Enteric ChAT‐Expressing Neurons Mediate the Protective Effect of Lactobacillus plantarum in Inflammatory Bowel Disease

ABSTRACT The gut microbiota plays a crucial role in inflammatory bowel diseases (IBD), yet how specific microbial components influence disease progression remains incompletely understood. Our study reveals that decreased abundance of Lactobacillus species correlates with ulcerative colitis severity in patients. Among tested strains, L. plantarum A736, isolated from traditional fermented foods, demonstrated protective effects in ameliorating dextran sulfate sodium (DSS)‐induced colitis in a mouse model. Strikingly, multi‐omics analysis revealed that L. plantarum A736 uniquely enhances choline acetyltransferase‐expressing (ChAT + ) neurons in the enteric nervous system and elevates acetylcholine (ACh) levels. Further analysis identified that L. plantarum A736 metabolizes tryptophan to produce indole‐3‐lactic acid (ILA), and supplementation with ILA significantly mimics this strain's anti‐inflammatory effects by restoring ChAT + neurons and cholinergic signaling. Crucially, selective ablation of colonic ChAT + neurons abolished the protective effect of both L. plantarum A736 and ILA, establishing their essential role in mediating these effects. These findings demonstrate that microbial metabolites can modulate enteric neuronal circuits to regulate gut immunity. The identified ILA‐ChAT + neuron axis represents a novel neuro‐immune pathway that could be targeted for IBD treatment.