Gut-brain cholinergic signaling mediates the antiseizure effects of Bacteroides fragilis

Gut dysbiosis has been implicated in epilepsy, yet probiotic efficacy and mechanisms remain unclear. Here, we identify that Bacteroides fragilis ( B. fragilis ) is markedly reduced in children with epilepsy and show that oral B. fragilis administration suppresses seizures in both pentylenetetrazole- and kainic-acid-induced mouse models. Mechanistically, B. fragilis activates colonic choline acetyltransferase-positive (ChAT + ) cells and enhances gut-vagus-brain cholinergic signaling, as demonstrated by vagal recordings, pharmacological blockade, and chemogenetic manipulation, identifying a colonic ChAT + -nodose ganglion circuit mediating seizure suppression. Its antiseizure effects associate with enriched intestinal Lactobacillus colonization. A randomized clinical trial (CHiCTR2100042203) further confirms the therapeutic efficacy of B. fragilis in pediatric refractory epilepsy. These findings define a gut-brain cholinergic pathway through which B. fragilis exerts antiseizure effects and establish a mechanistic basis for microbiota-targeted therapies in epilepsy.