The gut microbiome has major roles in modulating host physiology. One such function is colonization resistance, or the ability of the microbial collective to protect the host against enteric pathogens^1,2,3, including enterohaemorrhagic Escherichia coli (EHEC) serotype O157:H7, an attaching and effacing (AE) food-borne pathogen that causes severe gastroenteritis, enterocolitis, bloody diarrhea and acute renal failure^4,5 (haemolytic uremic syndrome). Although gut microorganisms can provide colonization resistance by outcompeting some pathogens or modulating host defence provided by the gut barrier and intestinal immune cells^6,7, this phenomenon remains poorly understood. Here, we show that activation of the neurotransmitter receptor dopamine receptor D2 (DRD2) in the intestinal epithelium by gut microbial metabolites produced upon dietary supplementation with the essential amino acid l-tryptophan protects the host against Citrobacter rodentium, a mouse AE pathogen that is widely used as a model for EHEC infection^8,9. We further find that DRD2 activation by these tryptophan-derived metabolites decreases expression of a host actin regulatory protein involved in C. rodentium and EHEC attachment to the gut epithelium via formation of actin pedestals. Our results reveal a noncanonical colonization resistance pathway against AE pathogens that features an unconventional role for DRD2 outside the nervous system in controlling actin cytoskeletal organization in the gut epithelium. Our findings may inspire prophylactic and therapeutic approaches targeting DRD2 with dietary or pharmacological interventions to improve gut health and treat gastrointestinal infections, which afflict millions globally.

肠道微生物组在调节宿主生理学方面发挥着重要作用。其中一个功能是定植抗性，或微生物群体保护宿主免受肠道病原体侵害的能力^1,2,3，包括肠出血性大肠杆菌(EHEC) 血清型 O157:H7，一种附着和消除 (AE) 食源性病原体导致严重胃肠炎、小肠结肠炎、血性腹泻和急性肾功能衰竭^4,5（溶血性尿毒症综合征）。尽管肠道微生物可以通过竞争某些病原体或调节肠道屏障和肠道免疫细胞提供的宿主防御来提供定植抵抗力^6,7，但这种现象仍然知之甚少。在这里，我们发现，通过饮食补充必需氨基酸L-色氨酸产生的肠道微生物代谢物激活肠上皮中的神经递质受体多巴胺受体 D2 (DRD2)，从而保护宿主免受啮齿类柠檬酸杆菌的侵害，这是一种广泛存在的小鼠 AE 病原体。用作肠出血性大肠杆菌感染的模型^8,9。我们进一步发现，这些色氨酸衍生的代谢物激活 DRD2 会降低宿主肌动蛋白调节蛋白的表达，该蛋白参与啮齿类弯曲杆菌和肠出血性大肠杆菌通过肌动蛋白基座的形成与肠上皮的附着。我们的结果揭示了针对 AE 病原体的非常规定植抵抗途径，该途径的特点是 DRD2 在神经系统外控制肠道上皮肌动蛋白细胞骨架组织方面发挥非常规作用。我们的研究结果可能会激发针对 DRD2 的预防和治疗方法，通过饮食或药物干预来改善肠道健康并治疗胃肠道感染，这些感染困扰着全球数百万人。