Gut Microbiota–Bile Acid–Brain Axis and TGR5-ERK1/2 Signaling Mediate ADT-Induced Cognitive Impairment

IF 5 1区医学 Q1 NEUROSCIENCES

CNS Neuroscience & Therapeutics Pub Date : 2025-09-15 DOI:10.1111/cns.70608

Fan Yang, Yanbo Liu, Zhien Zhou, Dong Yang, Weigang Yan

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引用次数: 0

Abstract

Aims

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.

Methods

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.

Results

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.

Conclusion

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.

Abstract Image

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肠道微生物-胆汁酸-脑轴和TGR5-ERK1/2信号介导adt诱导的认知障碍。

目的：尽管雄激素剥夺治疗是晚期前列腺癌的关键干预措施，但它与认知功能障碍有关，这一现象主要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ADT后肠道代谢变化与认知功能障碍之间的相关性。方法：建立adt诱导的PC3荷瘤小鼠皮下认知功能障碍模型。行为测试（OFT、NORT和Y-maze）评估认知表现。通过16S rRNA测序和靶向代谢组学分析肠道菌群组成、粪便和海马胆汁酸谱。为了探讨潜在的机制，我们进一步通过灌胃方式给adt易感（ADT-su）小鼠补充牛头脱氧胆酸（TDCA），并用PD98059抑制ERK1/2信号传导，随后进行行为测试和Western blot分析海马Takeda g蛋白偶联受体5 （TGR5）和ERK1/2的表达。结果：层次聚类分析显示adt诱导的认知障碍小鼠亚群（adt易感和adt不易感）。这些小鼠表现出肠道菌群失调，表现为胆汁酸转化类群的消耗，包括拟杆菌和梭状芽孢杆菌。此外，从ADT-su小鼠到伪无菌小鼠的FMT有效地转移了认知缺陷和改变了海马胆汁酸谱，证实了肠道微生物群在adt诱导的神经认知能力下降中的因果作用。值得注意的是，ADT-su小鼠的肠道和海马TDCA水平均显著降低。在机制上，补充TDCA可以改善认知能力，上调海马TGR5和p-ERK1/2的表达，而PD98059抑制ERK1/2部分逆转了这些作用。结论：我们的研究结果表明，肠道微生物介导的胆酸失调，特别是TDCA的减少，通过TGR5-ERK1/2信号受损，有助于adt诱导的认知功能障碍。靶向这一途径可能代表了一种新的治疗策略，以减轻前列腺癌患者接受ADT的认知障碍。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.