Drugs, Germs, and Joints: Antibiotics, Gut Microbiota, and Juvenile Idiopathic Arthritis

项目摘要 关于儿童患幼年特发性关节炎（JIA）的原因知之甚少。研究表明， 在类风湿性关节炎的发展和活动中口腔和肠道的微生物组不平衡（生态失调）， 一种与大多数JIA不同的疾病。肠道生态失调也可能介导眼部炎症（葡萄膜炎）， JIA常见的威胁视力的并发症。一些患有不太常见的JIA的儿童有证据表明 和抗生素（主要的微生物组干扰物）与新发JIA大 人口。这项研究的总体目标是了解发展的机制， 和病程，以期为这一家族慢性病的防治开辟新的途径。的 本研究的主要目的是研究抗生素、感染和 生态失调与JIA发病机制和活动有关。本项目将重点关注JIA最常见的形式， 少关节型JIA与葡萄膜炎的高发病率相关。 第一个目标是检查患有少关节JIA的儿童的肠道微生物群是否表现出 在一项多中心研究中，与匹配的未受影响儿童的肠道微生物群相比， 前瞻性招募儿童的病例对照研究。第二个目标将前瞻性地跟踪这些儿童 用少关节JIA来确定肠道生态失调A）是否随着非活动性疾病而消退（在一个自我对照的研究中， 一项比较诊断时和非活动性疾病时微生物群）和/或B）随JIA发作而增加的研究 (in一项病例对照研究，比较爆发时和非活动性疾病时的微生物群）。这两个目标将使用 自我采集的粪便样本沿着临床数据，包括抗生素使用（二次暴露）。生态失调 将被定义为具有减少的肠道微生物多样性和不同的总体微生物组成， 对照组。分析还将探讨特定物种相对丰度的差异 组之间以及JIA的生态失调和临床特征之间的关联（例如，葡萄膜炎）。第三 目的将测试JIA儿童使用抗生素，特别是抗厌氧药物， 与3个月内使用新的抗风湿药物相关，作为JIA疾病活动性增加的代表。这 aim将使用行政索赔数据和自我对照病例系列设计。 拟议的K23项目将为这位儿科风湿病学家提供一个综合计划， 以病人为导向的研究，职业发展活动，以及生物信息学的正规培训。指导 专家导师和有才华的合作者，本申请中概述的研究和培训活动将 使主要研究者从观察性流行病学家成长为独立的患者- 导向和翻译研究。这些机会将使这位调查员拥有更大的一套 技能，以回答有关小儿风湿性疾病的重要和新颖的问题。

Project Summary Little is known about why children develop juvenile idiopathic arthritis (JIA). Research implicates microbiome imbalance (dysbiosis) of the mouth and gut in the development and activity of rheumatoid arthritis, a disease distinct from most forms of JIA. Gut dysbiosis may also mediate eye inflammation (uveitis), a common, vision-threatening complication of JIA. Some children with a less common form of JIA have evidence of dysbiosis, and antibiotics (major microbiome disrupters) are associated with new-onset JIA in large populations. The overall goal of this research is to understand the mechanisms underlying the development and course of JIA in order to develop new ways of preventing and treating this family of chronic diseases. The main objective of this study is to examine the complex relationship between antibiotics, infections, and dysbiosis in relation to JIA pathogenesis and activity. This project will focus on the most common form of JIA, oligoarticular JIA, which is associated with high rates of uveitis. The first aim will examine whether gut microbiota from children with incident oligoarticular JIA exhibit dysbiosis (primary exposure) compared with gut microbiota of matched unaffected children in a multicenter case-control study of prospectively recruited children. The second aim will prospectively follow those children with oligoarticular JIA to determine whether gut dysbiosis A) resolves with inactive disease (in a self-controlled study comparing microbiota at diagnosis and at the time of inactive disease) and/or B) increases with JIA flare (in a case-control study comparing microbiota at flare and at the time of inactive disease). Both aims will use self-collected stool samples along with clinical data, including antibiotic use (secondary exposure). Dysbiosis will be defined as having decreased gut microbial diversity and distinct overall microbial composition relative to the comparator group. The analysis will also explore differences in the relative abundance of specific species between groups as well as associations between dysbiosis and clinical features of JIA (e.g., uveitis). The third aim will test whether antibiotic use in children with JIA, particularly drugs with antianaerobic coverage, is associated with new antirheumatic drug use within 3 months as a proxy for increased JIA disease activity. This aim will use administrative claims data and a self-controlled case series design. The proposed K23 project will provide this pediatric rheumatologist with an integrated plan of mentored patient-oriented research, career development activities, and formal training in bioinformatics. Guided by expert mentors and talented collaborators, the research and training activities outlined in this application will enable the principal investigator to mature from an observational epidemiologist into an independent patient- oriented and translational researcher. These opportunities will equip this investigator with a much larger set of skills to answer important and novel questions about pediatric rheumatic diseases.