Scientific Abstract

Proposal No. IBD-0249R
Principal Investigator:  Joanne K. Tobacman, M.D.
Applicant Organization:  The Board of Trustees of the University of Illinois (Chicago, U.S.A.)
Project Title:  Effects of carrageenan-free diet on activity of ulcerative colitis
Period of Award:  August 1, 2009 – July 31, 2012

The common food additive carrageenan (CGN) has been used for decades to induce intestinal inflammation that resembles ulcerative colitis in animal studies. These studies were often designed to test the effectiveness of anti-inflammatory agents or to study the characteristics of the inflammatory infiltrate. In recent work, we have identified CGN activation of two distinct pathways of inflammation in human colonic epithelial cells. These include a pathway of innate immunity, mediated by Toll-like Receptor 4 (TLR4), Bcl10, NFκB, and IL-8, and a reactive oxygen species (ROS) pathway, mediated by IKKα/β, NFκB, and IL-8. CGN exposure affects both the catalytic and regulatory domains of the IKK signalosome in human colonic epithelial cells in tissue culture, leading to a sustained, dose-related inflammatory response. Additional effects of CGN in human colonic epithelial cells in tissue culture include increases of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), p53, p21, β-catenin, and wnt9a, demonstrating profound effects of CGN exposure on vital mediators of inflammation, proliferation, and differentiation. In animal studies, CGN has induced significant intestinal lesions, including ulcerations, hemorrhage, polyps, and adenomas. These extensive changes suggest that human exposure to dietary CGN may have a role in the development of inflammatory bowel disease and colorectal carcinoma. Since CGN is consumed in significant quantities in the average Western diet (>100 mg/day), it is important and relevant to consider how its consumption might influence development of human disease or affect the manifestations of existing disease. In this study, we will determine if withdrawal of CGN from the diet impacts on the duration of remission in patients with ulcerative colitis. Patients with ulcerative colitis who required corticosteroids to induce remission and who have been in remission for at least one month will be enrolled. Patients will be followed in gastroenterology clinics of the University of Illinois at Chicago or the University of Chicago. They will be divided into two groups, and both groups will be instructed to follow a carrageenan-free diet. One group will receive supplements of carrageenan-containing capsules, and the other group a placebo. The study design will be double blind, with neither participants nor their personal gastroenterologists knowing whether or not they are assigned to the carrageenan-containing capsules. Participants will be followed for one year, during which time they will eat a carrageenan-free diet, complete questionnaires about their disease activity and medication use, and have bi-monthly follow up visits. The primary study outcome will be the duration of remission, defining the time of relapse as an increase in the Simple Clinical Colitis Activity Index (SCCI) score to 2 from a baseline of 0, in association with an increase in medications to control manifestations of ulcerative colitis. The SCCI, as measured by the method of Walmsley et al, will be the secondary study endpoint. Laboratory parameters of inflammation, including IL-8, NFκB, Bcl10, and fecal calprotectin, will be compared between the study groups. We hypothesize that CGN supplementation will be associated with shortened time to relapse, with increased SCCI scores and increased inflammation-associated laboratory tests. The study findings may lead to a new approach to treatment of ulcerative colitis based on reduced CGN consumption, as well as to preliminary data for an application for a federally funded multicenter trial.