Role of Nod2 in preventing intestinal disease downstream of microbial imbalances

Nod2 在预防微生物失衡下游肠道疾病中的作用

基本信息

批准号：
9105377
负责人：
Ken Hashigiwa Cadwell
金额：
$ 42.38万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105377
关键词：
Adverse effects Affect Animal Model B-Lymphocytes Bacteria Bacteroides CD4 Positive T Lymphocytes Characteristics Clostridium Communities Complex Crohn&apos s disease Data Defect Developed Countries Development Disease Disease model Employee Strikes Environmental Risk Factor Epidemiology Epithelial Epithelium Etiology Experimental Models Frequencies Functional disorder Gene Expression Genes Genetic Genetic Predisposition to Disease Goals Goblet Cells Health Helminths Hematopoietic Homeostasis Host Defense Immune response Immunity Incidence Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory Response Interferons Intervention Intestinal Diseases Intestines Lead Life Light Link Lymphocyte Mediating Microbe Modality Modeling Molecular Mucins Multiple Abnormalities Mus Mutation Parasites Pathology Pathway interactions Patients Pattern Piroxicam Play Population Predisposition Probiotics Production Property Resistance Resolution Risk Factors Role Small Intestines Susceptibility Gene Taxon Testing Therapeutic Therapeutic Intervention Trichuris commensal microbes disorder risk gene function gut microbiota humoral immunity deficiency improved insight member microbial microbiota mouse model novel pathogen prevent research study response risk variant sensor

项目摘要

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.

描述（由申请人提供）：遗传和流行病学证据表明，异常的宿主-微生物相互作用与克罗恩病的发生有关，克罗恩病是一种主要类型的炎症性肠病（IBD），经常影响小肠，因为共生细菌被认为是至关重要的。肠道细菌组成失衡，称为菌群失调，是该疾病的一个标志。菌群失调的机制需要进一步阐明。疾病发病率与蠕虫感染之间的负相关关系在机制上知之甚少，一个主要的挑战是将这些观察结果与细菌传感器 Nod2 的突变（克罗恩病的最强危险因素之一）联系起来，并了解该基因的功能。与肠道微生物失衡相关的可能是深入了解的关键我们发现Nod2-/-小鼠的小肠表现出多种异常，包括上皮炎症基因表达、杯状细胞功能障碍、上皮内淋巴细胞产生过多的干扰素-α，以及吡罗昔康诱导的病理。所有这些在患者中不同程度检测到的肠道异常都依赖于肠道细菌群落中常见成员拟杆菌的特定扩张所代表的菌群失调。值得注意的是，Nod2-/-小鼠感染了蠕虫，可以逆转普通蠕虫的定植并改善这些异常现象，因此，Nod2可以预防蠕虫感染所逆转的炎症失调。 Nod2 缺陷导致这种菌群失调的机制，以 B. vulgatus 扩张和下游炎症病理为代表，以及确定鼠 T. muris 如何逆转这种不平衡。这些实验不仅将阐明 Nod2 在小肠免疫中的基本功能，而且可能会阐明为什么某些微生物因素和干预措施适用于某些个体而不适用于其他个体。