Impact of Aspirin on the Gut Microbiome and Mucosal Microenvironment

阿司匹林对肠道微生物组和粘膜微环境的影响

• 批准号: 9892588
• 负责人: David A Drew
• 金额: $ 15.97万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-06 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892588
• 关键词: 3-Dimensional; AXIN2 protein; Address; Advisory Committees; Agonist; ApcMin/+ mice; Area; Aspirin; Basic Science; Bile Acids; Bioinformatics; Biological; Biological Models; Biopsy; Cells; Chemopreventive Agent; Chronic; Clinic; Clinical; Colon; Colorectal; Colorectal Adenoma; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Digestive System Disorders; Dinoprostone; Disease; Dose; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Feces; Funding; Fusobacterium nucleatum; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Generations; Genomics; Glycochenodeoxycholate; Goals; Gut Mucosa; Health; Health Benefit; Homeostasis; Human; Immune; In Vitro; Individual; Inflammation; Inflammatory; Intervention; Intestines; Joints; Laboratories; Lead; Link; Measures; Mediating; Metagenomics; Methodology; Mission; Modeling; Mucous Membrane; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Natural regeneration; Neoplasms; Organoids; Pathway interactions; Patients; Placebos; Postdoctoral Fellow; Prevention strategy; Preventive service; Primary Prevention; Prospective Studies; Prostaglandin Inhibition; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Randomized; Randomized Clinical Trials; Recording of previous events; Research Personnel; Resources; Risk; Role; Shotguns; Signal Transduction; Supplementation; Taurodeoxycholate; Tissues; Training; Tumor Burden; Work; adenoma; base; beta catenin; cardiovascular disorder prevention; cardiovascular disorder risk; colon microbiome; colorectal cancer progression; double-blind placebo controlled trial; experience; gut microbiome; individualized prevention; injury and repair; intestinal epithelium; metabolomics; metatranscriptomics; microbial; microbiome; microbiota; mouse model; neoplastic; novel; novel chemoprevention; pre-doctoral; receptor; skills; stem cell division; stem cell homeostasis; stem cell proliferation; stem cells; stool sample; transcriptome sequencing; translational scientist; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT Substantial evidence supports health benefits associated with aspirin use, particularly for individuals at increased risk for cardiovascular disease (CVD) and colorectal cancer (CRC). In 2016, the U.S. Preventive Services Task Force recommended low-dose (81 mg) aspirin for primary prevention of CVD and CRC despite an incomplete understanding of the biological mechanisms underlying aspirin’s effects on the colon. We have proposed an interrelated framework for aspirin’s biological mechanisms through direct inhibition of prostaglandins within epithelial cells. To expand this framework, we now propose the novel hypothesis supported by compelling preliminary data that the gut microbiome may mediate the biological effects on colorectal mucosa associated with aspirin. The gut microbiome is a key determinant for gut homeostasis and is increasingly implicated in the development of colorectal neoplasia. However, prospective studies are required to define the specific role of the gut microbiome in the development of mucosa at-risk for neoplasia and how microbial dynamics are impacted following intervention with aspirin. The overall goal of this proposal is to interrogate the joint impact of aspirin on colonic epithelial cells and the gut microbiome in humans to refine and establish causal mechanisms, including PG pathways, which will be further validated using novel, in vitro, patient-derived modeling approaches. We hypothesize that by fully interrogating these additional mechanisms an integrated network may be developed that comprehensively informs a precision prevention strategy. To address this, we will leverage biospecimens (colonic biopsies and stool) collected within our randomized, double-blind, placebo- controlled trial of aspirin, ASPIRED. In Aim 1, we will deeply characterize the effects of randomized aspirin treatment on colorectal mucosa through RNA sequencing of epithelial cells collected from mucosal biopsies and on the gut microbiome by performing integrated whole-shotgun metagenomics, metatranscriptomics, and metabolomics to investigate the effect of randomized aspirin treatment on the gut microbiome. In Aim 2, will leverage intestinal organoid cultures, or three-dimensional ‘mini-guts’, to culture epithelial cells derived from the same patients with aspirin (direct effects) and/or a priori microbial metabolites (indirect effects) to refine chemopreventive mechanisms. The results will further elucidate a role for the gut microbiome in the health and disease states of the alimentary tract and aligns with the overall mission of the NIDDK. This proposal will also offer a promising young investigator the opportunity to further develop a niche within which to pursue independent lines of inquiry and expand his bioinformatics and translational methodological skillsets. This will be an important first step for the candidate to achieve his goal of leveraging basic science training (pre-doctoral) and experience in clinical gastroenterology trials (post-doctoral) to become an effective bridge between the laboratory and the clinic as an independent academic investigator.

项目摘要/摘要 大量证据支持与阿司匹林使用相关的健康益处，尤其是针对个人 心血管疾病（CVD）和结直肠癌（CRC）的风险增加。 2016年，美国预防性 服务工作队推荐低剂量（81 mg）阿司匹林用于一次预防CVD和CRC目的地 对阿司匹林对结肠的影响的生物学机制的不完全理解。我们有 通过直接抑制阿司匹林生物学机制提出了一个相互关联的框架 上皮细胞中的前列腺素。为了扩展此框架，我们现在提出了支持的新假设 通过诱人的初步数据，肠道微生物组可以介导生物直肠粘膜的生物学作用 与阿司匹林相关。肠道微生物组是肠道稳态的关键决定剂，并且越来越多 在结直肠肿瘤的发展中实施。但是，需要前瞻性研究来定义 肠道微生物组在肿瘤的发育中的特定作用 干预阿司匹林后，动态受到影响。该提议的总体目标是审问 阿司匹林对人类结肠上皮细胞和肠道微生物组的关节影响，以完善和建立因果关系 包括PG途径在内的机制，将使用新颖的体外，患者衍生 建模方法。我们假设通过完全询问这些额外机制的综合机制来假设 可以全面地为预防精确的预防策略开发网络。为了解决这个问题，我们 将利用在我们的随机，双盲，安慰剂中收集的生物测量（结肠活检和凳子） 阿司匹林的对照试验，急速。 在AIM 1中，我们将深入描述随机阿司匹林治疗对结直肠粘膜的影响 通过从粘膜活检和肠道微生物组收集的上皮细胞的RNA测序 执行整体弹药元基因组学，元文字组学和代谢组学来研究 随机阿司匹林处理对肠道微生物组的影响。在AIM 2中，将利用肠道器官培养物， 或三维的“迷你甲状腺”，培养源自同一患者阿司匹林患者的上皮细胞（直接 效果）和/或先验微生物代谢物（间接效应），以完善化学预防机制。结果 将进一步阐明肠道微生物组在消化道的健康和疾病状态中的作用 与NIDDK的整体任务保持一致。该提议还将为年轻调查员提供承诺 进一步发展一个利基市场的机会 生物信息学和翻译方法学技能。这将是候选人的重要第一步 实现他利用基础科学培训（博士前）和临床胃肠病学经验的目标 试验（博士后）成为实验室与诊所之间的有效桥梁，作为独立 学术研究员。