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The role of small intestinal permeability in the pathogenesis of colitis in the interleukin-10 gene deficient mouse

  • Author / Creator
    Arrieta Mendez, Marie Claire
  • It is currently believed that the etiology of inflammatory bowel disease involves an aberrant immune response towards the gastrointestinal microbial flora. In addition, an increase in intestinal paracellular permeability may also be a contributing factor of disease, as it precedes disease in several animal models. However, it remains unclear whether increased intestinal permeability is an epiphenomenon of disease or if it can lead to it. The goal of this thesis is to elucidate this cause-effect relationship. The IL-10-/- mouse is a model of IBD that spontaneously develops colitis after 12 weeks of age. We measured intestinal permeability in this mouse from 4-17 weeks of age and observed that there was a significant increase in small intestinal permeability early in life and before the onset of colitis. When small intestinal permeability was selectively decreased with AT-1001 (a ZOT antagonist peptide) colitis was significantly ameliorated. In contrast, when it was increased with AT-1002 (a ZOT agonist peptide) colitis worsened, indicating that modifications in the paracellular traffic of the small intestine had a significant effect on the severity of colonic disease. In order to study the possible mechanisms by which small intestinal permeability modulated disease in the colon, we measured the effect of increasing small intestinal permeability on the colonic microbial flora of IL-10-/- mice. After AT-1002 treatment from 4-12 weeks of age, there was an evident shift in colonic adherent flora. This effect was not a consequence of inflammation as there was a similar effect in wild type mice. We also studied the effect of increasing small intestinal permeability in the development of oral tolerance to dietary antigens. When wild-type mice were fed OVA under conditions of increased small intestinal permeability there was a significant increase in the proliferation of B cells in the spleen and an increase in OVA-specific humoral response, compared to animals fed OVA alone. Moreover, the production of IL-10 in response to oral OVA was prevented when OVA was given with AT-1002, both in the small intestine and the colon. The studies presented in the doctoral thesis suggest that small intestinal permeability has a critical role in the development of colitis in IL-10-/-mice, and that increasing paracellular traffic in the small intestine may lead to changes in colonic bacterial flora and the abrogation of tolerance to oral antigens, two features of inflammatory bowel disease in humans.

  • Subjects / Keywords
  • Graduation date
    2011-06
  • Type of Item
    Thesis
  • Degree
    Doctor of Philosophy
  • DOI
    https://doi.org/10.7939/R36013
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
    English
  • Institution
    University of Alberta
  • Degree level
    Doctoral
  • Department
    • Medicine
  • Supervisor / co-supervisor and their department(s)
    • Karen Madsen (Medicine)
    • Jon Meddings (Medicine)
  • Examining committee members and their departments
    • Monica Keelan (Department of Laboratory Medicine and Pathology).
    • Derek McKay (Department of Physiology and Pharmacology, University of Calgary)
    • Catherine FIeld (Food and Nutritional Science)