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，潜在致病性共生菌群（即病原体）在炎症性肠病 (IBD) 中含量丰富，并导致克罗恩病 (CD) 和溃疡性结肠炎 (UC) 的发病机制。致病生物触发和/或加剧肠道炎症仍未完全了解该提案的长期目标是阐明 IBD 相关致病生物导致炎症的机制。在我们的初步实验中，我们发现了能够有效诱导宿主单核吞噬细胞分泌促炎细胞因子 IL-1 的病原体（以下称为 IBIP）。 CD 患者中，IBIP 的定植可能与肠道微生物群的致结肠炎能力有关，但引人注目的是，肠道定植是持续的，但不是短期的。暴露于 IBIP 会使宿主加重葡聚糖硫酸钠 (DSS) 诱发的结肠炎。值得注意的是，适应性免疫（T 细胞和 B 细胞淋巴）对于宿主的这种“致病训练”不是必需的，这表明 IBIP 的持续定植可能。我们证明，IBIPs 的持续定植会导致骨中的骨髓生成。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 的持续肠道定植导致肠漏和随后的 BM 介导的先天性训练。通过系统性消除 IBIP 或 IBIP 诱导的炎症介质（例如 IL-1）来增强免疫力。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 对诱导训练后的先天免疫的影响我们将检查结肠粘膜和 BM 中骨髓细胞（巨噬细胞和中性粒细胞）的功能和表观遗传调节。此外，我们还将测试 IL-1b 在此过程中的重要性。在目标 2 中，我们将确定 IBIP 定植对结肠上皮完整性的影响。我们发现 IBIP 定植可能会导致上皮损伤，从而导致结肠上皮损伤。腔内细菌和/或细菌因子的传播，反过来又会影响致病性训练的免疫。拟议研究的基本原理是，确定 IBD 中病原体驱动的炎症反应的精确机制将产生治疗 IBD 的新方法。 。