailability of androgens. Our hypothesis will be tested through two specific aims: Aim 1) Identify androgen-related bacterial enzymes in the gut microbiome of prostate cancer patients. Aim 2) Functional characterization of bacterial species possessing androgen-related enzymes. At completion, this project will identify bacterial enzymes involved in androgen biotransformation and biosynthesis and obtain bacterial species harboring these enzymes. This knowledge will serve as a springboard for future functional studies using preclinical models of CRPC and inhibitors targeting bacterial androgen biotransformation and synthesis enzymes and/or species that harbor them to alleviate CRPC, thus providing an innovative approach to slow or prevent prostate cancer progression.