Host-Microbiota Interactions in Crohn's Disease-associated Spondyloarthritis

克罗恩病(CD)相关性脊柱炎(SpA)是最常见的肠外疾病 IBD的表现。遗传分析独立确定了IL23R和IL23R中的共享遗传变异 TNFSF15基因座同时存在于IBD和SpA中，突出了这些通路在发病机制中的潜在作用 CD-SPA。尽管临床证据表明肠道炎症与SPA有关 肠道微生物区系作为异常全身性关节炎症的来源：一种机制的理解 微生物组和CD-SPA之间的联系还没有出现。为了解决这一未得到满足的临床需求， 这项研究的长期目标是确定CD-SpA的生物学机制，并使更多 精准运用医学和生物疗法。这项提议的目标是识别与免疫相关的 与cd-spa相关的微生物区系和细胞途径。中心假设是包有IgA的 CD-SpA中的微生物群富含pduC+粘附性侵袭性大肠杆菌(AIEC)，这些分离株起作用 作为推动黏膜和全身IL-23和TL1A依赖的炎症性疾病的病理共生菌 通过CX3CR1+单核巨噬细胞。为了验证这一假设，提出了以下三个目标。 首先，使用一种创新的方法来分类、测序和培养包被IgA的微生物区系，即浓缩 将对CD SpA患者IgA包被微生物区系中独特的pduC+AIEC菌株进行评估。 其次，使用诺生菌和转基因小鼠的结肠炎和关节炎模型，贡献 将测试pduC+AIEC对黏膜和全身依赖IL-23的炎症性疾病的作用。第三， 肠道CX3CR1+单核巨噬细胞的贡献及其产生TNFSF15的研究 (也称为TL1A)在AIEC诱导的Th17免疫中将使用新的遗传小鼠模型进行测试。 这些实验将从根本上提高我们对pduC+免疫影响的理解。 检测IL-23和CX3CR1+MNP来源的TL1a在介导Th17细胞中的作用 归纳法。这种对微生物群和脊椎炎之间联系的机械性理解将 帮助推动CD-SPA患者的早期诊断和更精确的治疗。

Crohn's disease (CD)-associated spondyloarthritis (SpA) is the most common extra-intestinal manifestation of IBD. Genetic analysis independently identified shared genetic variants in the IL23R and TNFSF15 loci in both IBD and SpA, highlighting the potential role for these pathways in the pathogenesis of CD-SpA. Although clinical evidence linking intestinal inflammation with SpA has implicated the intestinal microbiota as the source of aberrant systemic joint inflammation, a mechanistic understanding of the link between the microbiome and CD-SpA has yet to emerge. To address this unmet clinical need, the long-term goal of this research is to define the biologic mechanisms of CD-SpA and enable the more precise use of medical and biologic therapy. The objective of this proposal is to identify immune-relevant microbiota and cellular pathways associated with CD-SpA. The central hypothesis is that IgA-coated microbiota in CD-SpA are enriched with pduC+ Adherent-invasive E. coli (AIEC) and these isolates act as pathosymbionts that drive mucosal and systemic IL-23- and TL1A-dependent inflammatory disease via CX3CR1+ mononuclear phagocytes. To test this hypothesis, the following three aims are proposed. First, using an innovative approach to sort, sequence and culture IgA-coated microbiota, the enrichment of unique pduC+ AIEC strains in the IgA-coated microbiota of CD patients with SpA will be evaluated. Second, using gnotobiotic and genetically modified mouse models of colitis and arthritis, the contribution of pduC+ AIEC to mucosal and systemic IL-23-dependent inflammatory disease will be tested. Third, the contribution of intestinal CX3CR1+ mononuclear phagocytes (MNPs) and their production of TNFSF15 (also called TL1A) in AIEC-induced Th17 immunity will be tested using novel genetic mouse models. These experiments will fundamentally advance our understanding of the immunological impact of pduC+ AIEC in CD-SpA and test the role for both IL-23 and CX3CR1+ MNP-derived TL1A in mediating Th17 cell induction. This mechanistic understanding of the link between the microbiome and spondyloarthritis will help drive earlier diagnosis and more precise therapy for patients with CD-SpA.