PROJECT SUMMARY/ABSTRACT Microscopic colitis (MC) is a debilitating T-cell-mediated inflammatory disease of the large intestine with an incidence that now rivals that of inflammatory bowel disease (IBD), but has no FDA-approved therapies. Emerging evidence supports that MC occurs due to an inappropriate immune response to environmentally- induced disturbances in the luminal microenvironment. Diet is a critical regulator of the luminal microenvironment through alteration in gut epithelial integrity, microbiome composition and function, and immune cell activation. Yet, its role in the pathogenesis of MC remains unknown. Two dietary patterns, the Empiric Dietary Inflammatory Pattern (EDIP) and the Mediterranean diet, are of particular interest in MC pathogenesis due to their associations with changes in downstream metabolites, including short chain fatty acids, sphingolipids, and tryptophan metabolites, that have a plausible mechanistic basis in MC and a known role in the pathogenesis of other models of colitis. Furthermore, these dietary patterns and downstream metabolic pathways are associated with 1) systemic inflammatory markers known to be elevated in MC, and 2) incidence, disease activity, and treatment response of other IBD. Accordingly, our overarching hypothesis is that specific metabolic pathways, influenced by diet, impact risk of incident disease and treatment outcomes in MC. To test this hypothesis, we will first examine the associations between derived dietary patterns, EDIP and modified Mediterranean diet (Aim 1a), and their individual components (Aim 1b) and risk of MC within three population-based cohorts, the Nurses’ Health Studies and Health Professionals Follow-up Study. Second, within these cohorts we will evaluate the association between plasma metabolites and risk of MC (Aim 2a), and determine if metabolites mediate the associations between diet and MC (Aim 2b). Third, we will evaluate metabolites that predict therapeutic response in a prospective cohort of individuals with incident MC at Massachusetts General Hospital (MGH). We anticipate this work will provide valuable insight into the pathogenesis of MC, offering the basis for novel dietary therapies for MC in the future. Further, it will promote the career development of a junior faculty gastroenterologist at MGH with the long-term career goal of becoming an independent physician-investigator, focused on defining the etiopathogenesis of disease to inform preventive strategies and treatment algorithms that enhance patient outcomes. To achieve this goal, this proposal builds on the candidate’s background in epidemiology to provide focused training in nutritional epidemiology, analysis of metabolomic data to understand implicated biological pathways, and prospective cohort development. The candidate will thrive with the support of 1) a renowned mentorship team with expertise in MC, nutritional epidemiology, and metabolomics, 2) experiential and formal didactic training, and 3) the outstanding scientific environment of the MGH Clinical and Translational Epidemiology Unit, Harvard School of Public Health, and Broad Institute. By the completion of this award, the candidate will demonstrate the scientific independence and preliminary data for a successful R01 application.

PROJECT NARRATIVE Microscopic colitis, a relapsing inflammatory disease of the large intestine caused by a dysregulated immune response to changes in the gut luminal microenvironment, affects approximately 1 in 115 females and 1 in 286 males over a lifetime but has no FDA-approved therapies. Diet is the largest contributor to the gut luminal microenvironment but remains unexplored in microscopic colitis; as such, this proposal comprehensively examines the role of dietary patterns and downstream plasma and gut-microbiome-derived metabolites in disease pathogenesis and treatment outcomes. This proposal represents a critical step to advancing our understanding of microscopic colitis pathogenesis, with the goal of ultimately advancing treatment strategies for this debilitating disease.