HOW GUT MICROBIOTA MAY MEDIATE THE ANTI-SEIZURE EFFECTS OF KETOGENIC DIET IN PEDIATRIC DRUG-RESISTANT EPILEPSY: A NARRATIVE REVIEW

Abstract

Drug-resistant epilepsy (DRE) affects a substantial proportion of children with epilepsy, with cumulative incidence estimates reaching approximately 25% according to the International League Against Epilepsy (ILAE) consensus definition. This review aims to synthesize current evidence on the epidemiology and definition of pediatric DRE, the clinical efficacy of the ketogenic diet (KD) as an established therapeutic option, and the emerging mechanistic role of the gut-brain axis in mediating KD's anti-seizure effects. A non-systematic literature search was conducted, focusing on key studies addressing the relationship between KD, gut microbiota, and seizure outcomes in pediatric DRE, with literature on the gut-brain mechanism primarily drawn from the past decade, reflecting when substantive research in this area began to emerge. Findings indicate that KD produces clinically meaningful seizure reduction across randomized controlled trials and multicenter cohort studies, with a generally favorable safety profile. Beyond ketosis and elevated beta-hydroxybutyrate (BHB), preclinical evidence demonstrates that an intact gut microbiota, particularly Akkermansia muciniphila and Parabacteroides, is required for KD's anti-seizure efficacy, acting through short-chain fatty acid production and modulation of the hippocampal GABA/glutamate ratio. This mechanism converges with that of a conventional antiseizure medication, topiramate, supporting the gut-brain axis as a biologically plausible therapeutic pathway. Furthermore, distinct microbiota signatures have been associated with treatment response, suggesting potential utility as predictive biomarkers. These findings support the continued use of KD in pediatric DRE and highlight the gut microbiota as a promising target for future mechanistic and translational research.