Mechanisms associated with flares and remission in colitis

总结

Summary Inflammatory bowel diseases (IBD) affect millions of individuals worldwide and its incidence is increasing. Both genetic and environmental factors appear to play a role in IBD development. Genetic studies in humans have linked the interleukin-23 (IL-23) signaling pathway with IBD, but the environmental factors contributing to disease, have remained elusive. The rising incidence of worldwide IBD has been associated with westernization of dietary habits in developing countries, however there is little scientific evidence to support causality. In this application we will examine the role of a particular group of dietary additives, namely food colorants, to development of colitis. We have now discovered that the food colorant Red 40, also known as Allura Red AC, promotes colitis in mice that conditionally express low levels of IL-23 (referred to as R23FR mice), but not in wild type mice. Red 40 is the most abundant food colorant in the world, with annual production exceeding 2.3 million kg. It is widely used in as red colorant in soft drinks, cherry flavored products, candy, dairy, drugs, and cosmetics. Of interest, the Red 40-containing beverages, Kool-Aid and the hydrating solution Pedialyte Cherry can also cause colitis in R23FR mice. Red 40-induced colitis in R23FR mice requires the microbiota and CD4+ T cells. Based on these and other results presented here, we formulate a central hypothesis that the Red 40 or its metabolites haptenize bacterial or endogenous proteins to generate tolerance in wild type mice, or colitis in mice in which IL-23 expression is dysregulated. We will study in this proposal the mechanisms involved in generation and prevention of these responses. Specifically, we will define: 1) if Red 40 and its metabolite ANSA are haptens; 2) how Red 40 induces tolerance in control mice; and 3) if Red 40 or ANSA-specific T cells are generated in R23FR mice