FEBS Letters · Aug 7, 2026

Microbiome-blood-brain barrier interactions in aging - mechanisms and therapeutic potential

By Cuervo-Zanatta D, Balasubramanian HB, Pasokh A et al.

Age-related decline in neurovascular integrity is an increasingly recognized contributor to cognitive impairment and neurodegenerative vulnerability. A central feature is blood-brain barrier (BBB) dysfunction arising from endothelial senescence, altered barrier regulation, and chronic low-grade inflammation. In parallel, aging remodels the gut microbiota, with reduced diversity, loss of short-chain fatty acid-producing commensals, and expansion of pro-inflammatory taxa. Converging evidence indicates that age-related shifts in the gut microbiota alter microbiome function and can modulate BBB physiology through microbial metabolites, immune-endothelial signaling, and systemic metabolic pathways. These data position the gut-brain axis as an important, but not sole, modulator of neurovascular aging. Preclinical and emerging human data suggest that dysbiosis lowers the threshold for BBB dysfunction, and microbiome-targeted interventions in experimental models can improve barrier-relevant features. Notably, no human trial has yet demonstrated that microbiome modulation prevents or reverses BBB impairment using validated neuroimaging or fluid biomarkers. This review synthesizes mechanisms of microbiota-BBB crosstalk in aging, distinguishes correlation from causation, and outlines translational opportunities and limitations of dietary, probiotic, and fecal microbiota-based strategies for preserving neurovascular health in older adults.

doi.org/10.1002/1873-3468.70412Open accessPubMed 42568240Mechanisms