Metabolomics of symptomatic gallstone disease in COMETS

项目总结/摘要 在R 03的应用中，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的关系。胆石病是一种 是美国胃肠相关住院的主要原因，每年的经济负担 6.5约占美国联邦卫生预算的2%。我们的首要假设是 捕获症状性GSD风险的血浆代谢组学特征可能受到肠道微生物的影响， 初级胆汁酸的去结合、次级胆汁酸的合成以及通过影响 胆汁酸和胆固醇代谢途径中分子的肝肠循环。申请人已经 最近领导了一项研究，以确定胆结石疾病的血浆代谢组学标志物在三个大的前瞻性美国- 作为他的K 01项目“症状性胆囊疾病的风险预测”的一部分。目标1 R 03提案，我们计划在NIH领导的大型会议中继续这项关于胆囊疾病的工作， 代谢组学研究（COMETS），以（i）复制最近确定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 症状性胆石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学基础 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 症状性胆石病。新出现的证据还表明，肠道微生物组可能在 在维持胆汁酸的多样性和胆汁的组成方面的作用。因此，在本申请的目标2中， 我们建议在来自马萨诸塞州总医院的参与者中进行一项试点研究，以调查 肠道微生物群落在有症状的胆结石疾病的风险，并确定这是否是 通过其对血浆代谢组的影响来介导。本拟议R 03的预期结果 应用和正在进行的K 01研究是症状性胆结石的综合代谢组学分析 不同人群中的疾病，症状性胆石病的准确风险预测，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 项目目标的实现将有助于生成初步数据，为申请人未来的R 01做好准备 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，这是NIDDK研究的优先事项。

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.