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REDUCING SMALL INTESTINAL PERMEABILITY ATTENUATES COLITIS IN THE IL-10 GENE DEFICIENT MOUSE
MC Arrieta1, J Doyle2, K Madsen1, J Meddings1
1Division of Gastroenterology, Department of Medicine, University of Alberta; 2Department of Laboratory Medicine and Pathology, Vernon Jubilee Hospital, Vernon, British Columbia
Background & Aims: Defects in the intestinal epithelial barrier have been associated with inflammatory bowel disease for decades but their role in the causation of disease is still a matter of debate. In some models of disease (and in man) increased permeability appears to be a very early event. The IL-10 gene deficient mouse spontaneously develops colitis after 12 weeks of age. Using in vitro techniques these mice have been shown to have a defect in small bowel permeability that appears early in life. Furthermore, the development of their colitis is dependant upon luminal agents, as they do not develop disease if raised under germ free conditions. The purpose of this study was to determine first, if the elevated small bowel permeability can be prevented, and secondly, if by doing so colonic disease would be prevented or attenuated.
METHODS: IL-10 –/– mice were treated with a zonulin receptor antagonist. Zonulin has been previously shown to increase small intestinal permeability but has no effect in the colon. Small intestinal permeability was measured in vivo weekly from 4-17 weeks of age. Colonic disease was assessed at 8 weeks in Ussing chambers. At 17 weeks of age the colonic production of inflammatory cytokines and myeloperoxidase were measured, as well as colonic permeability and histology.
RESULTS: Animals treated with the antagonist showed a marked reduction in small intestinal permeability. In vitro experiments at 8 weeks of age showed a significant reduction of colonic mucosal permeability damage and increased electrical resistance. By 17 weeks of age, all markers of disease showed a clear reduction of colitis in the treated animals.
CONCLUSIONS: This work suggests that increased intestinal permeability is an important etiological event in the development of colitis in the IL-10 –/– mice.