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

克罗恩病（CD）相关脊柱关节炎（SpA）是最常见的肠外 IBD的表现。遗传分析独立地鉴定了IL 23 R和IL 24 R中共有的遗传变异。 IBD和SpA中的TNFSF 15位点，突出了这些途径在发病机制中的潜在作用 关于CD-SpA尽管临床证据表明肠道炎症与SpA有关， 肠道微生物群作为异常全身性关节炎症的来源， 微生物组和CD-SpA之间的联系尚未出现。为了解决这一未满足的临床需求， 这项研究的长期目标是确定CD-SpA的生物学机制， 精确使用药物和生物疗法。该提案的目的是确定免疫相关的 微生物群和与CD-SpA相关的细胞通路。核心假设是IgA包被的 CD-SpA中的微生物群富含pduC+粘附侵袭性E.大肠杆菌（AIEC），这些分离株 作为致病共生菌，驱动粘膜和全身IL-23和TL 1A依赖性炎症性疾病 通过CX 3CR 1+单核吞噬细胞。为了验证这一假设，提出了以下三个目标。 首先，使用创新方法对IgA包被的微生物群进行分选、测序和培养， 将评估具有SpA的CD患者的IgA包被的微生物群中独特的pduC+ AIEC菌株的数量。 第二，使用无菌和转基因小鼠结肠炎和关节炎模型， 将测试pduC+ AIEC对粘膜和全身性IL-23依赖性炎性疾病的作用。三是 肠CX 3CR 1+单核吞噬细胞（MNP）的贡献及其TNFSF 15的产生 (also称为TL 1A）在AIEC诱导的Th 17免疫中的作用将使用新的遗传小鼠模型进行测试。 这些实验将从根本上推进我们对pduC+免疫学影响的理解。 CD-SpA中的AIEC，并测试IL-23和CX 3CR 1 + MNP衍生的TL 1A在介导Th 17细胞中的作用 诱导这种对微生物组和脊柱关节炎之间联系的机械理解将 有助于推动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.