Impact of Aspirin on the Gut Microbiome and Mucosal Microenvironment

项目摘要/摘要 大量证据支持与使用阿司匹林相关的健康益处，特别是对 心血管疾病(CVD)和结直肠癌(CRC)风险增加。2016年，美国预防性的 服务工作组建议使用小剂量(81毫克)阿司匹林作为心血管疾病和结直肠癌的一级预防药物，尽管 对阿司匹林对结肠影响的生物学机制的不完全理解。我们有 提出了阿司匹林直接抑制阿司匹林的生物学机制的相关框架 上皮细胞内的前列腺素。为了扩展这一框架，我们现在提出支持的新假说 通过令人信服的初步数据，肠道微生物群可能介导了对大肠粘膜的生物学效应 与阿司匹林有关。肠道微生物群是肠道动态平衡的关键决定因素，而且越来越多地 与大肠肿瘤的发生有关。然而，需要进行前瞻性研究来确定 肠道微生物组在癌变高危粘膜发生发展中的特殊作用及其微生物 阿司匹林干预后，动力学会受到影响。这项提案的总体目标是审问 阿司匹林对人结肠上皮细胞和肠道微生物群的联合影响以提炼和确定病因 机制，包括PG途径，这将进一步验证使用新的，体外，患者来源 建模方法。我们假设，通过充分询问这些附加机制，一个完整的 可以开发全面通知精准预防策略的网络。为了解决这个问题，我们 将利用我们随机、双盲、安慰剂中收集的生物标本(结肠活检和大便)- 阿司匹林的对照试验，渴望。 在目标1中，我们将深入研究随机阿司匹林治疗对大肠粘膜的影响。 通过对从粘膜活检组织和肠道微生物群收集的上皮细胞进行RNA测序 进行完整的元基因组学、元转录组学和代谢组学的综合研究 阿司匹林随机治疗对肠道菌群的影响。在目标2中，将利用肠道器官培养， 或三维“迷你肠道”，培养来自服用阿司匹林的同一患者的上皮细胞(直接 (间接影响)和/或先验微生物代谢物(间接影响)，以完善化学预防机制。结果是 将进一步阐明肠道微生物群在消化道健康和疾病状态中的作用 与NIDDK的总体使命一致。这项提议还将为一位有前途的年轻调查员提供 有机会进一步发展一个利基市场，在这个利基市场内进行独立的调查并扩大他的 生物信息学和翻译方法技能。这将是候选人重要的第一步 达到利用基础科学培训(博士前)和临床胃肠病学经验的目标 试验(博士后)作为独立的实验室和临床之间的有效桥梁 学术调查员。

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.