{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T11:38:33Z","timestamp":1792755513037,"version":"4.5.0"},"reference-count":144,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Late-life epilepsy is an increasingly important neurological and public health challenge, yet its biological basis remains incompletely understood. The microbiota\u2013gut\u2013brain 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\u2013gut\u2013brain axis in ways relevant to epilepsy in older adults. We summarize aging-related remodeling of this axis, including gut dysbiosis, impaired intestinal and blood\u2013brain 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\u2013brain communication. On this basis, we propose that aging may increase the likelihood that epilepsy-associated microbiota\u2013gut\u2013brain 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\u2013gut\u2013brain 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.<\/jats:p>","DOI":"10.3389\/fnmol.2026.1861519","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:12:11Z","timestamp":1789377131000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Aging, the microbiota\u2013gut\u2013brain axis, and late-life epilepsy: a hypothesis-driven review"],"prefix":"10.3389","volume":"19","author":[{"given":"Yingsi","family":"Cao","sequence":"first","affiliation":[{"name":"School of Health Medicine, Nantong Institute of Technology","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiying","family":"Li","sequence":"additional","affiliation":[{"name":"School of Health Medicine, Nantong Institute of Technology","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minzheng","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Health Medicine, Nantong Institute of Technology","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuting","family":"Teng","sequence":"additional","affiliation":[{"name":"School of Health Medicine, Nantong Institute of Technology","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Ying","family":"Gu","sequence":"additional","affiliation":[{"name":"School of Health Medicine, Nantong Institute of Technology","place":["Nantong, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"661","DOI":"10.1161\/strokeaha.122.040578","article-title":"Blood-brain barrier dysfunction in Normal aging and neurodegeneration: mechanisms, impact, and treatments","volume":"54","author":"Andjelkovic","year":"2023","journal-title":"Stroke"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"108588","DOI":"10.1016\/j.yebeh.2022.108588","article-title":"Probiotic supplementation alleviates absence seizures and anxiety- and depression-like behavior in WAG\/Rij rat by increasing neurotrophic factors and decreasing proinflammatory cytokines","volume":"128","author":"Aygun","year":"2022","journal-title":"Epilepsy Behav."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"3256","DOI":"10.1093\/brain\/awn271","article-title":"A novel non-transcriptional pathway mediates the proconvulsive effects of interleukin-1 beta","volume":"131","author":"Balosso","year":"2008","journal-title":"Brain"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1111\/j.1365-2672.2012.05344.x","article-title":"\u0393-Aminobutyric acid production by culturable bacteria from the human intestine","volume":"113","author":"Barrett","year":"2012","journal-title":"J. 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