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.