Zhou Chenglong, Feng Xin, Liu Huina, Cai Ting, Li Yihong, Fan Huadong
College of Biological & Environmental Sciences, Zhejiang Wanli University, Ningbo, China.
Ningbo No. 2 Hospital, Ningbo, China.
Front Neurosci. 2025 May 23;19:1593854. doi: 10.3389/fnins.2025.1593854. eCollection 2025.
Emerging evidence implicates gut microbiota dysbiosis as a key modulator for the pathogenesis of Alzheimer's disease (AD) via the gut-brain axis. To investigate the causal role of microbial communities in AD progression, we performed fecal microbiota transplantation (FMT) in APP/PS1 transgenic mice using donor microbiota from healthy wild-type mice or dextran sulfate sodium (DSS)-induced colitis mice.
Cognitive function, amyloid-beta (Aβ) pathology, and pro-inflammatory cytokine levels were assessed in mice. 16S ribosomal RNA sequencing of gut microbiota and bioinformatic functional analyses were applied to identify the specific microbial communities potentially involved in AD progression.
FMT-WT mice (fecal microbiota transplantation from healthy wild-type mice) exhibited significant improvements in spatial memory (Morris Water Maze), exploratory behavior (Y-maze), and locomotor activity (Open Field Test), alongside reduced Aβ plaque burden and normalized expression of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) in both gut and brain tissues. Conversely, FMT-DSS mice (fecal microbiota transplantation from DSS-treated donors) displayed exacerbated cognitive deficits, heightened Aβ deposition, and elevated pro-inflammatory cytokine levels. Microbial profiling revealed stark contrasts: FMT-WT mice harbored beneficial taxa (, ) linked to anti-inflammatory products like short-chain fatty acid, while FMT-DSS mice showed blooms of pathogenic genera (, ) associated with neurotoxic metabolites. Functional analyses predicted enrichment of neuroprotective pathways (e.g., lysine metabolism) in FMT-WT and pro-inflammatory pathways (e.g., carbon metabolism) in FMT-DSS. Crucially, neuroinflammation occurred independently of gut barrier disruption, implicating circulating microbial metabolites as key mediators.
Our findings demonstrate that gut microbiota composition bidirectionally influences AD progression, with FMT from healthy donors attenuating neuroinflammation and pathology, while colitis-associated dysbiosis exacerbates disease hallmarks. Our study positions microbiota-targeted therapies as a promising strategy to modulate AD progression through the gut-brain axis.
新出现的证据表明，肠道微生物群失调是通过肠-脑轴在阿尔茨海默病（AD）发病机制中起关键调节作用的因素。为了研究微生物群落在AD进展中的因果作用，我们使用来自健康野生型小鼠或硫酸葡聚糖钠（DSS）诱导的结肠炎小鼠的供体微生物群，对APP/PS1转基因小鼠进行了粪便微生物群移植（FMT）。
对小鼠的认知功能、淀粉样β蛋白（Aβ）病理学和促炎细胞因子水平进行评估。应用肠道微生物群的16S核糖体RNA测序和生物信息学功能分析来鉴定可能参与AD进展的特定微生物群落。
FMT-WT小鼠（来自健康野生型小鼠的粪便微生物群移植）在空间记忆（莫里斯水迷宫）、探索行为（Y迷宫）和运动活动（旷场试验）方面表现出显著改善，同时肠道和脑组织中的Aβ斑块负担减轻，促炎细胞因子（IL-6、IL-1β、TNF-α）的表达恢复正常。相反，FMT-DSS小鼠（来自DSS处理供体的粪便微生物群移植）表现出更严重的认知缺陷、更高的Aβ沉积和更高的促炎细胞因子水平。微生物谱分析显示出鲜明对比：FMT-WT小鼠含有与抗炎产物如短链脂肪酸相关的有益分类群（，），而FMT-DSS小鼠则显示出与神经毒性代谢物相关的致病属（，）大量繁殖。功能分析预测FMT-WT中神经保护途径（如赖氨酸代谢）的富集和FMT-DSS中促炎途径（如碳代谢）的富集。至关重要的是，神经炎症的发生与肠道屏障破坏无关，这表明循环微生物代谢物是关键介质。
我们的研究结果表明，肠道微生物群组成双向影响AD进展，来自健康供体的FMT可减轻神经炎症和病理，而结肠炎相关的失调会加剧疾病特征。我们的研究将以微生物群为靶点的疗法定位为一种通过肠-脑轴调节AD进展的有前景的策略。
