Role of Nod2 in preventing intestinal disease downstream of microbial imbalances

 描述（由申请方提供）：遗传学和流行病学证据表明，克罗恩病（一种主要类型的炎症性肠病（IBD），经常影响小肠）的发生中存在异常的宿主-微生物相互作用。共生细菌被认为是至关重要的，因为肠道细菌组成的不平衡，称为生态失调，是疾病的标志。生态失调的机制需要进一步阐明。另一个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比关系。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。细菌传感器Nod 2中的突变是克罗恩病最强的风险因素之一，了解该基因与肠道微生物失衡相关的功能可能是深入了解克罗恩病的关键。 这种疾病病因复杂。我们已经发现，Nod 2-/-小鼠在小肠中显示出多种异常，包括上皮中的炎性基因表达、杯状细胞功能障碍、上皮内淋巴细胞产生的过量干扰素-γ，以及吡罗昔康诱导的病理。所有这些在患者中检测到的不同程度的肠道异常都依赖于肠道细菌群落的共同成员Bacteroides vulgatus的特异性扩增所代表的生态失调。值得注意的是，Nod 2-/-小鼠感染蠕虫鞭虫逆转了B。vulgatus定植并改善这些异常。因此，Nod 2可以防止炎症性生态失调，而炎症性生态失调可以通过蠕虫感染逆转。本提案的目标是阐明Nod 2缺陷导致这种由B代表的生态失调的机制。vulgatus扩张和下游炎症病理学，并确定这种不平衡是如何逆转T。穆里斯。这些实验不仅将阐明Nod 2在小肠免疫中的基本功能，还可能揭示为什么某些微生物因素和干预措施适用于某些个体而不是其他个体。

 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.