Fan Kang-Chen, Lin Chen-Ching, Chiu Yen-Ling, Koh Seong-Ho, Liu Yi-Chien, Chuang Yi-Fang
School of Medicine, National Yang Ming Chiao Tung University, 155 Sec. 2, Linong St., Beitou Dist, Taipei City, 112304, Taiwan.
Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, 155 Sec. 2, Linong St., Beitou Dist, Taipei City, 112304, Taiwan.
Alzheimers Res Ther. 2025 May 30;17(1):122. doi: 10.1186/s13195-025-01769-9.
Emerging evidence highlights the bidirectional communication between the gut microbiota and the brain, suggesting a potential role for gut dysbiosis in Alzheimer's disease (AD) pathology and cognitive decline. Existing literature on gut microbiota lacks species-level insights. This study investigates gut microbiota alterations in mild cognitive impairment (MCI), focusing on their association with comprehensive AD biomarkers, including amyloid burden, tau pathology, neurodegeneration, and cognitive performance.
We analyzed fecal samples from 119 individuals with MCI and 320 cognitively normal controls enrolled in the Taiwan Precision Medicine Initiative on Cognitive Impairment and Dementia cohort. Shotgun metagenomic sequencing was conducted with taxonomic profiling using MetaPhlAn4. Amyloid burden and plasma pTau181 were quantified via PET imaging and Simoa assays, respectively, while APOE genotyping was performed using TaqMan assays. Microbial diversity, differential abundance analysis, and correlation mapping with neuropsychological and neuroimaging measures were conducted to identify gut microbiota species signatures associated with MCI and AD biomarkers.
We identified 59 key microbial species linked to MCI and AD biomarkers. Notably, species within the same genera, such as Bacteroides and Ruminococcus, showed opposing effects, while Akkermansia muciniphila correlated with reduced amyloid burden, suggesting a protective role. Functional profiling revealed microbial pathways contributing to energy metabolism and neuroinflammation, mediating the relationship between gut microbes and brain health. Co-occurrence network analyses demonstrated complex microbial interactions, indicating that the collective influence of gut microbiota on neurodegeneration.
Our findings challenge genus-level microbiome analyses, revealing species-specific modulators of AD pathology. This study highlights gut microbial activity as a potential therapeutic target to mitigate cognitive decline and neurodegeneration.
新出现的证据突显了肠道微生物群与大脑之间的双向交流，提示肠道菌群失调在阿尔茨海默病（AD）病理和认知衰退中可能发挥作用。现有关于肠道微生物群的文献缺乏物种水平的见解。本研究调查轻度认知障碍（MCI）患者的肠道微生物群变化，重点关注其与包括淀粉样蛋白负荷、tau病理、神经退行性变和认知表现在内的综合AD生物标志物的关联。
我们分析了台湾认知障碍与痴呆精准医学计划队列中119名MCI患者和320名认知正常对照的粪便样本。使用MetaPhlAn4进行鸟枪法宏基因组测序和分类分析。分别通过PET成像和Simoa检测对淀粉样蛋白负荷和血浆pTau181进行定量，同时使用TaqMan检测进行APOE基因分型。进行微生物多样性、差异丰度分析以及与神经心理学和神经影像学指标的相关性映射，以确定与MCI和AD生物标志物相关的肠道微生物物种特征。
我们鉴定出59种与MCI和AD生物标志物相关的关键微生物物种。值得注意的是，同一属内的物种，如拟杆菌属和瘤胃球菌属，表现出相反的作用，而嗜黏蛋白阿克曼氏菌与淀粉样蛋白负荷降低相关，提示其具有保护作用。功能分析揭示了有助于能量代谢和神经炎症的微生物途径，介导了肠道微生物与大脑健康之间的关系。共现网络分析显示了复杂的微生物相互作用，表明肠道微生物群对神经退行性变的集体影响。
我们的研究结果对属水平的微生物组分析提出了挑战，揭示了AD病理的物种特异性调节因子。本研究强调肠道微生物活性作为减轻认知衰退和神经退行性变的潜在治疗靶点。
