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:
    10642900
  • 负责人:
  • 金额:
    $ 42.37万
  • 依托单位:
  • 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

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.
摘要 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 以CD 4 + T辅助1(TH 1)细胞驱动的慢性复发性炎症为标志,这些细胞可以影响 胃肠道CD被认为是由对肠道的不适当的粘膜免疫反应引起的。 微生物群在遗传易感个体中。与这一观点一致,CD患者体内存在一种 微生物群然而,目前尚不清楚CD相关的生态失调是否起着偶然的作用或继发于 炎症超过100个基因座易患CD,其中NOD 2的多态性是已知最强的 成人和儿童CD发病的遗传风险因素。然而,绝大多数 NOD 2 CD相关变异体纯合子个体不发生CD, 模拟CD的炎症发生在Nod 2 −/−小鼠或CD相关基因纯合子的敲入小鼠中。 L1007 insC NOD 2变体。这些发现表明,其他遗传和/或环境因素是 对疾病的发展至关重要。我们发现NOD 2和吞噬细胞的联合缺乏,而不是单一的缺乏, NAPDH氧化酶活性引发小鼠早期自发性TH 1型肠道炎症, CD的病理和免疫特征。疾病的发展需要粘螺菌的存在 schaedleri,一种革兰氏阴性厌氧菌,是正常结肠粘膜层的居民。 小鼠NOD 2和CYBB的缺乏导致Mucispirillum在肠道中显着积累,这是 与中性粒细胞的募集受损和管腔中性粒细胞对细菌的杀伤有关。突变体 在哺乳期间,小鼠通过抗黏菌属的母体免疫球蛋白而免受疾病的侵害。 这些结果表明,一种特定的肠道微生物可以在受损的细胞存在的情况下引发CD样疾病。 通过先天免疫清除细菌。我们假设NOD 2和NAPDH氧化酶调节 通过控制特定致病菌的丰度和局部侵袭, 粘螺菌我们进一步假设,通过NOD 2调节的嗜中性粒细胞杀死特定微生物, NAPDH氧化酶对于预防CD样疾病的发展是重要的。最后,我们假设 针对结肠炎引起的致病生物,如使用饮食的Mucispirillum,可能是治疗CD样 结肠炎在这项资助申请中,我们提出了三个具体的目的,以了解NOD 2和吞噬细胞的作用, NAPDH氧化酶在微生物群调节和结肠炎诱导中的作用, 表现出CD特有的病理学和免疫学改变。

项目成果

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Gabriel Nunez其他文献

Gabriel Nunez的其他文献

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{{ truncateString('Gabriel Nunez', 18)}}的其他基金

Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity
Cryopyrin/NLRP3 信号在炎症和先天免疫中的作用
  • 批准号:
    10536627
  • 财政年份:
    2020
  • 资助金额:
    $ 42.37万
  • 项目类别:
Bile acids in intestinal homeostasis and allogeneic hematopoietic transplantation
胆汁酸在肠道稳态和同种异体造血移植中的作用
  • 批准号:
    10650323
  • 财政年份:
    2020
  • 资助金额:
    $ 42.37万
  • 项目类别:
Bile acids in intestinal homeostasis and allogeneic hematopoietic transplantation
胆汁酸在肠道稳态和同种异体造血移植中的作用
  • 批准号:
    10441581
  • 财政年份:
    2020
  • 资助金额:
    $ 42.37万
  • 项目类别:
Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity
Cryopyrin/NLRP3 信号在炎症和先天免疫中的作用
  • 批准号:
    9964988
  • 财政年份:
    2020
  • 资助金额:
    $ 42.37万
  • 项目类别:
Cryopyrin/NLRP3 Signaling in Inflammation and Innate Immunity
Cryopyrin/NLRP3 信号在炎症和先天免疫中的作用
  • 批准号:
    10308668
  • 财政年份:
    2020
  • 资助金额:
    $ 42.37万
  • 项目类别:
Bile acids in intestinal homeostasis and allogeneic hematopoietic transplantation
胆汁酸在肠道稳态和同种异体造血移植中的作用
  • 批准号:
    10241906
  • 财政年份:
    2020
  • 资助金额:
    $ 42.37万
  • 项目类别:
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
  • 批准号:
    10187558
  • 财政年份:
    2019
  • 资助金额:
    $ 42.37万
  • 项目类别:
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
  • 批准号:
    10020402
  • 财政年份:
    2019
  • 资助金额:
    $ 42.37万
  • 项目类别:
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
  • 批准号:
    10426166
  • 财政年份:
    2019
  • 资助金额:
    $ 42.37万
  • 项目类别:
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
  • 批准号:
    9914560
  • 财政年份:
    2019
  • 资助金额:
    $ 42.37万
  • 项目类别:

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