The Role of Enteric Infection in Flares of Inflammatory Bowel Disease

项目摘要和摘要 炎症性肠病(IBD)，包括克罗恩病(CD)和溃疡性结肠炎(UC)，是一种慢性、 进行性胃肠道炎症性疾病，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群或生物失调的不适当免疫反应驱动的，具有 发炎病程以炎症或红斑的缓解和复发为特征的病程尽管不断增加 了解肠道微生物群、生物失调和对粘膜的影响之间的关系 免疫，关于煽动环境因素和潜在机制仍有许多未知之处 会导致肠道发炎。此外，尽管IBD有了戏剧性的改善 治疗方面，病程相对保持不变，患者仍处于 反复发作红斑、并发症、手术和生活质量下降。肠道感染是一种常见的 生态失调，已被认为是IBD发病和发作的一个环境因素。我们的初步数据 在近30%的IBD症状中发现了肠道感染，最常见的病原体包括 艰难梭状芽胞杆菌、致病性肠杆菌和诺如病毒。这份K23提案将 通过检验肠道感染是人类感染的主要环境因素这一假设来解决这一知识差距。 IBD的耀斑，产生一种特殊亚型的耀斑，其特征是独特的临床表现和对 IBD进展，不同于有红斑但没有肠道感染的患者。为了检验这一假设，我们 将招募和前瞻性地跟踪IBD发作并存在艰难梭菌、EPEC或 诺如病毒，单独有IBD发作，但没有胃肠道病原体。我们将确定临床上的 (目标1)、肠道微生物组和免疫因素(目标2)，以区分肠道感染并发的红斑 直接改善这些患者的IBD预后。这将是第一次纵向确定 特定肠道病原体对IBD病程的临床和分子影响 关于肠道病原体在IBD中作为环境因素的作用的创新机制，以及新的 管理这一复杂临床场景的方法。为了进行这项研究，进一步的培训是 Axelrad博士已经组建了一个多学科的导师团队，在 免疫学和微生物学，生物统计学和定量方法，以及资金和资助金。这 K23提案将使Axelrad博士实现确定特定肠道的作用的目标 病原体在炎症性肠病的发作和促进他的发展成为独立的，以患者为中心和 IBD领域的翻译研究员。

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.