Aging, the microbiota-gut-brain axis, and late-life epilepsy: a hypothesis-driven review.

Abstract

Late-life epilepsy is an increasingly important neurological and public health challenge, yet its biological basis remains incompletely understood. The microbiota-gut-brain axis has emerged as a systems-level framework linking peripheral metabolism, barrier integrity, immune signaling, and brain excitability. Growing evidence supports an association between gut dysbiosis and epilepsy, particularly drug-resistant epilepsy, although direct evidence specifically addressing this axis in late-life epilepsy remains limited. Most available data instead come from aging biology, general epilepsy cohorts, pediatric populations, and preclinical models. This review considers how aging may reshape the microbiota-gut-brain axis in ways relevant to epilepsy in older adults. We summarize aging-related remodeling of this axis, including gut dysbiosis, impaired intestinal and blood-brain barrier/neurovascular unit homeostasis, loss of protective microbial metabolites, chronic low-grade inflammation, and neuroimmune priming. We then review clinical, functional, and mechanistic evidence linking microbiota-related abnormalities to epilepsy, with emphasis on broad ecological imbalance, barrier dysfunction, neuroinflammatory signaling, short-chain fatty acid pathways, and vagal gut-brain communication. On this basis, we propose that aging may increase the likelihood that epilepsy-associated microbiota-gut-brain axis abnormalities translate into persistent peripheral inflammation, BBB/NVU vulnerability, amplified neuroinflammation, and reduced neural network resilience, thereby increasing seizure susceptibility. We further discuss microbiota-targeted interventions, including ketogenic diet, probiotics and prebiotics, fecal microbiota transplantation, and metabolite-based strategies, as hypothesis-informed translational directions rather than established therapies for late-life epilepsy. Overall, we suggest that the microbiota-gut-brain axis functions as a context-dependent modifier of vulnerability in late-life epilepsy and provides a useful framework for guiding future age-stratified, biomarker-oriented, and etiology-aware studies.