The Role of Enteric Infection in Flares of Inflammatory Bowel Disease

项目总结和摘要 炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），是慢性的， 胃肠道进行性炎症，影响多达300万美国人。IBD是 被认为是由对改变的肠道微生物组或生态失调的不适当免疫反应驱动的， 以缓解和复发性炎症或炎症发作为特征的疾病过程。尽管越来越多 关于肠道微生物组、生态失调和对粘膜影响之间关系的知识 免疫，许多仍然未知的煽动环境因素和根本机制 导致肠道炎症此外，尽管IBD有了显著的改善， 在治疗方面，病程保持相对不变，患者仍处于高风险， 复发、并发症、手术和生活质量下降。肠道感染是一种常见的原因， 生态失调，并且已经被认为是IBD发作和爆发的环境因素。我们的初步数据 在近30%的IBD发作中发现了肠道感染，最常见的病原体包括 艰难梭菌、肠致病性大肠杆菌（EPEC）和诺如病毒。K23计划将 通过检验肠道感染是一个主要环境因素的假设， IBD发作，产生一种特定的发作亚型，其特征在于独特的临床表现和对 IBD进展，与有发作但无肠道感染的患者不同。为了验证这个假设，我们 将招募并前瞻性随访存在C的IBD发作患者。艰难梭菌、EPEC或 诺如病毒，并且分别具有IBD发作但没有胃肠道病原体。我们将确定临床 (Aim 1），肠道微生物组和免疫因子（目的2），区分肠道感染并发的耀斑， 直接改善这些患者的IBD结局。这将是第一项纵向确定 特定肠道病原体对IBD病程的临床和分子影响，有可能揭示 关于肠道病原体在IBD中作为环境因素的作用的创新机制， 管理这种复杂的临床情况的方法。为了进行这项研究，进一步的培训是 阿克塞尔拉德博士组建了一个多学科的导师团队，提供详细的培训， 免疫学和微生物学，生物统计学和定量方法，以及资金和赠款。这 K23提案将使Axelrad博士能够完成确定特定肠毒素的作用的目标。 病原体在炎症性肠病的耀斑，并促进他发展成为一个独立的，以病人为导向， IBD领域的翻译研究者。

PROJECT SUMMARY AND ABSTRACT Inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract that affect up to 3 million Americans. IBD is thought to be driven by inappropriate immune responses to an altered gut microbiome, or dysbiosis, with a disease course characterized by remitting and relapsing episodes of inflammation, or flares. Despite increasing knowledge regarding the relationship between the gut microbiome, dysbiosis, and the impact on mucosal immunity, much remains unknown regarding the inciting environmental factors and underlying mechanisms that result in intestinal inflammation. In addition, although there have been dramatic improvements in IBD therapeutics, the disease course has remained relatively unchanged with patients remaining at high risk for recurrent flares, complications, surgeries, and reduced quality of life. Enteric infections are a common cause of dysbiosis, and have been implicated as an environmental factor in onset and flare of IBD. Our preliminary data has identified enteric infection in nearly 30% of IBD flares, with the most common pathogens including Clostridioides difficile, Enteropathogenic Escherichia coli (EPEC), and norovirus. This K23 proposal will address this knowledge gap by testing the hypothesis that enteric infection is a major environmental factor in flare of IBD, producing a specific subtype of flare characterized by a unique clinical presentation and impact on IBD progression, distinct from patients with a flare but without an enteric infection. To test this hypothesis, we will recruit and prospectively follow patients with flare of IBD with the presence of C. difficile, EPEC, or norovirus, and separately with flare of IBD but without a gastrointestinal pathogen. We will identify the clinical (Aim 1), gut microbiome, and immune factors (Aim 2) that distinguish flares complicated by enteric infection to directly improve IBD outcomes in these patients. This will be the first study to longitudinally determine the clinical and molecular impact of specific enteric pathogens on the course of IBD with the potential to reveal innovative mechanisms regarding the role of enteric pathogens as environmental factors in IBD, and novel approaches to the management of this complex clinical scenario. To conduct this research, further training is required, and Dr. Axelrad has assembled a multidisciplinary team of mentors to provide detailed training in immunology and microbiology, biostatistics and quantitative methods, and funding and grantsmanship. This K23 proposal will position Dr. Axelrad to accomplish the goal of determining the role of specific enteric pathogens in flares of IBD and facilitate his development into an independent, patient-oriented and translational investigator in the field of IBD.