Prevention of Crohns Disease in High-Risk Individuals

PROJECT SUMMARY/ABSTRACT Crohn’s disease (CD) is a chronic, disabling inflammatory bowel disease (IBD) associated with enormous social and economic impact, decreased quality of life, increased mortality, and rising global incidence. Despite the approval of a number of biologic and small molecule inhibitors for the treatment of CD, the therapeutic

ceiling for CD appears to have plateaued. Therefore, there is an unmet need to explore prevention strategies in CD. Dietary and lifestyle factors are thought to be primary CD risk factors, and may exert influence on CD development in the pre-clinical disease phase via pathways that mediate intestinal permeability and abnormal

immune responses. CD-specific biomarkers, which emerge in the pre-clinical phase, predict subclinical inflammation, correlate with disease activity, and may decrease with dietary changes. Thus, dietary and lifestyle modification may normalize CD biomarkers and reduce disease risk. High-risk individuals for CD, such

as first-degree relatives (FDRs) of patients with IBD or those who carry genetic variants associated with CD, may be an attractive group for disease prevention strategies. Our overarching hypothesis is that lifestyle modification in individuals at high-risk for CD reduces risk of CD development, and that personalized risk

disclosure and risk factor counseling can be feasibly delivered to FDRs via the personalized risk estimation for CD (PRE-CD) tool. To test this hypothesis, we will assess how adherence to a healthy diet and lifestyle impacts risk for CD in FDRs (Aim 1) and those with elevated polygenic risk scores for CD (Aim 2) from the

Nurses’ Health Study (NHS), NHSII, Health Professionals Follow-up Study and Growing Up Today Study using a target-trial methodology to emulate a randomized controlled trial of a healthy lifestyle intervention. Second, we will develop and test the feasibility (Aim 3a) and explore the efficacy of the PRE-CD tool on behaviors (Aim

3b) and pre-clinical biomarkers (Aim 3c) associated with CD in FDR recruited from the Massachusetts General Hospital (MGH) Crohn’s and Colitis Center. This work will provide valuable insight into the role of lifestyle and dietary modification in CD development and prevention strategies in high-risk individuals, addressing a critical

gap in the field of IBD prevention. Further, through the proposed work, as well as a formal didactic curriculum, the candidate will gain additional training in the fields of nutritional epidemiology, causal inference, and conducting clinical trials. This career development plan will enable the candidate to achieve her long-term

goals of becoming an independently funded clinical-investigator and generate preliminary data to subsequently apply for an NIH R01 award. The candidate will conduct her work in the supportive, robust research environment of the MGH Division of Gastroenterology, MGH Clinical and Translational Epidemiology Unit, and

Harvard School of Public Health supervised by a dedicated and distinguished mentorship team and research advisory committee.