Role of Nod2 in preventing intestinal disease downstream of microbial imbalances

 描述(由申请人提供)：遗传和流行病学证据表明，宿主-微生物的异常相互作用与克罗恩病的发展有关，克罗恩病是一种主要类型的炎症性肠病(IBD)，经常影响小肠。共生细菌被认为是至关重要的，因为肠道细菌组成的失衡，即所谓的生物失调，是这种疾病的一个标志。生物失调的机制还需要进一步阐明。另一种机制上知之甚少的相关性是疾病发病率和蠕虫感染之间的反向关系。一个主要的挑战是将这些观察结果与遗传易感性联系起来。细菌感应器NOD2的突变是克罗恩病的最大危险因素之一，了解该基因与肠道微生物失衡的功能可能是深入了解 这种复杂的疾病病因学。我们发现NOD2/-小鼠在小肠表现出多种异常，包括上皮中炎性基因的表达、杯状细胞功能障碍、上皮内淋巴细胞过度产生干扰素-以及吡罗昔康诱导的病理改变。所有这些在患者身上不同程度检测到的肠道异常，都依赖于肠道细菌群落中一种常见成员--寻常型杆菌的特定扩张所表现的生态失调。值得注意的是，感染NOD2-/-小鼠的鞭毛虫逆转了普通芽胞杆菌的定植，并改善了这些异常。因此，NOD2可以预防炎症性生物失调，而这种失调可以被蠕虫感染逆转。这项建议的目的是阐明NOD2缺乏导致这种以普通芽孢杆菌扩张和下游炎症病理为代表的生物失调的机制，并确定这种失衡是如何被T。这些实验不仅将阐明NOD2在小肠免疫中的基本功能，而且可能会揭示为什么某些微生物因素和干预措施适用于某些人，而不适用于其他人。

 DESCRIPTION (provided by applicant): Genetic and epidemiological evidence have implicated aberrant host-microbe interactions in the development of Crohn's disease, a major type of inflammatory bowel disease (IBD) that frequently affects the small intestine. Commensal bacteria are thought to be critical because an imbalance in the composition of bacteria in the intestine, referred to as dysbiosis, is a hallmark of the disease. The mechanism of dysbiosis requires further elucidation. Another correlation that is mechanistically poorly understood is the inverse relationship between disease incidence and helminth infections. A major challenge has been linking these observations with genetic susceptibility. Mutations in the bacterial sensor Nod2 are among the strongest risk factors for Crohn's disease, and understanding the function of this gene in relation to imbalances in intestinal microbes is likely key to gaining insight into this complex disease etiology. We have found that Nod2-/- mice display multiple abnormalities in the small intestine including inflammatory gene expression in the epithelium, goblet cell dysfunction, and excess interferon- production by intra-epithelial lymphocytes, and piroxicam-induced pathologies. All of these intestinal abnormalities, which are detected to various degrees in patients, were dependent on dysbiosis represented by the specific expansion of a common member of the intestinal bacterial community, Bacteroides vulgatus. Remarkably, infection of Nod2-/- mice with the helminth Trichuris muris reversed B. vulgatus colonization and ameliorated these abnormalities. Therefore, Nod2 prevents inflammatory dysbiosis, which can be reversed by helminth infection. The goal of this proposal is to elucidate the mechanism by which Nod2-deficiency leads to this dysbiosis represented by B. vulgatus expansion and downstream inflammatory pathologies, and determine how this imbalance is reversed by T. muris. These experiments will not only elucidate the basic function of Nod2 in small intestinal immunity, but will likely shed light on why certain microbial factors and interventions apply to some individuals but not others.