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: 10343857
• 负责人: David A Drew
• 金额: $ 15.82万
• 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/10343857
• 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; Equilibrium; Feces; Funding; Fusobacterium nucleatum; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Generations; Genomics; Glycochenodeoxycholate; Goals; Gut Mucosa; Health; Health Benefit; 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; antagonist; base; beta catenin; cardiovascular disorder prevention; cardiovascular disorder risk; colon microbiome; colorectal cancer progression; double-blind placebo controlled trial; experience; gut homeostasis; 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/文摘