Diet and metabolic factors in the pathogenesis of microscopic colitis

项目总结/摘要 显微镜下结肠炎（MC）是一种使人衰弱的T细胞介导的大肠炎性疾病， 发病率现在与炎症性肠病（IBD）相当，但没有FDA批准的治疗方法。 新出现的证据支持MC的发生是由于对环境的不适当的免疫反应- 在管腔微环境中引起干扰。饮食是管腔微环境的重要调节器 通过改变肠道上皮完整性、微生物组组成和功能以及免疫细胞活化。 然而，其在MC发病机制中的作用仍不清楚。两种饮食模式，经验性饮食炎症 模式（EDIP）和地中海饮食，是特别感兴趣的MC发病机制，由于他们的协会 下游代谢物发生变化，包括短链脂肪酸、鞘脂和色氨酸 代谢物，在MC中具有合理的机制基础，并在其他模型的发病机制中具有已知作用 结肠炎此外，这些饮食模式和下游代谢途径与1） 已知在MC中升高的全身炎症标志物，和2）发病率、疾病活动和治疗 其他IBD的反应。因此，我们的总体假设是，特定的代谢途径， 影响MC的发病风险和治疗结果。为了验证这个假设， 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关系 (Aim 1a），以及它们的各个组成部分（目标1b）和三个基于人群的队列中的MC风险， 护士健康研究和健康专业人员随访研究。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MC风险。 饮食和MC之间的关联（目标2b）。第三，我们将评估预测治疗反应的代谢物 在马萨诸塞州总医院（MGH）的一个前瞻性队列中，我们预计 这项工作将为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 MC在未来此外，它将促进MGH初级胃肠病学家的职业发展 长期的职业目标是成为一名独立的医生调查员，专注于定义 疾病的发病机制，以告知预防策略和治疗算法， 结果。为了实现这一目标，本提案以候选人的流行病学背景为基础， 营养流行病学的重点培训，代谢组学数据分析，以了解相关的生物学 路径和前瞻性队列发展。这位候选人将在一位著名的 导师团队具有MC，营养流行病学和代谢组学方面的专业知识，2）经验和正式 教学培训，以及3）MGH临床和转化的杰出科学环境 流行病学单位，哈佛公共卫生学院和布罗德研究所。在这个奖项完成后， 候选人将展示科学的独立性和初步数据，以成功申请R 01。

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.