Diet and metabolic factors in the pathogenesis of microscopic colitis

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.

Grant Number: 5K23DK131366-05
NIH Institute/Center: NIH
Principal Investigator: Kristin Burke