Risk Factors for Microscopic Colitis

项目摘要 显微镜下结肠炎是老年人慢性水样腹泻的最常见原因。这种病的症状 疾病使人衰弱。患者描述了孤立和退出社会生活和活动。治疗是 仅限于昂贵的治疗，有时无效。药物治疗后疾病复发很常见 都停止了虽然发病率与炎症性肠病相当，但该疾病已收到 更少的研究关注。许多药物（PPI、NSAID、他汀类药物、SSRI）与 显微镜下结肠炎虽然指南建议停止这些药物作为第一步， 然而，支持这一建议的证据并不充分。这项研究的第一阶段招募了 用显微镜检查结肠炎和腹泻与现有的观点相反， 以前与显微镜下结肠炎有关的药物。与肥胖有很强的负相关性， 外源激素通过16 S rRNA扩增子测序表明，微生物组α多样性是 与对照组相比，显微镜下结肠炎病例显著降低。几个分类群的情况下，丰富。的 本研究旨在扩展和扩大初步调查结果。病例对照研究的目的 研究内容为：1）调查药物、口服避孕药、绝经后激素与肥胖的关系， 将显微镜下结肠炎病例与两个对照组进行比较-因腹泻而接受结肠镜检查的患者 和结肠镜检查进行结肠直肠癌筛查。2)使用鸟枪式宏基因组测序 生物多样性和功能。3)为了使用来自显微镜下结肠炎患者的粘膜样品的RNA测序， 腹泻对照和筛选对照，以揭示与显微镜下结肠炎相关的遗传特征， 发现潜在的可药物治疗的疾病靶点。该研究将招募150例显微镜下结肠炎病例，300例腹泻病例， 对照组和300例结肠镜检查筛查对照组。结肠活检将用于评估粘附 在100例显微镜下结肠炎病例、100例腹泻病例中进行RNAseq实验， 对照组和100例结肠镜检查筛查对照组。结构化的电话采访将获得详细的饮食， 研究对象的药物和生活方式信息。前瞻性数据收集纠正重要 其他人先前研究的局限性。增加第二个对照组可以提供更明确的 避免不必要地停止治疗重要药物（PPI，NSAID，他汀类药物， SSRIs）。鸟枪式宏基因组学可以提供微生物病原学或功能基因的信息， 从而导致预防或治疗该疾病的策略。这项研究将提高我们对风险因素的理解， 为更科学的未来研究奠定了基础，并可能提出新的干预措施， 这种疾病目前还知之甚少。

PROJECT SUMMARY Microscopic colitis is the most common cause of chronic watery diarrhea in older adults. The symptoms of this disease are debilitating. Patients describe isolation and withdrawal from social life and activities. Treatment is limited to expensive therapies that are sometimes ineffective. Disease relapse is common after medications are stopped. Although the incidence is comparable to inflammatory bowel disease, the disease has received much less research attention. A number of medications (PPIs, NSAIDs, statins, SSRIs) have been linked with microscopic colitis. Although guidelines suggest discontinuing these medications as the initial step in treatment, the evidence supporting this recommendation is weak. The first phase of this study enrolled patients with microscopic colitis and diarrhea controls. Contrary to existing beliefs, there was no association with medications previously linked to microscopic colitis. There was a strong inverse association with obesity and exogenous hormones. Amplicon sequencing by 16S rRNA demonstrated that microbiome alpha-diversity was significantly lower in microscopic colitis cases compared to controls. Several taxa were enriched in cases. The present study is designed to extend and expand on the initial findings. The aims of the proposed case-control study are: 1) To investigate medications, oral contraceptives, postmenopausal hormones and obesity by comparing microscopic colitis cases to two comparison groups – patients referred for colonoscopy for diarrhea and colonoscopy for colorectal cancer screening. 2) To use shotgun metagenomic sequencing to gain insight into biodiversity and function. 3) To use RNA sequencing of mucosal samples from microscopic colitis patients, diarrhea controls and screening controls to reveal genetic signatures associated with microscopic colitis and discover potential druggable disease targets. The study will enroll 150 microscopic colitis cases, 300 diarrhea controls and 300 screening colonoscopy controls. Biopsies from the colon will be used to evaluate adherent bacterial organisms and to conduct RNAseq experiments in 100 microscopic colitis cases, 100 diarrhea controls and 100 screening colonoscopy controls. Structured telephone interviews will obtain detailed dietary, medication and lifestyle information on study subjects. The prospective data collection corrects important limitations of prior research by others. The addition of a second control group could provide more definitive evidence to avoid unnecessarily stopping therapeutically important medications (PPIs, NSAIDs, statins, SSRIs). Shotgun metagenomics could provide information on microbial etiology or functional genes potentially leading to strategies to prevent or treat the disease. The study will improve our understanding of risk factors, set the stage for more scientifically grounded future research, and potentially suggest new interventions for a disease that is currently poorly understood.