Vagus Nerve Stimulation Ameliorates Epilepsy via a Gut Microbiota–Butyrate–Vagus Nerve–Brain Axis

SUMMARY Vagus nerve stimulation (VNS) is an established therapy for drug-resistant epilepsy, yet its mechanism remains partially understood. Here, through an integrated clinical–translational approach, we demonstrate that VNS modulates the gut microbiome and alter the level of butyrate to reduce seizure susceptibility via vagus nerve–dependent signaling. In a longitudinal cohort of epilepsy patients, VNS enriched short-chain fatty acid–producing bacteria, including Akkermansia muciniphila , Prevotella , Alistipes , and Odoribacter . Among clinical responders, fecal butyrate levels decreased concomitantly with an increase in plasma butyrate concentrations. Fecal microbiota transplantation from post-VNS patients into mice reduced seizure severity and improved gut barrier integrity. In a murine model of epilepsy, VNS similarly increased the abundance of Akkermansia and plasma butyrate concentrations, decreased fecal butyrate levels, and abolished its antiseizure effects upon vagotomy. Either colonization with Akkermansia muciniphila or exogenous butyrate supplementation was sufficient to reduce seizures and anxiety-like behavior, effects that also required intact vagal signaling. Our findings define a microbiota–butyrate–vagal pathway essential for the therapeutic effects of VNS, highlighting the gut–brain axis as a target for epilepsy treatment. GRAPHICAL ABSTRACT HIGHLIGHTS Vagus nerve stimulation (VNS) remodels the gut microbiota and alter the level of butyrate. VNS enriches short-chain fatty acids-producing bacteria, specifically Akkermansia muciniphila , in both humans and mice. Transplantation of VNS-conditioned microbiota confers seizure protection and restores gut barrier integrity. Akkermansia muciniphila or exogenous butyrate is sufficient to reduce seizures via a vagus nerve-dependent pathway.