Background: Defects in the small intestinal epithelial barrier have been associated with inflammatory bowel disease but their role in the causation of disease is still a matter of debate. In some models of disease increased permeability appears to be a very early event. The IL-10 gene deficient mouse spontaneously develops colitis after 12 weeks of age. These mice have been shown to have increased small intestinal permeability that appears early in life. Furthermore, the development of colitis is dependant upon luminal agents, as animals do not develop disease if raised under germ free conditions.
Aims: To determine if the elevated small bowel permeability can be prevented, and if by doing so colonic disease is prevented or attenuated.
Methods: IL-10 -/- mice were treated with AT-1001, a small peptide previously demonstrated to reduce small intestinal permeability. Small intestinal permeability was measured, in vivo, weekly from 4-17 weeks of age. Colonic disease was assessed at 8 weeks in Ussing chambers and at 17 weeks of age inflammatory cytokines and myeloperoxidase were measured in the colon. Colonic permeability and histology were also endpoints.
Results: Treated animals showed a marked reduction in small intestinal permeability. Average area under the lactulose/mannitol time curve: 5.36 ± 0.08 in controls vs. 3.97 ± 0.07 in the high dose AT-1001 group, p<0.05. At 8 weeks of age there was a significant reduction of colonic mucosal permeability and increased electrical resistance. By 17 weeks of age, TNF- á secretion from a colonic explant was significantly lower in the treated group (25.33 ± 4.30 pg/mg vs 106.93 ± 17.51 pg/ml in controls, p<0.01). All other markers also demonstrated a clear reduction of colitis in the treated animals. Additional experiments were performed that demonstrated that AT-1001 was functionally active only in the small intestine.
Conclusions: This work suggests that increased intestinal permeability may be an important etiological event in the development of colitis in the IL-10 -/- mice.
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