Role of oral and intestinal microbiota in Rheumatoid Arthritis

描述(申请人提供)：长期以来，肠道微生物区系一直被认为与炎症性疾病有关，在动物模型和人类中的多项报告表明，抗生素治疗改变了自身免疫性疾病的表现。我们最近在啮齿动物身上证明了特定的微生物诱导肠道固有层中的Th17细胞分化。有强有力的遗传学和基于治疗的证据表明，“促炎”Th17和“抗炎”调节性T细胞(Treg)在自身免疫性疾病中发挥关键作用，包括类风湿性关节炎(RA)、牛皮癣关节炎(PSA)和克罗恩病。我们建议研究肠道(肠道和口腔)微生物区系在类风湿关节炎和其他炎症性关节炎中的作用。我们的主要假设是：1)人类肠道中Th17诱导微生物的特征将有助于了解疾病的发病机制；2)对肠道微生物区系的直接操作将导致关节炎生物标志物的改变，包括Th17/Treg平衡。所获得的见解可能阐明T细胞网络如何响应微生物与宿主肠道成分的相互作用，并为开发新的类风湿关节炎治疗方法提供理论基础。提出了三个具体目标：1)建立一个多学科中心，以表征类风湿关节炎患者及相关疾病患者的肠道微生物群。2)采用Th17依赖的类风湿关节炎小鼠模型，研究微生物区系/T细胞相互作用在疾病发生发展中的作用，直接评估类风湿关节炎患者体内的特定细菌是否参与疾病的发病机制。直接细菌鸡尾酒和在RA患者中发现的细菌都将接种到小鼠体内。3)研究人类肠道微生物区系在类风湿性关节炎发病机制中的作用：a)横断面研究，以确定人类肠道中的特定分类群或细菌家族是否与类风湿性关节炎或前列腺癌相关；b)临床和血液检查，以评估关节炎患者与对照组的基线疾病活动性、遗传易感性和免疫细胞功能；c)前瞻性、干预性概念验证生物标志物研究，以确定肠道微生物区系的改变是否使类风湿性关节炎患者的细胞免疫功能正常化。我们将对两种抗生素方案进行比较，以评估治疗是否导致1)肠道微生物组的特征性变化(包括特定靶标的丰度变化)，以及2)免疫生物标记物的变化，特别是Th17和Treg细胞水平和/或功能的变化。精心选择的结果应该允许我们将特定微生物或微生物组模式的存在与细胞免疫反应、其他特定生物标志物和临床活动的变化联系起来。相关性：该项目与美国国立卫生研究院的一项主要路线图计划--人类微生物组计划的目标一致，并有可能通过填补有关炎症性关节炎病因的基本知识空白而真正实现变革。这一结果可能会改变我们对微生物和人类之间关系的理解，并导致创新的诊断测试和未来的治疗方法。

DESCRIPTION (provided by applicant): Gut microbiota has long been thought to contribute to inflammatory diseases, and multiple reports in animal models and humans suggest that antibiotic treatment alters autoimmune disease manifestations. We have recently demonstrated in rodents that specific microbes induce the differentiation of Th17 cells in the intestinal lamina propria. There is strong genetic and therapy-based evidence that "pro-inflammatory" Th17 and "anti- inflammatory" regulatory T cells (Treg) have critical roles in autoimmune diseases, including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and Crohn's disease. We propose to study the role of gut (intestinal and oral) microbiota in RA and other inflammatory arthritides. Our primary hypotheses are that: 1) characterization of Th17-inducing microbes in human intestine will provide insight into disease pathogenesis; and 2) directed manipulation of the gut microbiota will result in alteration of arthritis biomarkers, including Th17/Treg balance. Insights attained may elucidate how the T cell network responds to microbial interactions with host intestinal components and provide a rationale for the development of new therapeutic approaches for RA. Three Specific Aims are proposed: 1) To create a multidisciplinary center to characterize human gut microbiome in patients with RA and related conditions. 2) To employ Th17-dependent mouse models of RA to study the role of microbiota/T cell interactions in development of disease, to directly assess whether specific bacteria in RA patients can be implicated in disease pathogenesis. Both direct bacterial cocktails and bacteria identified in RA patients will be inoculated into the mice. 3) To study the role of human gut microbiota in RA pathogenesis by: a) cross-sectional study to determine whether a specific taxon or bacterial family in the human gut is associated with RA or PsA; b) clinical and blood examinations to assess baseline disease activity, genetic predisposition and immune cellular function of arthritis patients vs controls; c) prospective, interventional proof of concept biomarker study to determine whether alteration of the gut microbiota normalizes cellular immune functions in patients with RA. We will compare 2 antibiotic regimens to assess whether therapy induces i) characteristic changes in the gut microbiome (including changes in abundance of specific target taxons), and ii) alterations in immune biomarkers, particularly Th17 and Treg cell levels and/or function. Carefully selected outcomes should permit us to correlate the presence of a specific microorganism or microbiome pattern with changes in cellular immune response, other specific biomarkers, and clinical activity. Relevance: This project is consistent with the goals of the Human Microbiome Project, a major NIH Roadmap initiative, and has the potential to be truly transformative by filling a fundamental knowledge gap regarding the cause of inflammatory arthritis. The results could transform our understanding of the relationships between microbes and humans, and lead to innovative diagnostic tests and future treatments.