Multi-omics analyses identify gut microbiota-fecal metabolites-brain-cognition pathways in the Alzheimer’s disease continuum

作者：Han Zhao, Xia Zhou, Yu Song, Wenming Zhao, Zhongwu Sun, Jiajia Zhu, Yongqiang Yu · 发表于：Alzheimer s Research & Therapy · 年份：2025 · DOI：10.1186/s13195-025-01683-0 · 被引用次数：58 · 研究领域：Gut microbiota and health、Metabolomics and Mass Spectrometry Studies、Tryptophan and brain disorders

BACKGROUND: Gut microbiota dysbiosis is linked to Alzheimer's disease (AD), but our understanding of the molecular and neuropathological bases underlying such association remains fragmentary. METHODS: Using 16S rDNA amplicon sequencing, untargeted metabolomics, and multi-modal magnetic resonance imaging, we examined group differences in gut microbiome, fecal metabolome, neuroimaging measures, and cognitive variables across 30 patients with AD, 75 individuals with mild cognitive impairment (MCI), and 61 healthy controls (HC). Furthermore, we assessed the associations between these multi-omics changes using correlation and mediation analyses. RESULTS: There were significant group differences in gut microbial composition, which were driven by 8 microbial taxa (e.g., Staphylococcus and Bacillus) exhibiting a progressive increase in relative abundance from HC to MCI to AD, and 2 taxa (e.g., Anaerostipes) showing a gradual decrease. 26 fecal metabolites (e.g., Arachidonic, Adrenic, and Lithocholic acids) exhibited a progressive increase from HC to MCI to AD. We also observed progressive gray matter atrophy in broadly distributed gray matter regions and gradual micro-structural integrity damage in widespread white matter tracts along the AD continuum. Integration of these multi-omics changes revealed significant associations between microbiota, metabolites, neuroimaging, and cognition. More importantly, we identified two potential mediation pathways: (1) microbiota → metabolites → n...