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 mechanisms is poorly defined. Here, we demonstrated that the bacteriocin Microcin J25 (J25) significantly alleviated diarrhea and intestinal 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. 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 potential of J25.

中文翻译：

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细菌素 Microcin J25 的抗菌感染作用和新型非微生物调节机制：多巴胺能受体的差异调节


细菌素的抗菌和免疫调节活性使其成为作为抗感染药物开发的有吸引力的靶标。尽管肠道神经系统 （ENS） 在对抗肠道感染中的重要性已经得到证实，但它是否参与细菌素抗感染机制尚不清楚。在这里，我们证明细菌素 Microcin J25 （J25） 显着缓解了由产肠毒素大肠杆菌 （ETEC） 感染引起的仔猪腹泻和肠道炎症。从机制上讲，J25 处理后巨噬细胞水平显着下调，这在小鼠模型中进行了复制。组学分析和验证筛选显示，J25 处理诱导多巴胺能神经元通路发生显著变化，但微生物结构变化不大。炎症的缓解可能通过下调多巴胺受体 （DR） D1 和下游 DAG-PKC 通路，从而抑制花生四烯酸的分解，而对巨噬细胞的抑制可能通过上调 DRD5 和下游 cAMP-PKA 通路，从而抑制 NF-κB。我们的研究结果为 ENS 在 J25 治疗 ETEC 感染中的变化和可能的作用提供了见解，为开发 J25 的应用潜力提供了更复杂的基础理解。