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

Bacteroides fragilis is markedly reduced in children with epilepsy compared to healthy controls.

• Gut dysbiosis was identified as implicated in epilepsy, with B. fragilis specifically depleted in the pediatric epilepsy population.
• The reduction was sufficient to motivate investigation of B. fragilis as a probiotic intervention.
• This clinical observation formed the basis for the subsequent mechanistic and therapeutic studies.

Oral B. fragilis administration suppresses seizures in pentylenetetrazole (PTZ)- and kainic-acid (KA)-induced mouse models.

• Two established chemically-induced seizure mouse models were used: PTZ model and KA model.
• B. fragilis was administered orally to mice prior to seizure induction.
• Seizure suppression was observed in both models, establishing antiseizure efficacy across different seizure induction paradigms.

B. fragilis activates colonic choline acetyltransferase-positive (ChAT+) cells and enhances gut-vagus-brain cholinergic signaling.

• Mechanistic studies demonstrated activation of colonic ChAT+ cells following B. fragilis treatment.
• Vagal recordings provided direct electrophysiological evidence of enhanced cholinergic signaling along the gut-vagus-brain axis.
• Pharmacological blockade experiments confirmed that cholinergic signaling was required for the antiseizure effects.
• Chemogenetic manipulation was used to selectively activate or inhibit components of the circuit to establish causality.

A colonic ChAT+-nodose ganglion circuit was identified as the specific neural circuit mediating B. fragilis-induced seizure suppression.

• The nodose ganglion, which contains cell bodies of vagal afferent neurons, was identified as a key relay in the circuit.
• The circuit connects colonic ChAT+ enteroendocrine/neuronal cells to the brain via the vagus nerve.
• Disruption of this circuit abolished the antiseizure effects of B. fragilis.
• This finding defines a specific gut-brain cholinergic pathway for microbiota-mediated seizure control.

The antiseizure effects of B. fragilis are associated with enriched intestinal Lactobacillus colonization.

• Metagenomic or microbiome analyses revealed increased Lactobacillus abundance following B. fragilis treatment.
• This association suggests B. fragilis may exert effects partly through modulation of the broader gut microbial community.
• Lactobacillus enrichment was identified as a correlate of seizure suppression.

A randomized clinical trial confirmed the therapeutic efficacy of B. fragilis in pediatric refractory epilepsy.

• The trial was registered as CHiCTR2100042203.
• The study population consisted of children with refractory epilepsy.
• The trial design was randomized, providing controlled evidence for clinical benefit.
• Results confirmed the translational relevance of the preclinical mechanistic findings.

These findings establish a mechanistic basis for microbiota-targeted therapies in epilepsy through a defined gut-brain cholinergic pathway.

• The study integrates clinical observation, animal models, circuit-level neuroscience, and a clinical trial to define a complete mechanistic framework.
• The gut-brain cholinergic pathway represents a previously uncharacterized mechanism by which a specific probiotic exerts antiseizure effects.
• The authors propose this pathway as a target for future microbiota-based epilepsy therapeutics.