The role of IL-1?-inducing pathobionts in the pathogenesis of Crohn?s disease

项目概要/摘要： 克罗恩病（CD）是一种胃肠道慢性炎症性疾病， 在美国的人。白细胞介素（IL）-1β是一种重要的促炎介质，被认为是 与CD中的肠道炎症相关，因为IL-1β表达在CD患者的肠粘膜中升高， CD患者同样，NLRP 3的遗传变异，炎症体蛋白在炎症中起关键作用， IL-1β的产生与CD风险增加有关。此外，Atg 16 l1缺陷的小鼠， 与CD相关的自噬基因，显示NLRP 3依赖性IL-1β产生增加和对结肠炎的敏感性。 因此，IL-1β似乎有助于CD，但IL-1β在CD中被诱导的机制以及IL-1β如何在CD中被诱导的机制尚不清楚。 促进CD发病机制仍不确定。鉴于我们最近的发现，肠道微生物群是必不可少的， 诱导粘膜IL-1β，这项研究的长期目标是揭示肠道微生物群如何 可能通过诱导IL-1β参与CD的发病机制。为此，我们已经产生了 人源化的无菌小鼠（hGB）模型，其中无菌（GF）小鼠被人（健康） 个体和CD患者）微生物。利用该模型，我们发现GF小鼠被 CD微生物制剂诱导结肠粘膜中促炎因子（包括IL-1β）显著升高， 而健康的微生物菌群则不会引起这些反应。引人注目的是，CD的殖民化，但不是健康的， 在两种不同的结肠炎小鼠模型（硫酸葡聚糖）中， 钠诱导的结肠炎和用人微生物菌群定殖的GF IL-10缺陷小鼠）。IL-1β的诱导是 这是CD微生物群的产大肠杆菌能力所需的。此外，我们还鉴定了IL-1β- 诱导致病菌，其选择性地在CD患者中积累。根据这些结果，我们的中心 一种假说认为，CD患者体内富含IL-1β诱导的致病菌，这导致了CD的发展。 和/或肠道炎症的进展。具体目标是：1。澄清裁谈会的机制， 相关的致病菌激活炎性小体。我们将确定哪些以及如何与CD相关 致病菌激活炎性小体。2.确定CD相关免疫系统引起的免疫途径 致病菌诱导的IL-1β。我们将分析CD-10诱导的IL-1β下游的T细胞应答。 相关的致病菌3.确定CD相关致病菌诱导IL-1β的机制 导致结肠炎我们将确定IL-1β通过CD-10的选择性成员诱导的机制。 相关的致病菌导致结肠炎的发展。因此，拟议的研究将阐明这种联系 肠道微生物群诱导的IL-1β与CD发病机制之间的关系。

Project Summary/Abstract: Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that affects 0.7 million people in the United States. Interleukin (IL)-1β is an important pro-inflammatory mediator that is believed to be associated with intestinal inflammation in CD, as the IL-1β expression is elevated in the intestinal mucosa of patients with CD. Likewise, genetic variation in NLRP3, the inflammasome protein which plays a pivotal role in the production of IL-1β, is associated with increased risk for CD. Furthermore, mice deficient in Atg16l1, an autophagy gene linked to CD, display increased NLRP3-dependent IL-1β production and sensitivity to colitis. Thus, IL-1β appears to contribute to CD, yet the mechanisms by which IL-1β is induced in CD and how IL-1β promotes CD pathogenesis remain uncertain. Given our recent findings that the gut microbiota is essential for the induction of mucosal IL-1β, the long-term objective of this study is to unravel how the gut microbiota contributes to disease pathogenesis in CD likely through the induction of IL-1β. To this end, we have generated a humanized gnotobiotic mouse (hGB) model, in which germ-free (GF) mice are colonized with human (healthy individuals and CD patients) microbiotas. Utilizing this model, we have found that GF mice colonization by the CD microbiotas induces a marked elevation of pro-inflammatory factors, including IL-1β, in colonic mucosa, while healthy microbiotas did not elicit these responses. Strikingly, colonization of CD, but not healthy, microbiotas led to the development of severe colitis in two different mouse models of colitis (dextran sulfate sodium-induced colitis and GF IL-10-deficient mice colonized with human microbiotas). Induction of IL-1β is required for the colitogenic capacity of the CD microbiota. Furthermore, We have identified candidates of IL-1β- inducing pathobionts, which selectively accumulated in CD patients. Based on these results, our central hypothesis is that IL-1β-inducing pathobionts are enriched in CD patients, which leads to the development and/or progression of intestinal inflammation. Specific aims are: 1. Clarify the mechanism by which CD- associated pathobionts activate the inflammasome. We will identify which and how the CD-associated pathobionts activate the inflammasome. 2. Identify the immune pathways elicited by CD-associated pathobiont-induced IL-1β. We will analyze the T cell responses downstream of IL-1β that are induced by CD- associated pathobionts. 3. Determine the mechanism by which CD-associated pathobiont-induced IL-1β leads to colitis. We will determine the mechanisms by which IL-1β induced by selective members of CD- associated pathobionts leads to the development of colitis. Thus, the proposed study will shed light on the link between the microbiota-induced IL-1β in the intestine and the pathogenesis of CD.