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.