Dynamic dual roles of gut microbial metabolites in Alzheimer's disease: Translational insights for gut-brain axis interventions.

Alzheimer's disease (AD) is a complex neurodegenerative disorder in which the microbiome-gut-brain axis (MGBA) plays a crucial regulatory role through microbial metabolites. This review analyzes the concentration trajectories of representative metabolites across different disease stages and compartments, and synthesizes current preclinical evidence on how these metabolites influence AD pathogenesis, with particular attention to the mechanisms underlying their dual roles. We integrate evidence for bidirectional pathological crosstalk: gut dysbiosis accelerates central neurodegeneration through altered metabolite signaling, while AD-related neuropathology concurrently disrupts gut homeostasis. The review also evaluates MGBA-targeted intervention strategies and critically identifies key limitations that hinder clinical translation, including unclear dose-response relationships and insufficient patient stratification. We note that brain-to-gut mechanistic evidence remains considerably less developed than that for the gut-to-brain direction, and that signaling crosstalk among multiple metabolites is poorly characterized. Future studies should prioritize the neuroendocrine and immune pathways linking central pathology to gut dysbiosis, the dose-response relationships of individual metabolites, and standardized multi-metabolite profiling within prospective longitudinal cohorts. Addressing these gaps will advance mechanism-guided, precision-targeted interventions that mitigate the prevalent gut dysfunction in AD and confer global therapeutic benefits.