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.
Gallbladder disease is the leading cause for gastrointestinal-related hospital admissions in the United States, resulting in substantial morbidity and healthcare costs. This study aims to determine whether circulating small molecules in blood (plasma metabolites) are associated with the risk of symptomatic gallstone disease within a large consortium of metabolomic studies (COMETS). The proposed research will also examine the role of gut microbiome in the risk of gallstone disease.