Gut–Brain Axis Modulation by Short‐Chain Fatty Acids Exerts Disease‐Modifying Effects in a Murine Model of Drug‐Resistant Epilepsy

Objective Drug‐resistant epilepsy (DRE) remains a clinical challenge, as therapies modifying disease trajectory are lacking. Increasing evidence implicates gut microbiota dysbiosis in epilepsy pathophysiology, with short‐chain fatty acids (SCFAs) emerging as key microbial metabolites with neuroprotective and anti‐inflammatory properties. Clinical studies show that people with DRE exhibit gut microbiota alterations that may impair fecal SCFAs production. Here, we investigated whether supplementation of SCFAs confers disease‐modifying effects in a preclinical model of DRE. Methods Adult male mice were subjected to status epilepticus (SE) and subsequently treated with a balanced mixture of acetate, propionate, and butyrate, or vehicle. Seizure frequency and temporal progression were monitored for 70 days by electroencephalography (EEG). At the study end point, cognitive performance, brain and gut histopathology, and neuroinflammation were assessed, together with metabolomic profiling of feces and blood. Brain SCFA levels and receptor expression were also analyzed in mice and in brain tissue from individuals with DRE. Results SCFA supplementation reduced the proportion of mice exhibiting a progressive phenotype and decreased the overall progression index (PI) 3‐fold, without significantly altering overall daily seizure frequency. Treatment reduced seizure clustering, improved cognitive deficits, restored hippocampal and intestinal alterations, and partially normalized cerebral SCFAs levels. Metabolomic profiling in epileptic mice and analysis of human epilepsy brain tissue support a mechanistic contribution of gut‐brain axis dysfunction to disease progression. Interpretation These findings identify SCFAs supplementation as a therapeutic strategy capable of modifying disease trajectory in experimental DRE, with clear translational relevance.