Lei Wenhui, Cheng Yiwen, Liu Xia, Gao Jie, Zhu Zhangcheng, Ding Wenwen, Xu Xiaocui, Li Yating, Ling Zongxin, Jiang Ruilai, Chen Xiaoying
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China.
Front Immunol. 2025 Jun 26;16:1582119. doi: 10.3389/fimmu.2025.1582119. eCollection 2025.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques, tau hyperphosphorylation, and chronic neuroinflammation. While neuroinflammation-mediated by microglial and astrocyte activation-has long been considered a secondary response to Aβ pathology, emerging evidence positions it as a primary driver of cognitive decline. Notably, the gut microbiota, through the microbiota-gut-brain axis (MGBA), is crucial in modulating neuroinflammation. Dysbiosis disrupts gut barrier integrity, promotes systemic inflammation, and exacerbates neuroinflammatory responses, thereby accelerating AD progression. Recent advances reveal that gut microbiota-derived metabolites (e.g., short-chain fatty acids, lipopolysaccharides) directly influence microglial activation and Aβ aggregation. These findings have opened new therapeutic possibilities, with microbiota-targeted approaches such as probiotics, prebiotics, and fecal microbiota transplantation demonstrating promising neuroprotective effects in preclinical studies by reducing neuroinflammation and preserving cognitive function. However, translating these findings into clinical applications requires further validation through randomized controlled trials. This review summarizes the current understanding of gut microbiota-driven neuroinflammation in AD, from molecular mechanisms to potential therapeutic strategies. Targeting the MGBA represents a paradigm shift in AD management, emphasizing the modulation of neuroinflammation and pathological progression through gut microbiota interventions. The discussion also addresses existing research challenges and outlines future directions to advance this promising field.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，其特征为β淀粉样蛋白（Aβ）斑块、tau蛋白过度磷酸化和慢性神经炎症。虽然由小胶质细胞和星形胶质细胞激活介导的神经炎症长期以来被认为是对Aβ病理的继发反应，但新出现的证据表明它是认知衰退的主要驱动因素。值得注意的是，肠道微生物群通过微生物群-肠道-脑轴（MGBA）在调节神经炎症方面起着关键作用。微生物群失调会破坏肠道屏障完整性，促进全身炎症，并加剧神经炎症反应，从而加速AD的进展。最近的研究进展表明，肠道微生物群衍生的代谢产物（如短链脂肪酸、脂多糖）直接影响小胶质细胞的激活和Aβ聚集。这些发现开辟了新的治疗可能性，益生菌、益生元、粪便微生物群移植等针对微生物群的方法在临床前研究中通过减轻神经炎症和保护认知功能显示出有前景的神经保护作用。然而，将这些发现转化为临床应用需要通过随机对照试验进一步验证。本综述总结了目前对AD中肠道微生物群驱动的神经炎症的理解，从分子机制到潜在的治疗策略。针对MGBA代表了AD管理中的范式转变，强调通过肠道微生物群干预来调节神经炎症和病理进展。讨论还涉及了现有的研究挑战，并概述了推动这一有前景领域发展的未来方向。
