The Blood–Brain Barrier as an Integration Hub in Alzheimer's Disease: How Microbiota Metabolites Modulate Central Signal Processing

Background: While both gut–brain axis dysfunction and blood–brain barrier (BBB) breakdown are documented in Alzheimer's disease (AD), current research treats these as separate phenomena. However, emerging evidence suggests that the BBB may function as an active integration interface that processes microbiota-derived metabolites and thereby potentially modulates how peripheral signals influence cognitive health. Objective: This review synthesizes current evidence on microbiota metabolites as modulators of BBB integration capacity, discussing how such mechanisms may contribute to variability in cognitive outcomes despite similar gut microbiome profiles by demonstrating how BBB signal-integration mechanisms determine gut–brain communication effectiveness in AD. Methods: We analyzed peer-reviewed literature from 2010 to 2025, focusing on BBB dynamic properties, microbiota metabolite effects on BBB function, and their integration patterns, emphasizing functional evidence supporting the BBB's active signal processing capabilities. Results: Current evidence suggests that the BBB exhibits integration properties, including dynamic permeability regulation, context-dependent metabolite processing, and coordinated responses to complex signal streams. Short-chain fatty acids enhance integration capacity through HDAC inhibition and coordinated receptor activation, while lipopolysaccharides and trimethylamine N-oxide may overwhelm integration processes through TLR4-mediated disruption. BBB dysfunction precedes classical AD pathology and correlates with altered metabolite processing capacity. Individual variations in BBB integration capacity may help account for why individuals with similar gut microbiome profiles show different cognitive outcomes. Conclusion: Viewing the BBB as an active integration interface offers a useful perspective for organizing current evidence on gut–brain interactions in AD. This conceptual perspective suggests that therapeutic strategies might benefit from supporting BBB integration capacity and optimizing metabolite-processing mechanisms alongside improving gut health. © 2025 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.