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

： 最近的研究表明，潜在的致病共生群体，即致病细菌，在炎症性肠病(IBD)中富含，并在克罗恩病(CD)和溃疡性结肠炎(UC)的发病机制中起重要作用。然而，病原体的身份以及这些病原体如何触发和/或加剧肠道炎症仍然不完全清楚。这项提议的长期目标是解开IBD相关病原体促进肠道炎症过程的机制。在我们的初步实验中，我们发现了能够有效地诱导宿主单核吞噬细胞分泌促炎细胞因子IL-1的病原体。这种IL-1诱导的致病菌(以下称为IBIP)在CD患者体内选择性地富含，IBIP的定植可能与肠道微生物的产肠能力有关。值得注意的是，持续的肠道定植，但不是短期暴露于IBIP，使宿主容易患上加重的葡聚糖硫酸钠(DSS)诱导的结肠炎。值得注意的是，获得性免疫(T和B淋巴细胞)不是宿主这种“致病训练”所必需的，这表明IBIP的持续定植可能会在先天性免疫细胞或非免疫细胞(如上皮细胞)中留下炎性记忆。我们证明了IBIPs的持续定植导致了骨髓(BM)的骨髓生成。此外，我们还发现IBIP附着在结肠上皮细胞上，并引起气孔形成。基于这些初步结果，我们的中心假设是，IBIP持续的肠道定植导致肠道渗漏，随后BM通过系统循环的IBIP或IBIP诱导的炎症介质(如IL-1)介导训练性先天免疫。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对诱导训练性先天免疫的影响。我们将研究结肠粘膜和骨髓中髓系细胞(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在这一过程中的重要性。在目标2中，我们将确定IBIP定植对结肠上皮完整性的影响。我们假设IBIP定植可以导致上皮损伤，导致管腔细菌和/或细菌因子的传播，这反过来又印记了病原体训练的免疫。提出这项研究的理由是，确定IBD中病理性炎症反应的精确机制将导致治疗IBD的新的和创新的方法。

: 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.