Scientific Abstract
Proposal No. IBD-0250
Principal Investigator: Thaddeus S. Stappenbeck, M.D., Ph.D.
Applicant Organization: Washington University (St. Louis, Missouri, U.S.A.)
Project Title: Identification of colitogenic bacteria in an antibiotic-responsive model of fulminant ulcerative colitis
Period of Award: September 1, 2008 – February 28, 2011
Multiple genetic hits to the host immune system may contribute to the susceptibility and severity of IBD. Several genetic mouse models that re-capitulate some aspects of human IBD have utilized a single gene defect to induce colitis. We hypothesized that multiple genetic hits to the regulatory machinery that normally inhibits immune activation in the intestine would generate more severe, reproducible pathology that would mimic either ulcerative colitis or Crohn’s disease. Therefore, we generated a novel mouse line (dnKO) that possessed defects in both TGFβRII and IL-10R2 signaling. These mice rapidly and reproducibly developed a disease resembling fulminant human ulcerative colitis that was quite distinct from the much longer and more variable course of pathology observed previously in mice possessing only single defects. Pathogenesis was driven by uncontrolled production of pro-inflammatory cytokines resulting in large part from T cell activation. The disease process could be partially ameliorated by administration of antibodies against IFNγ and TNFα.
Importantly, the disease in dnKO was completely inhibited by a combination of broad spectrum antibiotics (metronidazole and ciprofloxacin). We have further explored the microbial-sensitivity of the colitis that develops in this model and found that metronidazole treatment alone can prevent disease. We have gone on to develop an experimental system whereby the dnKO mice are treated with metronidazole for one week. Treated mice that then have this antibiotic discontinued remain free of disease for several weeks. Conversely, metronidazole-treated dnKO mice that are colonized with whole cecal contents (i.e., representation of the entire microbiota of a WT mouse). This result is consistent with an indigenous, metronidazole-sensitive microbe (or microbes) that trigger fulminant colitis in this sensitized host (the dnKO mouse). We propose to utilize this completely penetrant, fast-acting experimental system to determine the microbial factors that induce immune activation and discover the indigenous microbes that can cause disease. Our goal is to then apply these results to human patients with pouchitis (a form of IBD that is sensitive to metronidazole and ciprofloxacin).