The Gut Microbiota in Metabolic Surgery: A Multi-Ethnic, Multi-Omic, Longitudinal Study

PROJECT SUMMARY Metabolic and bariatric surgery is an emerging option to treat obesity-related metabolic diseases, e.g., type 2 diabetes, and prevent atherosclerotic cardiovascular disease (ASCVD). Metabolic surgery can profoundly alter the gut microbiota; meanwhile, gut microbiota and their metabolites may affect cardiometabolic outcomes after the surgery. Investigation of these “host-microbiota interactions” will offer novel mechanistic understanding of metabolic surgery and evidence for developing potential microbiota-based models/therapies to achieve better cardiometabolic health. Yet, longitudinal patient studies that examined pre- to post-surgery gut microbiota and their metabolites in relation to cardiometabolic outcomes are scarce. Existing studies are limited by small sample sizes XVXDOO\ Q” , non-prospective design, no evaluation of microbial functionality nor activity (e.g., via multi-omics), and little consideration of diet or medication use. Of note, no studies have evaluated gut microbiota in relation to estimated 10-year ASCVD risk, which reflects the overall cardiometabolic benefit of metabolic surgery and is widely used in clinical practice per ACC/AHA guideline. Furthermore, no studies have included African Americans (AAs), a population with high rates of cardiometabolic diseases. We aim to fill these research gaps by establishing a longitudinal, multi-ethnic cohort of metabolic surgery patients and applying multi-omics to identify microbial features (e.g., species, pathways, and metabolites) associated with estimated 10-year ASCVD risk and/or improvements in A1C, blood pressure, and blood lipids. In a pilot study, we enrolled 20 patients (including AAs), collected longitudinal stool/blood samples, conducted surveys, and found significant changes in microbiome and microbial metabolites after surgery, demonstrating the feasibility and our ability to carry out the proposed full-scale study. Specifically, we will enroll and follow 200 patients to collect biospecimen and conduct surveys at pre-surgery and 3-month and 1-year post-surgery visits. We will evaluate pre- to post-surgery changes in gut microbiome and fecal and circulating levels of metabolites, especially microbiota-derived metabolites, and the prospective associations of pre-surgery and 3-month microbiome and metabolites with ASCVD risk and metabolic outcomes at 1-year post-surgery. We will also explore potential effect modifications by diet and medication, focusing on fiber intake and metformin use. Our proposed research will provide substantial novel data to advance our understanding of the role of gut microbiota in cardiometabolic improvements after metabolic surgery, which may translate into novel microbial approaches to identify and treat patients for better cardiometabolic health. Our team has extensive expertise in cardiometabolic diseases, diet-microbiota-host interactions, metagenomics and metabolomics in longitudinal cohorts, as well as in metabolic surgery with experiences as patients, care providers, and/or researchers, and thus, is uniquely positioned to accomplish the proposed research.