Role of oral and intestinal microbiota in Rheumatoid Arthritis

描述（由申请人提供）：长期以来，肠道微生物群一直被认为会导致炎症性疾病，动物模型和人类的多项报告表明抗生素治疗可以改变自身免疫性疾病的表现。我们最近在啮齿类动物中证明，特定微生物可诱导肠道固有层中 Th17 细胞的分化。有强有力的遗传和治疗证据表明，“促炎”Th17 和“抗炎”调节性 T 细胞 (Treg) 在自身免疫性疾病中发挥着关键作用，包括类风湿关节炎 (RA)、银屑病关节炎 (PsA) 和克罗恩病。我们建议研究肠道（肠道和口腔）微生物群在 RA 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 诱导微生物的表征将有助于深入了解疾病发病机制； 2) 肠道微生物群的定向调控将导致关节炎生物标志物的改变，包括 Th17/Treg 平衡。获得的见解可能会阐明 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 RA 新治疗方法提供依据。提出了三个具体目标：1）创建一个多学科中心来表征 RA 及相关疾病患者的人类肠道微生物组。 2) 利用Th17依赖的RA小鼠模型来研究微生物群/T细胞相互作用在疾病发展中的作用，以直接评估RA患者中的特定细菌是否可能与疾病发病机制有关。直接细菌混合物和在 RA 患者中鉴定的细菌都将被接种到小鼠体内。 3) 通过以下方式研究人类肠道微生物群在 RA 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 RA 或 PsA 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、介入性概念验证生物标志物研究，以确定肠道微生物群的改变是否可以使 RA 患者的细胞免疫功能正常化。我们将比较 2 种抗生素治疗方案，以评估治疗是否会引起 i) 肠道微生物组的特征性变化（包括特定目标分类群丰度的变化），以及 ii) 免疫生物标志物的改变，特别是 Th17 和 Treg 细胞水平和/或功能。仔细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：该项目与人类微生物组项目（NIH 路线图的一项主要举措）的目标一致，并且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实现真正的变革。这些结果可能会改变我们对微生物与人类之间关系的理解，并带来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.