The Microbiome, Metabolome, and Genome in Multiplex IBD Family Clusters

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This project will seek to define the relative risk contributions of microbial and genetic factors to the development of inflammatory bowel disease (IBD) within a cohort of high-risk multiplex (3 first-degree relatives affected) IBD families. Candidate: The primary objective of this application is to support Dr. Elizabeth Spencer’s career development into an independent, patient-oriented investigator in the field of prevention and personalized medicine for IBD patients. Dr. Spencer’s career goal is to become an independent researcher and leader in the application of risk stratification and prevention for IBD. Dr. Spencer’s proposed training activities are in five areas: 1) microbiomics, 2) metabolomics, 3) computational genomics and metagenomics, 4) longitudinal cohort building, and 5) leadership. To achieve this, she has assembled a mentoring team led by Dr. Marla Dubinsky, Co-Director of the IBD Clinical Center at Mount Sinai and Chief of the Division of Pediatric Gastroenterology, an expert in IBD risk stratification, Dr. Judy Cho, Ward-Coleman Professor, Vice-Chair of Genetics & Genomics & Gastroenterology, and Director of the Charles Bronfman Institute for Personalized Medicine (IPM) at the Icahn School of Medicine at Mount Sinai (ISMMS), an expert in the genetics of IBD, and Dr. Jeremiah Faith, Associate Professor of Genetics and Genomic Sciences and Clinical Immunology and Director of the Microbiome Translational Center, an expert in microbiomic analysis. Environment: The ISMMS has a strong tradition of outstanding research and is one of the top 20 medical schools in NIH funding. The Mount Sinai Division of Pediatric Gastroenterology is an international leader in IBD research and clinical care. Research: IBD is a heterogenous set of chronic inflammatory disorders that arise from the complex interplay of genetic, environmental and microbial factors, and immune responses. These complicated interactions arise before the identification of overt disease, making it difficult to tease out the causative factors behind disease inception given the need for a pre-clinical, high-risk cohort. The Multiplex Families Research Program at ISMMS provides a unique cohort of affected and unaffected members of multiplex families with IBD to examine the relative contribution of these factors. Dr. Spencer’s preliminary observations in this cohort have shown that siblings with IBD tend to cluster together in birth order, likely due to some environmental sharing, which could be attributed to microbial changes. We would like to explore this further by characterizing the microbial and genetic contributions to familial IBD to improve stratification of those at high-risk for developing both pre-clinical and overt IBD. Therefore, our specific aims are (1) to define the features of microbial and metabolomic profiles in sibling clusters of IBD and their association with genetic risk and (2) to develop an IBD risk score incorporating genetic, microbial, and metabolomic factors with validation in a similar, external cohort. The general approaches and skills developed during this award can be applied to further IBD risk stratification and continued exploration of possible inciting environmental triggers for those at high-risk for IBD.