Metabolomics of symptomatic gallstone disease in COMETS

COMETS 中症状性胆石病的代谢组学

• 批准号: 10358593
• 负责人: Amit Dolar Joshi
• 金额: $ 12.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358593
• 关键词: Abdominal Pain; Address; Adult; Affect; Area; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; Biological; Biological Markers; Blood; Branched-Chain Amino Acids; Budgets; Cholecystectomy; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Clinical stratification; Collaborations; Data; Databases; Development; Diagnostic; Diglycerides; Disease; Economic Burden; Enrollment; Enterohepatic Circulation; Epigenetic Process; Etiology; Extramural Activities; Feces; Follow-Up Studies; Fostering; Future; Gall Bladder Diseases; General Hospitals; Generations; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genomics; Goals; Health; Health Care Costs; Health Professional; Hospitalization; Human; Individual; International; Intervention; Intestinal Absorption; Link; Maps; Massachusetts; Mediating; Metabolism; Metagenomics; Modality; Morbidity - disease rate; National Institute of Diabetes and Digestive and Kidney Diseases; Nurses' Health Study; Outcome; Participant; Pathway interactions; Patients; Pilot Projects; Plasma; Play; Population; Population Heterogeneity; Positioning Attribute; Prospective cohort; Research; Research Priority; Risk; Risk Factors; Role; Sample Size; Scanning; Susceptibility Gene; Symptoms; Triglycerides; United States; United States National Institutes of Health; Work; base; bile acid metabolism; cholesterol absorption; cohort; cost effective; cost estimate; disorder risk; experience; gallstone disease; gastrointestinal; genome wide association study; gut microbes; gut microbiome; gut microbiota; improved; lifestyle factors; metabolome; metabolomics; metagenome; metagenomic sequencing; microbial; novel; novel marker; patient stratification; persistent symptom; precision medicine; prevent; prospective; public health relevance; risk prediction; risk stratification; small molecule; tool

PROJECT SUMMARY/ ABSTRACT In this proposed R03 application, we will investigate plasma metabolomics and its interaction with the gut metabolome and metagenome in relation to risk of symptomatic gallstone disease. Gallstone disease is the leading cause for gastrointestinal-related hospital admissions in the U.S., with an annual economic burden of 6.5 billion dollars and accounts for about 2% of the US federal health budget. Our overarching hypothesis is that plasma metabolomic signatures that capture symptomatic GSD risk may be influenced by gut microbes through alterations in deconjugation of primary bile acids, synthesis of secondary bile acids, and by affecting enterohepatic circulation of molecules in bile acid and cholesterol metabolism pathways. The applicant has recently led a study to identify plasma metabolomic markers of gallstone disease in three large prospective US- based cohorts, as part of his K01 project, “Risk prediction of symptomatic gallbladder disease.” In Aim 1 of this R03 proposal, we plan to continue this work on gallbladder disease within the NIH-led large COnsortium of METabolomics Studies (COMETS) to (i) replicate recently identified metabolomics-based biomarkers of symptomatic gallstone disease in diverse populations, (ii) to utilize the larger sample sizes in COMETS to identify novel plasma metabolomic signatures of symptomatic gallstone disease. This project aligns with the applicant’s long-term goal to use ‘omics approaches to understand the etiological underpinnings of symptomatic gallstone disease and to develop genomic and metabolomics-based biomarker tools to improve risk prediction of symptomatic gallstone disease. Emerging evidence also suggests that the gut microbiome may play a critical role in maintaining the diversity of bile acids, and the composition of bile. Therefore, in Aim 2 of this application, we propose to conduct a pilot study in participants from Massachusetts General Hospital to investigate the role of gut-microbial communities in the risk of symptomatic gallstone disease and to determine whether this is mediated through their influence on the plasma metabolome. The expected outcome of this proposed R03 application and the ongoing K01 research is the comprehensive metabolomic profiling of symptomatic gallstone disease in distinct populations, accurate risk prediction of symptomatic gallstone disease, and the examination of a link between plasma metabolomics and the gut microbiome in gallstone disease risk. The successful accomplishment of project aims will help generation of preliminary data to position the applicant for future R01 studies that can provide proof-of-principle of the potential of exploiting metabolomics for precision medicine- based risk stratification for clinical interventions, a high NIDDK research priority.

项目概要/摘要 在这个拟议的 R03 应用中，我们将研究血浆代谢组学及其与肠道的相互作用 代谢组和宏基因组与症状性胆石病风险相关。胆结石病是 在美国，胃肠道相关住院的主要原因，每年造成的经济负担 65亿美元，约占美国联邦卫生预算的2%。我们的总体假设是 捕获症状性 GSD 风险的血浆代谢组学特征可能通过肠道微生物受到影响 初级胆汁酸解离、次级胆汁酸合成的改变，以及影响 胆汁酸和胆固醇代谢途径中分子的肠肝循环。申请人有 最近领导了一项研究，以确定美国三个大型前瞻性胆石病的血浆代谢组标记物 作为他的 K01 项目“症状性胆囊疾病的风险预测”的一部分。在这个目标1中 R03 提案，我们计划在 NIH 领导的大型联盟内继续开展胆囊疾病方面的工作 代谢组学研究 (COMETS) 旨在 (i) 复制最近发现的基于代谢组学的生物标志物 不同人群中的症状性胆石病，(ii) 利用 COMETS 中较大的样本量来识别 有症状的胆结石疾病的新血浆代谢组学特征。该项目符合申请人的 长期目标是使用“组学方法来了解症状性胆结石的病因基础” 疾病并开发基于基因组学和代谢组学的生物标志物工具，以改善疾病的风险预测 有症状的胆结石疾病。新出现的证据还表明，肠道微生物组可能发挥着关键作用。 维持胆汁酸的多样性和胆汁的组成的作用。因此，在本申请的目标 2 中， 我们建议对马萨诸塞州总医院的参与者进行一项试点研究，以调查其作用 肠道微生物群落与症状性胆石病风险的关系，并确定这是否是 通过它们对血浆代谢组的影响来介导。 R03 提案的预期成果 应用和正在进行的 K01 研究是有症状胆结石的综合代谢组学分析 不同人群的疾病，准确预测症状性胆石病的风险以及检查 血浆代谢组学和肠道微生物组在胆结石疾病风险中的联系。成功者 项目目标的实现将有助于生成初步数据，为申请人未来的 R01 定位 可以为利用代谢组学进行精准医学的潜力提供原理证明的研究 基于临床干预的风险分层，是 NIDDK 研究的高度优先事项。