Microbiome dysbiosis and phytochemical interactions in Alzheimer's disease: the oral–gut–brain axis

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by amyloid-β deposition, tau hyperphosphorylation, chronic neuroinflammation, and progressive cognitive decline. Increasing evidence suggests that, beyond classical neuropathology, alterations in the oral and gut microbiota contribute to AD through interconnected inflammatory, metabolic, immune, and epigenetic mechanisms. This review synthesizes recent findings on the oral–gut–brain axis, highlighting how oral dysbiosis may influence gut microbial ecology and how gut microbial metabolites mediate communication between the gastrointestinal tract and the CNS. Particular emphasis is placed on microbial metabolites, including short-chain fatty acids (SCFAs), lipopolysaccharide, trimethylamine N-oxide, bile acids, tryptophan-derived metabolites, vitamins, and neurotransmitter-related compounds, which regulate blood–brain barrier integrity, immune cell activation, microglial function, and neuronal survival. We further discuss how these metabolites modify host epigenetic machinery through histone acetylation, DNA methylation, and non-coding RNA regulation, thereby providing a mechanistic link between microbial dysbiosis and AD pathogenesis. The review also examines the reciprocal interactions between dietary phytochemicals and the gut microbiota, demonstrating that microbial biotransformation is often required to generate bioactive metabolites with improved bioavailability, blood–brain barrier penetration, and neuroprotective efficacy. Consequently, individual differences in microbial metabolic capacity may underlie the heterogeneous responses observed in clinical studies of nutraceutical interventions. Finally, we propose that integrating microbiome modulation, microbial metabolite profiling, epigenetic regulation, and microbiome-dependent phytochemical bioactivation offers a promising framework for developing personalized therapeutic strategies. Future research combining longitudinal human cohorts with multi-omics approaches and mechanistic studies will be essential to establish causality and translate microbiome-informed interventions into effective disease-modifying therapies for Alzheimer's disease.