Yu Yao, Li Leqian, Yang Qishen, Xue Jingwen, Wang Benlin, Xie Ming, Shangguan Wentai, Zhu Zhangrui, Wu Peng
Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Microorganisms. 2024 Aug 12;12(8):1653. doi: 10.3390/microorganisms12081653.
Prostate cancer (PCa) is initially sensitive to androgen deprivation therapy (ADT) but ultimately develops resistance and progresses to castration-resistant prostate cancer (CRPC) with a poor prognosis. This study indicated that some PCa patients and mice were more sensitive to ADT and entered CRPC later, which was related to the gut microbiota, especially the enrichment of (AKK). Untargeted metabolomics analysis found that serum inosine level was upregulated in the treatment-sensitive group and significantly correlated with AKK. Furthermore, we revealed that intestinal permeability and serum lipopolysaccharide (LPS) levels increased in treatment-resistant mice. LPS stimulated the upregulation of p-NF-κB p65 and AR in tumors. Supplementing AKK metabolite inosine could alleviate intestinal barrier damage and reduce serum LPS level, ultimately inhibiting castration resistance via the LPS/NF-κB/AR axis. Finally, we constructed a predictive model for CRPC combining gut microbiota and clinical information (AUC = 0.729). This study revealed the potential mechanism of gut microbiota on CRPC and provided potential therapeutic targets and prognostic indicators.
前列腺癌（PCa）最初对雄激素剥夺疗法（ADT）敏感，但最终会产生耐药性并进展为去势抵抗性前列腺癌（CRPC），预后较差。本研究表明，一些PCa患者和小鼠对ADT更敏感，且较晚进入CRPC阶段，这与肠道微生物群有关，尤其是阿克曼菌（AKK）的富集。非靶向代谢组学分析发现，治疗敏感组血清肌苷水平上调，且与AKK显著相关。此外，我们发现治疗抵抗小鼠的肠道通透性和血清脂多糖（LPS）水平升高。LPS刺激肿瘤中p-NF-κB p65和AR的上调。补充AKK代谢产物肌苷可减轻肠道屏障损伤并降低血清LPS水平，最终通过LPS/NF-κB/AR轴抑制去势抵抗。最后，我们构建了一个结合肠道微生物群和临床信息的CRPC预测模型（曲线下面积=0.729）。本研究揭示了肠道微生物群对CRPC的潜在作用机制，并提供了潜在的治疗靶点和预后指标。
