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

项目摘要 微生物组在癌症中的新作用是微生物影响治疗、药物疗效的能力 和新陈代谢。例如，我们最近表明，肠道微生物组在阉割中起着重要作用， 通过微生物来源的雄激素合成治疗耐药前列腺癌（CRPC）（Pernigoni等人，Science. 2021;374（6564）：216-224）。在那项研究中，我们发现，在小鼠和人类中，雄激素剥夺都会促进 能够将睾酮前体转化为活性睾酮的特定肠道细菌的扩增， 通过细菌CYP 17 A1样酶（活泼瘤胃球菌、瘤胃球菌属和拟杆菌属 产酸杆菌），从而增加其在CRPC患者和小鼠中的水平，并防止CRPC的完全抑制。 雄激素剥夺治疗期间的睾酮水平。除了生物合成途径，睾酮 生物利用度可以代表调节治疗反应的附加手段。雄激素 葡萄糖醛酸化的雄激素在肝脏中消除，一部分到达肠道 通过胆汁，并被细菌β-葡萄糖醛酸酶（GUS）（活泼瘤胃球菌，瘤胃球菌 sp.，产酸拟杆菌和产酸梭菌）用于“再活化”和潜在的重吸收。事实上， 男性肠内雄激素浓度高于血清。另一条肠道 微生物群有助于雄激素的生物利用度是通过皮质醇到11β-羟基雄烯二酮 通过细菌类固醇-17，20-碳链酶（Clostridium dendens desABCD操纵子）转化。11β- 羟基雄烯二酮转化为11-氧雄激素，这有助于肿瘤雄激素库。是 目前还不清楚这些不同途径中的每一种对循环雄激素库的贡献有多大。我们的中央 假设是肠道微生物组通过一种代谢途径促进雄激素的产生和生物利用度。 生物合成和生物利用度途径的组合。本项目的目标是通过计算确定 CRPC患者肠道微生物组中的雄激素相关细菌酶（CYP 17 A1样、GUS、德萨和desB） 并分离携带这些酶的细菌物种用于功能分析。建议的理由 研究结果将为CRPC干预措施的未来发展和评估提供目标 最小化或阻止雄激素生物利用度的患者。我们的假设将通过两个 具体目标：目标1）识别前列腺癌肠道微生物组中雄激素相关的细菌酶 患者目的2）研究具有雄激素相关酶的细菌的功能。在 完成后，该项目将确定参与雄激素生物转化和生物合成的细菌酶 并获得携带这些酶的细菌物种。这一知识将作为今后工作的跳板。 使用CRPC的临床前模型和靶向细菌雄激素生物转化的抑制剂进行的功能研究 和合成酶和/或包含它们的物质以减轻CRPC，从而提供了一种创新的 前列腺癌的治疗方法有哪些

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.