美国康奈尔大学Pamela V. Chang团队近期取得重要工作进展，他们研究提出，多巴胺受体D2通过微生物代谢产物赋予定植抗性。相关研究成果2024年3月13日在线发表于《自然》杂志上。

据介绍，肠道微生物组在调节宿主生理方面发挥着重要作用。其中一种功能是定植抗性（或微生物集体保护宿主免受肠道病原体侵害的能力），包括肠出血性大肠杆菌（EHEC）血清型O157:H7，这是一种附着性和消退性（AE）食源性病原体，可导致严重肠胃炎、小肠结肠炎、带血腹泻和急性肾功能衰竭（溶血性尿毒症综合征）。尽管肠道微生物可以通过击败一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抗性，但研究人员对这一现象仍知之甚少。

研究人员发现，在饮食中补充必需氨基酸L-色氨酸后产生的肠道微生物代谢产物激活肠上皮中的神经递质受体多巴胺受体D2（DRD2），可以保护宿主免受鼠柠檬酸杆菌感染的影响。柠檬酸杆菌是一种被广泛用作肠出血性大肠杆菌感染模型的小鼠AE病原体。研究人员进一步发现，这些色氨酸来源的代谢产物对DRD2的激活降低了宿主肌动蛋白调节蛋白的表达，该蛋白参与鼠源性肠出血性大肠杆菌和肠出血性大肠杆菌通过肌动蛋白基座的形成附着于肠上皮。

总之，这一研究结果揭示了一种针对AE病原体的非经典定植抗性途径，其特征是神经系统外的DRD2在控制肠道上皮肌动蛋白细胞骨架组织中具有非常规作用。这一发现可能会启发针对DRD2的预防和治疗方法，包括饮食或药物干预，以改善肠道健康和治疗全球数百万人的胃肠道感染。

附：英文原文

Title: Dopamine receptor D2 confers colonization resistance via microbial metabolites

Author: Scott, Samantha A., Fu, Jingjing, Chang, Pamela V.

Issue&Volume: 2024-03-13

Abstract: 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 pathogens1,2,3, 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 failure4,5 (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 cells6,7, 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 infection8,9. 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.

DOI: 10.1038/s41586-024-07179-5

Source: https://www.nature.com/articles/s41586-024-07179-5