Yang Fan, Liu Yanbo, Zhou Zhien, Yang Dong, Yan Weigang
Department of Urology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Anesthesiology, Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
CNS Neurosci Ther. 2025 Sep;31(9):e70608. doi: 10.1111/cns.70608.
Although a key intervention for advanced Prostate Cancer, Androgen Deprivation Therapy has been associated with cognitive dysfunction, a phenomenon that has been largely attributed to systemic metabolic alterations and neuroinflammation. Nonetheless, the precise role of gut microbiota in ADT-induced cognitive impairment remains unclear, forming the basis of this study. Our aim is to explore the correlation between changes in gut metabolism and cognitive dysfunction following ADT in prostate cancer.
A subcutaneous PC3 tumor-bearing mouse model of ADT-induced cognitive dysfunction was established. Behavioral tests (OFT, NORT, and Y-maze) were conducted to assess cognitive performance. Gut microbiota composition, fecal, and hippocampal bile acid profiles were analyzed by 16S rRNA sequencing and targeted metabolomics. To investigate potential mechanisms, we further supplemented ADT-susceptible (ADT-su) mice with Taurodeoxycholic acid (TDCA) via oral gavage and inhibited ERK1/2 signaling with PD98059, followed by behavioral testing and Western blot analysis of hippocampal Takeda G-protein coupled Receptor 5 (TGR5) and ERK1/2 expression.
Hierarchical clustering analysis revealed ADT-induced cognitive impairment in a subset of mice (ADT-susceptible and ADT-unsusceptible). These mice exhibited gut microbiota dysbiosis, featuring the depletion of bile acid-transforming taxa, including Bacteroides spp. and Clostridium scindens. Additionally, FMT from ADT-su mice to pseudo-germ-free mice efficiently transferred cognitive deficits and altered hippocampal bile acid profiles, confirming gut microbiota's causal role in ADT-induced neurocognitive decline. Notably, both gut and hippocampal TDCA levels were significantly decreased in ADT-su mice. Mechanistically, TDCA supplementation improved cognitive performance and upregulated hippocampal TGR5 and p-ERK1/2 expression, while ERK1/2 inhibition by PD98059 partially reversed these effects.
Our findings suggest that gut microbiota-mediated bile acid dysregulation, particularly reduced TDCA, contributes to ADT-induced cognitive dysfunction via impaired TGR5-ERK1/2 signaling. Targeting this pathway may represent a novel therapeutic strategy to mitigate cognitive impairment in prostate cancer patients undergoing ADT.
雄激素剥夺疗法（ADT）虽是晚期前列腺癌的关键干预措施，但与认知功能障碍有关，这一现象很大程度上归因于全身代谢改变和神经炎症。尽管如此，肠道微生物群在ADT诱导的认知障碍中的确切作用仍不清楚，这构成了本研究的基础。我们的目的是探讨前列腺癌患者接受ADT后肠道代谢变化与认知功能障碍之间的相关性。
建立ADT诱导的认知功能障碍的皮下荷PC3肿瘤小鼠模型。进行行为测试（旷场试验、新物体识别试验和Y迷宫试验）以评估认知表现。通过16S rRNA测序和靶向代谢组学分析肠道微生物群组成、粪便和海马胆汁酸谱。为了研究潜在机制，我们通过口服灌胃进一步给ADT敏感（ADT-su）小鼠补充牛磺去氧胆酸（TDCA），并用PD98059抑制ERK1/2信号通路，随后进行行为测试和对海马中武田G蛋白偶联受体5（TGR5）和ERK1/2表达的蛋白质印迹分析。
层次聚类分析显示，一部分小鼠（ADT敏感和ADT不敏感）出现了ADT诱导的认知障碍。这些小鼠表现出肠道微生物群失调，其特征是胆汁酸转化类群减少，包括拟杆菌属和梭状芽孢杆菌。此外，将ADT-su小鼠的粪便微生物群移植到无菌小鼠有效地传递了认知缺陷并改变了海马胆汁酸谱，证实了肠道微生物群在ADT诱导的神经认知衰退中的因果作用。值得注意的是，ADT-su小鼠的肠道和海马TDCA水平均显著降低。从机制上讲，补充TDCA改善了认知表现，并上调了海马TGR5和p-ERK1/2表达，而PD98059对ERK1/2的抑制部分逆转了这些作用。
我们的研究结果表明，肠道微生物群介导的胆汁酸失调，特别是TDCA减少，通过受损的TGR5-ERK1/2信号通路导致ADT诱导的认知功能障碍。针对这一途径可能代表一种新的治疗策略，以减轻接受ADT的前列腺癌患者的认知障碍。
