摘要Background The antibacterial and immunomodulatory activities of bacteriocins make them attractive targets for development as anti-infective drugs.Although the importance of the enteric nervous system(ENS)in the struggle against infections of the intestine has been demonstrated,whether it is involved in bacteriocins anti-infective mecha-nisms is poorly defined.Results Here,we demonstrated that the bacteriocin Microcin J25(J25)significantly alleviated diarrhea and intesti-nal inflammation in piglets caused by enterotoxigenic Escherichia coli(ETEC)infection.Mechanistically,macrophage levels were significantly downregulated after J25 treatment,and this was replicated in a mouse model.Omics analysis and validation screening revealed that J25 treatment induced significant changes in the dopaminergic neuron pathway,but little change in microbial structure.The alleviation of inflammation may occur by down-regulating dopamine receptor(DR)D1 and the downstream DAG-PKC pathway,thus inhibiting arachidonic acid decomposition,and the inhibition of macrophages may occur through the up-regulation of DRD5 and the downstream cAMP-PKA pathway,thus inhibiting NF-κB.Conclusions Our studies'findings provide insight into the changes and possible roles of the ENS in J25 treatment of ETEC infection,providing a more sophisticated foundational understanding for developing the application poten-tial of J25.