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Increasing Small Intestinal Permeability Worsens Colitis in the IL-10−/− Mouse and Prevents the Induction of Oral Tolerance to Ovalbumin

Arrieta, Marie-Claire MSc, PhD*; Madsen, Karen L. PhD; Field, Catherine J. PhD; Meddings, Jonathan B. MD§

doi: 10.1097/MIB.0000000000000253
Original Basic Science Articles

Background: Increased intestinal permeability is found in noninflamed portions of the gut of inflammatory bowel disease patients and in their first-degree relatives, suggesting that it is not a consequence of inflammation. Additionally, increased small intestinal permeability precedes colonic disease in animal models of inflammatory bowel disease. However, it is not known how small intestinal permeability modulates disease in the colon. The aim of this study was to determine if increasing small intestinal permeability modulates colonic inflammation in interleukin (IL)-10−/− mice and if an increase in permeability is sufficient to prevent oral tolerance to a dietary antigen.

Methods: IL-10−/− mice were treated with the zonula occludens toxin pathway agonist AT-1002 for 8 weeks, and colitis severity was measured at 12 weeks of age. Wild-type mice were also treated with AT-1002 and fed ovalbumin (OVA) to determine the local and systemic immune response to this antigen under increased small intestinal permeability conditions.

Results: IL-10−/− mice treated with AT-1002 showed exacerbated colitis at 12 weeks of age. AT-1002 also induced a significant OVA-specific humoral response compared with mice that received OVA alone. In addition, the intestinal production of IL-10 and TGF-β in response to oral OVA was prevented when OVA was given with AT-1002.

Conclusions: Increasing small intestinal permeability worsens colitis in IL-10−/− mice, and it prevents the development of oral tolerance to OVA in wild-type mice. This study suggests that small intestinal permeability is not merely a consequence of inflammation but a condition that leads to two of the main pathological features of inflammatory bowel disease.

Article first published online 26 November 2014.

*Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada;

Department of Medicine, University of Alberta, Edmonton, AB, Canada;

Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada; and

§Faculty of Medicine, University of Calgary, Calgary, AB, Canada.

Reprints: Jonathan B. Meddings, MD, Faculty of Medicine, University of Calgary, 7D14, 7th Floor, TRW Building, 3280 Hospital Drive NW, Calgary T2N 4Z6, AB, Canada (e-mail:

Supported by generous grants from the Canadian Institute of Health Research and Alberta Innovates Health Solutions.

J. B. Meddings was a member of the scientific advisory board for Alba Therapeutics. The remaining authors have no conflicts of interest to disclose.

Received August 25, 2014

Accepted September 17, 2014

© Crohn's & Colitis Foundation of America, Inc.
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