Role of Gene-Microbial Interactions in the Development of Crohn's Disease-like Colitis

基因-微生物相互作用在克罗恩病样结肠炎发展中的作用

基本信息

批准号：
9914560
负责人：
Gabriel Nunez
金额：
$ 42.26万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9914560
关键词：
Adult Affect Animal Model Applications Grants Automobile Driving Bacteria Breast Feeding CYBA gene Cell Lineage Cells Characteristics Childhood Chronic Chronic Granulomatous Disease Colitis Complex Crohn&apos s disease Development Diet Disease Enterobacteriaceae Environmental Risk Factor Exhibits Fiber Gastrointestinal Diseases Gastrointestinal tract structure Genes Genetic Genetic Polymorphism Gnotobiotic Gram-Negative Anaerobic Bacteria House mice Human Immune Immune response Immunoglobulins Impairment Individual Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Intestines Knock-in Mouse Location Microbe Mucosal Immune Responses Mucous body substance Mus Mutant Strains Mice Mutation NADP NADPH Oxidase Natural Immunity Neutrophil Infiltration Oxidases Pathogenesis Pathologic Pathology Patients Phagocytes Play Predisposition Proteins Regulation Relapse Respiratory Burst Role Secondary to Testing Variant dysbiosis early onset genetic risk factor germ free condition gut microbiota high risk loss of function loss of function mutation microbiota microorganism interaction neutrophil pathobiont patient subsets prevent

项目摘要

ABSTRACT Crohn’s disease (CD), one of the major forms of Inflammatory Bowel Disease (IBD), is a complex disorder marked by chronic relapsing inflammation driven by CD4+ T helper 1 (TH1) cells that can affect any part of the gastrointestinal tract. CD is thought to result from an inappropriate mucosal immune response to the intestinal microbiota in genetically susceptible individuals. Consistent with this notion, CD patients harbor a dysbiotic microbiota. However, it remains unclear if the CD-associated dysbiosis plays a casual role or is secondary to inflammation. More than 100 loci predispose to CD of which polymorphisms in NOD2 are the strongest known genetic risk factor for disease development in adult and pediatric onset CD. However, the great majority of individuals homozygous for NOD2 CD-associated variants do not develop CD and no spontaneous intestinal inflammation mimicking CD occurs in Nod2−/− mice or knockin mice homozygous for the CD-associated L1007insC NOD2 variant. These findings suggest that additional genetic and/or environmental factors are critical for disease development. We found that combined, but not single deficiency, of NOD2 and phagocyte NAPDH oxidase activity triggers early-onset spontaneous TH1-type intestinal inflammation in mice with the pathological and immune hallmarks of CD. Development of disease required the presence of Mucispirillum schaedleri, a Gram-negative anaerobic bacterium that is an inhabitant of the colonic mucus layer of normal mice. The absence of NOD2 and CYBB led to marked accumulation of Mucispirillum in the gut which was associated with impaired recruitment of neutrophils and killing of the bacterium by luminal neutrophils. Mutant mice were protected from disease by maternal immunoglobulins against Mucispirillum during breastfeeding. These results indicate that a specific intestinal microbe can trigger CD-like disease in the presence of impaired clearance of the bacterium by innate immunity. We hypothesize that NOD2 and the NAPDH oxidase regulate the susceptibility to CD by controlling the abundance and local invasion of specific pathobionts such as Mucispirillum. We further hypothesize that killing of specific microbes by neutrophils regulated via NOD2 and NAPDH oxidase is important to prevent the development of CD-like disease. Finally, we hypothesize that targeting colitis-causing pathobionts such as Mucispirillum using diet could be an approach to treat CD-like colitis. In this grant application, we propose three specific Aims to understand the role of NOD2 and phagocyte NAPDH oxidase in the regulation of the microbiota and induction of colitis using a new animal model that exhibit pathology and immune alterations characteristic of CD.

抽象的克罗恩病（CD）是炎症性肠病（IBD）的主要形式之一，是一种复杂的疾病由CD4+ T辅助1（Th1）细胞驱动的慢性复发注射标记，可能会影响任何部分胃肠道。 CD被认为是由于对肠的不适当粘膜免疫反应而产生的一般易感个体的微生物群。与这个概念一致，CD患者患有不良生物微生物群。但是，尚不清楚CD相关的营养不良是否起着随意的作用，还是继发于炎。超过100个基因座对CD的易感性，其中NOD2中的多态性是已知的成人和小儿发作CD疾病发展的遗传危险因素。但是，绝大多数 NOD2 CD相关变体的纯合子不形成CD，也不发起肠道模仿CD的炎症发生在NOD2 - / - 小鼠或敲击蛋白小鼠中，纯合子与CD相关 L1007INSC NOD2变体。这些发现表明，其他遗传和/或环境因素是对于疾病发展至关重要。我们发现NOD2和吞噬细胞的合并但不是单一缺陷 NAPDH氧化物活性会触发与小鼠的早期发作Th1型肠道注射。 CD的病理和免疫标志。疾病的发展需要粘液螺旋藻 Schaedleri，一种革兰氏阴性厌氧菌，是正常的结肠粘液层的居民老鼠。 NOD2和CYBB的不存在导致肠道中粘液螺旋体显着积累与中性粒细胞杀死中性粒细胞的募集和杀死细菌有关。突变体在母乳喂养过程中，主要免疫球蛋白可抵抗粘液螺母，从而免受疾病的保护。这些结果表明，在存在受损的情况下，特定的肠道微生物会触发类似CD的疾病通过先天免疫史对细菌的清除。我们假设NOD2和NAPDH氧化物调节通过控制特定病原体的抽象和局部入侵，例如粘螺旋藻。我们进一步假设，通过NOD2和 NAPDH氧化物对于防止CD样疾病的发展很重要。最后，我们假设靶向引起结肠炎的病原体，例如使用饮食的粘液螺旋藻，这可能是一种治疗CD样的方法结肠炎。在此赠款应用中，我们提出了三个特定的目的，以了解NOD2和吞噬细胞的作用 NAPDH氧化物在调节微生物群中，并使用一种新的动物模型来诱导结肠炎表现出CD的病理和免疫改变的特征。