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Permanent link (DOI): https://doi.org/10.7939/R36013

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

Descriptions

Other title
Subject/Keyword
Intestinal Permeability
IL-10 gene deficient mouse
colitis
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Arrieta Mendez, Marie Claire
Supervisor and department
Karen Madsen (Medicine)
Jon Meddings (Medicine)
Examining committee member and department
Derek McKay (Department of Physiology and Pharmacology, University of Calgary)
Monica Keelan (Department of Laboratory Medicine and Pathology).
Catherine FIeld (Food and Nutritional Science)
Department
Medicine
Specialization

Date accepted
2011-04-06T14:15:49Z
Graduation date
2011-06
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
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.
Language
English
DOI
doi:10.7939/R36013
Rights
License granted by Marie Claire Arrieta (marrieta@ualberta.ca) on 2011-04-04T21:58:51Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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