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

克罗恩病相关脊柱关节炎中宿主-微生物群的相互作用

• 批准号: 10079481
• 负责人: randy s longman
• 金额: $ 37.59万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-02 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10079481
• 关键词: Address; Antibodies; Arthritis; Bacteria; Biological; Biological Response Modifier Therapy; Cells; Clinical; Colitis; Collaborations; Crohn' s disease; Data; Dependence; Diagnosis; Diagnostic; Disease; Early Diagnosis; Escherichia coli; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genetic Predisposition to Disease; Genomics; Gnotobiotic; Goals; Hydro-Lyases; ITGAX gene; Immune; Immunity; Immunoglobulin A; Immunologics; Inflammation; Inflammatory; Inflammatory Arthritis; Inflammatory Bowel Diseases; Interleukin-10; Intestines; K/BxN model; Link; Mediating; Medical; Medicine; Metabolic; Metagenomics; Microbe; Modeling; Mononuclear; Morbidity - disease rate; Mucositis; Mucous Membrane; Mus; Outcome; Pathogenesis; Pathway interactions; Patients; Peripheral; Phagocytes; Production; Propylene Glycols; Research; Resources; Role; Source; Spondylarthritis; TNFSF15 gene; Testing; Variant; Virulence Factors; cellular targeting; clinical phenotype; cohort; diphtheria toxin receptor; disease phenotype; experimental study; genetic analysis; genetic variant; gut microbiota; host microbiota; improved; in vivo; inflammatory disease of the intestine; innovation; interleukin-23; joint inflammation; microbial; microbiome; microbiota; mouse model; novel; novel therapeutic intervention; systemic inflammatory response

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.

克罗恩病（CD）相关的脊椎关节炎（SPA）是最常见的肠外 IBD的表现。遗传分析在IL23R和 IBD和水疗中心的TNFSF15基因座，突出了这些途径在发病机理中的潜在作用 CD-SPA。尽管将肠道炎症与水疗中心联系起来的临床证据暗示了 肠道菌群作为异常的全身关节炎症来源，一种机械理解 微生物组和CD-SPA之间的联系尚未出现。为了满足这种未满足的临床需求， 这项研究的长期目标是定义CD-SPA的生物学机制，并使更多 医学和生物疗法的精确使用。该提议的目的是确定免疫力 与CD-SPA相关的微生物群和细胞途径。中心假设是IGA涂层 CD-SPA中的微生物群富含PDUC+粘附的大肠杆菌（AIEC）和这些分离株ACT 作为驱动粘膜和全身IL-23-和TL1A依赖性炎症性疾病的情病性事件 通过CX3CR1+单核吞噬细胞。为了检验这一假设，提出了以下三个目标。 首先，使用创新的方法来分类，序列和培养IgA涂层的微生物群，富集 将评估CD患者的IgA涂层菌群中独特的PDUC+ AIEC菌株。 其次，使用gnotobiotic和遗传修饰的结肠炎和关节炎的小鼠模型，贡献 将测试PDUC+ AIEC的粘膜和全身IL-23依赖性炎症性疾病。第三， 肠道CX3CR1+单核吞噬细胞（MNP）及其产生TNFSF15的贡献 （也称为TL1A）在AIEC诱导的Th17免疫力中将使用新型遗传小鼠模型进行测试。 这些实验从根本上可以提高我们对PDUC+免疫学影响的理解 CD-SPA中的AIEC并测试IL-23和CX3CR1+ MNP衍生的TL1A的作用 就职。对微生物组和脊椎关节炎之间联系的机械理解将 有助于为CD-SPA患者提供早期诊断和更精确的疗法。