Integrated multi-omics profiling identifies a convergent gut-metabolic-immune signature in Alzheimer's disease.
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder with rising global prevalence, yet the peripheral mechanisms linking gut dysbiosis, systemic redox imbalance, and immune activation remain poorly understood. Here, we performed integrated multi-omics profiling of fecal microbiome, serum metabolome, and circulating cytokines in 40 patients with AD and 40 cognitively matched controls, with a specific focus on oxidative stress and antioxidant signatures. Compared with controls, AD patients exhibited marked gut microbial dysbiosis characterized by butyrate-producing genera (including Faecalibacterium and Roseburia) and enrichment of pro-inflammatory taxa (including Escherichia/Shigella). Serum metabolomics identified a distinct oxidative stress phenotype: AD samples showed significantly elevated levels of xanthosine, (±)-3-hydroxynonanoic acid, and several acyl-carnitines, alongside a marked reduction in the antioxidant carotenoid capsorubin (AUC = 0.98) and other protective compounds. Lipid peroxidation products, including 15,16-epoxy-9,12-octadecadienoic acid and (Z)-5,8,11-trihydroxyoctadec-9-enoic acid, inversely correlated with cognitive scores (MMSE, Barthel Index, WAIS-IV). Concurrently, circulating pro-inflammatory cytokines (IL-8, MCP-1, IP-10, TNF-α) were elevated and correlated positively with both AD-enriched bacteria and oxidative metabolites, while showing negative correlations with antioxidant-related compounds. Integrated network analysis linked loss of butyrate-producing microbes to accumulation of oxidative stress biomarkers and heightened chemokine signaling, which together associated with worse cognitive performance. Selected microbial and redox-related metabolic features achieved excellent diagnostic accuracy (AUC > 0.95). Collectively, these findings define a convergent gut-metabolic-immune axis in AD where systemic oxidative stress serves as a central hub, providing specific, measurable redox biomarkers and mechanistic insights for noninvasive screening and therapeutic targeting.