Diet and metabolic factors in the pathogenesis of microscopic colitis

项目摘要/摘要 显微镜结肠炎(MC)是一种衰弱的T细胞介导的大肠炎症性疾病，具有 发病率现在与炎症性肠病(IBD)不相上下，但没有FDA批准的治疗方法。 越来越多的证据支持MC的发生是由于对环境的不适当免疫反应- 引起管腔微环境的紊乱。饮食是管腔微环境的重要调节器 通过改变肠道上皮的完整性、微生物群的组成和功能以及免疫细胞的激活。 然而，它在MC发病机制中的作用仍不清楚。两种饮食模式，经验性炎症性饮食 模式(EDIP)和地中海饮食是MC发病机制中特别感兴趣的因素，因为它们之间存在关联 随着下游代谢物的变化，包括短链脂肪酸、鞘脂和色氨酸 代谢产物，在MC中有合理的机制基础，在其他模型的发病机制中也有已知的作用 结肠炎。此外，这些饮食模式和下游代谢途径与1) 已知的全身性炎症标记物在MC中升高，以及2)发病率、疾病活动性和治疗 其他IBD的反应。因此，我们的首要假设是特定的代谢途径， 在MC中受饮食、发病风险和治疗结果的影响。为了检验这一假设， 我们将首先研究衍生饮食模式、EDIP和改良地中海饮食之间的联系 (目标1a)及其个别组成部分(目标1b)和三个基于人群的队列中的MC风险， 护士健康研究和卫生专业人员的随访研究。其次，在这些队列中，我们将评估 血浆代谢物与MC风险之间的关联(目标2a)，并确定代谢物是否介导了 饮食与MC之间的联系(目标2b)。第三，我们将评估预测治疗反应的代谢物 在马萨诸塞州综合医院(MGH)发生MC事件的个人的前瞻性队列中。我们期待着 这项工作将对MC的发病机制提供有价值的见解，为新的饮食疗法提供基础 对于未来的MC来说。此外，它还将促进MGH初级教师胃肠病专家的职业发展。 以成为一名独立的医生-调查员为长期职业目标，专注于定义 疾病的病因，为提高患者的预防策略和治疗算法提供信息 结果。为了实现这一目标，这项建议建立在候选人的流行病学背景基础上，以提供 营养流行病学方面的重点培训，分析代谢组数据以了解相关生物学 路径，以及未来的队列发展。这位候选人将在一位著名候选人的支持下茁壮成长 具有MC、营养流行病学和代谢组学专业知识的导师团队，2)经验丰富和正规 教学培训，以及3)MGH临床和翻译的优秀科学环境 哈佛大学公共卫生学院流行病学部和布罗德研究所。到本奖项完成时， 候选人将展示成功申请R01所需的科学独立性和初步数据。

PROJECT SUMMARY/ABSTRACT Microscopic colitis (MC) is a debilitating T-cell-mediated inflammatory disease of the large intestine with an incidence that now rivals that of inflammatory bowel disease (IBD), but has no FDA-approved therapies. Emerging evidence supports that MC occurs due to an inappropriate immune response to environmentally- induced disturbances in the luminal microenvironment. Diet is a critical regulator of the luminal microenvironment through alteration in gut epithelial integrity, microbiome composition and function, and immune cell activation. Yet, its role in the pathogenesis of MC remains unknown. Two dietary patterns, the Empiric Dietary Inflammatory Pattern (EDIP) and the Mediterranean diet, are of particular interest in MC pathogenesis due to their associations with changes in downstream metabolites, including short chain fatty acids, sphingolipids, and tryptophan metabolites, that have a plausible mechanistic basis in MC and a known role in the pathogenesis of other models of colitis. Furthermore, these dietary patterns and downstream metabolic pathways are associated with 1) systemic inflammatory markers known to be elevated in MC, and 2) incidence, disease activity, and treatment response of other IBD. Accordingly, our overarching hypothesis is that specific metabolic pathways, influenced by diet, impact risk of incident disease and treatment outcomes in MC. To test this hypothesis, we will first examine the associations between derived dietary patterns, EDIP and modified Mediterranean diet (Aim 1a), and their individual components (Aim 1b) and risk of MC within three population-based cohorts, the Nurses’ Health Studies and Health Professionals Follow-up Study. Second, within these cohorts we will evaluate the association between plasma metabolites and risk of MC (Aim 2a), and determine if metabolites mediate the associations between diet and MC (Aim 2b). Third, we will evaluate metabolites that predict therapeutic response in a prospective cohort of individuals with incident MC at Massachusetts General Hospital (MGH). We anticipate this work will provide valuable insight into the pathogenesis of MC, offering the basis for novel dietary therapies for MC in the future. Further, it will promote the career development of a junior faculty gastroenterologist at MGH with the long-term career goal of becoming an independent physician-investigator, focused on defining the etiopathogenesis of disease to inform preventive strategies and treatment algorithms that enhance patient outcomes. To achieve this goal, this proposal builds on the candidate’s background in epidemiology to provide focused training in nutritional epidemiology, analysis of metabolomic data to understand implicated biological pathways, and prospective cohort development. The candidate will thrive with the support of 1) a renowned mentorship team with expertise in MC, nutritional epidemiology, and metabolomics, 2) experiential and formal didactic training, and 3) the outstanding scientific environment of the MGH Clinical and Translational Epidemiology Unit, Harvard School of Public Health, and Broad Institute. By the completion of this award, the candidate will demonstrate the scientific independence and preliminary data for a successful R01 application.