Table 8_Microbiota-derived metabolite signatures in Alzheimer’s disease across the cognitive aging continuum: a human-focused systematic review and evidence-weighted knowledge graph.xlsx

Module-level quantitative summaries were retained only where data were sufficiently comparable; otherwise, structured direction-of-effect synthesis and evidence mapping were used. Overlapping Alzheimer’s Disease Neuroimaging Initiative (ADNI) bile-acid analyses were synthesized as complementary outcome layers rather than treated as independent replications of the same association.</p>Results<p>The final evidence pool contains 60 records, including 32 direct, bridge, or intervention human evidence records and 28 mechanistic, translational, animal, cellular, resource, or background-mechanism records.

Bile-acid profiles and short-chain fatty acid (SCFA)-related functional capacity were recurrent human evidence modules. Trimethylamine N-oxide (TMAO)/choline-related findings were context dependent, varying by biological matrix, population, renal function, and cardiometabolic context, whereas selected tryptophan/indole/kynurenine pathways remained emerging. Across these metabolite modules, the evidence-weighted knowledge graph showed recurrent convergence on barrier dysfunction, inflammatory and glial signaling, and mitochondrial stress, while retaining context-dependent conflicts and gaps in human validation.</p>Conclusion<p>The current literature points to a convergent network of microbiota-related metabolic pathways rather than a single metabolite marker or causal route.

The synthesis prioritizes external validation of bile-acid signatures, matched multi-compartment assessment of SCFA- and TMAO-related pathways, and direct human testing of indole/kynurenine and lipid-like mechanisms. These priorities require longitudinal and interventional studies with harmonized metabolomics, AD biomarkers, and cognitive outcomes.</p>