MECHANISMS OF COLITIS INDUCED BY DEFINED BACTERIAL FLORA

Univ Of North Carolina Chapel Hill, Chapel Hill NC

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Abstract

Rodent model systems of chronic intestinal inflammation are now well established. Using HLAB27 transgenic rats, we have previously shown that the microflora of the intestinal tract plays a direct role in the initiation of colitis. Our studies will focus on the immunologic and physiologic parameters of the host response to a specific group of well-defined intestinal microflora. During the previous funding period, we determined that germ-free rats monoassociated with Bacteriodes vulgatus develop colitis. Not all bacteria induceinflammation however, as evidenced by our observation that HLAB27 transgenic rats monoassociated with E. coli do not develop colitis. The goal of the studies in the current proposal is to identify those species of Bacteroides that are able to induce colitis, to analyze the characteristics of the mucosal immune response to those specific strains, and to determine the mechanism(s) of the development of colitis associated with the immune response to the organisms. Once the strain(s) of Bacteroides that induce colitis have been identified, we will analyze the profile of cytokines produced by bacterial antigen-reactive T cells and by antigen-presenting cells isolated from HLAB27 transgenic rats. We will determine which bacterial antigens stimulate the mucosal immune response. In these studies we will focus on induction of the cytokines interleukin-12 and interferon-y and regulation of these two molecules by interleukin-10 and transforming growth factor p, two cytokines that have been the focus of investigation on suppression of immune and inflammatory responses. In addition, we will determine the capacity of cytotoxins isolated from Bacteroides species to alter intestinal permeability by measuring changes in short circuit current and electrical resistance of intact rat colonic epithelium exposed in vitro to the bacterial products. The results of these studies are the prerequisite for developing specific therapies for Crohn's disease and ulcerative colitis patients targeted towards eliminating or attenuating the dominant bacteria that induce and perpetuate colitis.