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.

项目总结/摘要 大量证据支持阿司匹林的使用对健康有益，特别是对于那些 增加患心血管疾病（CVD）和结直肠癌（CRC）的风险。2016年，美国预防 服务工作组建议低剂量（81 mg）阿司匹林作为CVD和CRC的一级预防， 对阿司匹林对结肠作用的生物学机制的不完全理解。我们有 提出了一个相互关联的框架，通过直接抑制阿司匹林的生物学机制， 上皮细胞内的胡萝卜素。为了扩展这个框架，我们现在提出了一个新的假设， 令人信服的初步数据表明，肠道微生物组可能介导对结直肠粘膜的生物学效应， 与阿司匹林有关。肠道微生物组是肠道内稳态的关键决定因素，并且越来越多地被认为是 与结直肠肿瘤的发展有关。然而，需要前瞻性研究来定义 肠道微生物组在肿瘤风险粘膜发展中的特定作用以及微生物如何 阿司匹林干预后动力学受到影响。该提案的总体目标是询问 阿司匹林对人类结肠上皮细胞和肠道微生物组的联合影响，以完善和建立因果关系 机制，包括PG途径，这将进一步验证使用新的，在体外，患者源性 建模方法。我们假设，通过充分询问这些额外的机制， 可以开发一个全面通报精确预防战略的网络。为了解决这个问题，我们 将利用我们的随机、双盲、安慰剂试验中收集的生物标本（结肠活检和粪便）， 阿司匹林的对照试验，阿司匹林。 在目标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， 通过对从粘膜活检收集的上皮细胞和肠道微生物组进行RNA测序， 进行整合的全鸟枪宏基因组学，元转录组学和代谢组学研究， 随机阿司匹林治疗对肠道微生物组的影响。在目标2中，将利用肠道类器官培养， 或三维“迷你肠道”，培养上皮细胞来源于同一患者与阿司匹林（直接 作用）和/或先验微生物代谢物（间接作用）来改进化学预防机制。结果 将进一步阐明肠道微生物组在消化道健康和疾病状态中的作用， 符合NIDDK的总体使命。这项提议还将为一名有前途的年轻调查员提供 有机会进一步发展一个利基，在其中寻求独立的调查路线，并扩大他的 生物信息学和翻译方法技能。这将是候选人重要的第一步， 实现利用基础科学培训（博士前）和临床胃肠病学经验的目标 试验（博士后）成为实验室和临床之间的有效桥梁，作为一个独立的 学术研究者