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

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

  • Neuron. 2026 Jan 16:S0896-6273(25)00926-2. doi: 10.1016/j.neuron.2025.11.029.
Yicong Jia 1,  Hong Chen 2,  Qianhui Zou 3,  Sijing Chen 4,  Jiahao Li 5,  Yiming Chen 6,  Liming Lu 6,  Feng Hong 5,  Shuhui Jia 7,  Xiaoyuan Jing 7,  Jiayan Ren 8,  Fahim Muhammad 8,  JiaYu Mi 2,  Jing Duan 2,  Jianxiang Liao 2,  Qing Liu 9,  Fuqiang Xu 9,  Paul J Kenny 10,  Ming-Hu Han 7,  Liping Wang 9,  Zuxin Chen 11,  Dezhi Cao 12,  Xin-An Liu 13
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, China.
  • 2 Neurology Department, Shenzhen Children's Hospital, Shenzhen 518055, China.
  • 3 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, China.
  • 5 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 6 South China Research Center for Acupuncture and Moxibustion, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 7 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 8 Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Key Laboratory of Drug Addiction, Shenzhen Neher Neural Plasticity Laboratory, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
  • 9 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 10 Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 11 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen Key Laboratory of Drug Addiction, Shenzhen Neher Neural Plasticity Laboratory, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
  • 12 Neurology Department, Shenzhen Children's Hospital, Shenzhen 518055, China. Electronic address: [email protected].
  • 13 Guangdong Provincial Key Laboratory of Brain Connectome and Behavior, the Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; Shenzhen-Hong Kong Institute of Brain Science, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: [email protected].
PMID: 41547348 DOI: 10.1016/j.neuron.2025.11.029
Abstract

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.

Keywords

Bacteroides fragilis; Lactobacillus; cholinergic transmission; gut-brain axis; pediatric epilepsy; randomized clinical trial; vagus nerve.

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