Integrated gut microbiome and fecal metabolome profiling identifies taurine-associated microbial dysbiosis across the Alzheimer's disease clinical spectrum.

Abstract

BACKGROUND: Gut microbiome alterations have been associated with Alzheimer's disease (AD), but how microbial composition, fecal metabolites, and cognitive function relate across the cognitive impairment spectrum-from subjective cognitive decline (SCD) through mild cognitive impairment (MCI) to AD-remains unclear. We integrated microbiome and metabolome profiles across this clinical spectrum. METHODS: Fecal samples from 84 participants [10 healthy controls (HC), 22 SCD, 23 MCI, 29 AD] underwent 16S rRNA V3-V4 sequencing and untargeted LC-MS metabolomics. Profiles were integrated via Procrustes analysis, sparse canonical correlation, MIMOSA2 community-metabolism modeling, and mediation analysis. Differential abundance was assessed by Kruskal-Wallis, ANCOM-BC2, and LinDA. RESULTS: Microbial composition differed across groups (ANOSIM R = 0.111, p = 0.001; Adonis R 2 = 0.070, p = 0.002). Cross-method validation confirmed 8 differentially abundant genera in AD vs. HC with 100% directional concordance between ANCOM-BC2 and LinDA, including depletion of butyrate-producing Lachnospiraceae (Blautia, Dorea, Fusicatenibacter) and enrichment of opportunistic pathobionts (Klebsiella, Escherichia-Shigella). Taurine showed the highest MIMOSA2 community-prediction R 2 (0.129; n = 62) and was positively associated with MMSE scores (r = 0.45, BH-FDR Q = 0.0005). A multi-omic random forest model (5 genera + 5 metabolites + age + sex) discriminated AD-clinical spectrum participants from HC with AUC = 0.86 (95% CI 0.82-0.90), although pairwise differences from the age + sex baseline (AUC = 0.75) did not reach statistical significance. Statistical mediation analysis was consistent with a Blautia → taurine → MMSE statistical mediation [ACME = 0.21, p = 0.008; 54% proportion mediated, bootstrap 95% CI (9%, 58%)]. CONCLUSION: Integrated multi-omic profiling reveals coordinated microbiome-metabolome dysregulation across the AD clinical spectrum, with taurine as a candidate microbial-metabolic node linking gut dysbiosis to cognitive performance. Microbial and metabolic alterations are detectable at the SCD stage, before objective cognitive impairment. These findings warrant validation in larger, age-matched cohorts and higher-resolution metagenomic studies.

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