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

IL-1 诱导病原体在克罗恩病发病机制中的作用

• 批准号: 10654935
• 负责人: Nobuhiko Kamada
• 金额: $ 49.55万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654935
• 关键词: Affect; B-Lymphocytes; Bacteria; Bone Marrow; Cells; Chronic; Colitis; Colon; Crohn' s disease; Development; Digestive System Disorders; Disease; Epigenetic Process; Epithelial Cells; Epithelium; Genetic Transcription; Goals; Immune; Immunity; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Intestines; Leaky Gut; Link; Macrophage; Mediating; Memory; Mononuclear; Mucous Membrane; Mus; Myeloid Cells; Myelopoiesis; Natural Immunity; Pathogenesis; Pathogenicity; Patients; Persons; Phagocytes; Play; Population; Predisposition; Process; Research; Role; Testing; Training; Ulcerative Colitis; United States; adaptive immunity; cytokine; dextran sulfate sodium induced colitis; epithelial injury; experimental study; gut colonization; gut inflammation; gut microbiota; imprint; in vivo; innovation; insight; member; neutrophil; novel; pathobiont; progenitor

: Recent studies have demonstrated that potentially pathogenic commensal populations, namely pathobionts, are enriched in inflammatory bowel disease (IBD) and contribute to the pathogenesis of both Crohn’s disease (CD) and ulcerative colitis (UC). However, the identity of pathobionts and how these pathobionts trigger and/or exacerbate intestinal inflammation remains incompletely understood. The long-term goal of this proposal is to unravel the mechanisms by which IBD-associated pathobionts contribute to inflammatory processes in the gut. In our preliminary experiments, we identified pathobionts that can potently induce secretion of the pro-inflammatory cytokine IL-1 from host mononuclear phagocytes. Such IL-1-inducing pathobionts (hereafter called IBIPs) are selectively enriched in CD patients, and the colonization by IBIPs may be linked to the colitogenic capacity of the gut microbiotas. Strikingly, the persistent gut colonization, but not short-term exposure, to IBIPs predisposes the host to exacerbated dextran sulfate sodium (DSS)-induced colitis. Notably, adaptive immunity (T and B lymphocytes) is not required for this “pathogenic training” of the host, suggesting that the persistent colonization of IBIPs may imprint inflammatory memory in innate immune cells or non-immune cells, such as epithelial cells. We demonstrated that the persistent colonization by IBIPs results in myelopoiesis in the bone marrow (BM). Moreover, we found that IBIPs adhere to the colonic epithelium and cause a pore formation. Based on these preliminary results, our central hypothesis is that persistent gut colonization by IBIPs results in a leaky gut and subsequent BM-mediated trained innate immunity through systemically circulated IBIPs or inflammatory mediators induced by IBIPs, such as IL-1. We will test this hypothesis through the following two specific aims: In Aim 1, we will define the impact of IBIPs on the induction of trained innate immunity. We will examine the function and epigenetic modulations of myeloid cells (macrophages and neutrophils) in the colonic mucosa and the BM. Also, we will test the importance of IL-1b in this process. In Aim 2, we will determine the impact of IBIP colonization on colonic epithelial integrity. We hypothesized that IBIP colonization could cause epithelial damage, leading to the dissemination of luminal bacteria and/or bacterial factors, which, in turn, imprints pathogenic trained immunity. The rationale for the proposed research is that identifying the precise mechanisms of pathobiont-driven inflammatory responses in IBD will result in new and innovative ways to treat IBD.

: 最近的研究表明，潜在的致病性肠道菌群，即致病菌，富含炎症性肠病（IBD），并有助于克罗恩病（CD）和溃疡性结肠炎（UC）的发病机制。然而，致病菌的身份以及这些致病菌如何触发和/或加剧肠道炎症仍然不完全清楚。该提案的长期目标是揭示IBD相关致病菌促进肠道炎症过程的机制。在我们的初步实验中，我们鉴定了可以有效诱导宿主单核吞噬细胞分泌促炎细胞因子IL-1 β的致病菌。这种IL-1 β诱导的致病生物（下文称为IBIP）在CD患者中选择性富集，并且IBIP的定殖可能与肠道微生物菌群的大肠杆菌能力有关。引人注目的是，IBIP的持续肠道定植（而不是短期暴露）容易使宿主加剧葡聚糖硫酸钠（DSS）诱导的结肠炎。值得注意的是，适应性免疫（T和B淋巴细胞）对于宿主的这种“致病性训练”是不需要的，这表明IBIP的持续定殖可能在先天免疫细胞或非免疫细胞（例如上皮细胞）中留下炎症记忆。我们证明了IBIP的持续定植导致骨髓（BM）中的骨髓生成。此外，我们发现IBIP粘附在结肠上皮上并导致孔形成。基于这些初步结果，我们的中心假设是IBIP的持续肠道定殖导致肠道渗漏，随后通过全身循环的IBIP或IBIP诱导的炎症介质（如IL-1 β）导致BM介导的训练型先天免疫。我们将通过以下两个具体目标来检验这一假设：在目标1中，我们将定义IBIP对诱导训练的先天免疫的影响。我们将研究结肠粘膜和BM中髓样细胞（巨噬细胞和中性粒细胞）的功能和表观遗传调节。此外，我们将测试IL-1b在这个过程中的重要性。在目标2中，我们将确定IBIP定殖对结肠上皮完整性的影响。我们假设IBIP定殖可能导致上皮损伤，导致管腔细菌和/或细菌因子的传播，这反过来又会影响致病性训练免疫力。这项研究的基本原理是，确定IBD中致病菌驱动的炎症反应的确切机制将导致治疗IBD的新的创新方法。