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Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse.

Arrieta MC, Madsen K, Doyle J, Meddings J - Gut (2008)

Bottom Line: Treated animals showed a marked reduction in small intestinal permeability.At 8 weeks of age there was a significant reduction of colonic mucosal permeability and increased electrical resistance.By 17 weeks of age, secretion of tumour necrosis factor alpha (TNFalpha) from a colonic explant was significantly lower in the treated group (25.33 (SE 4.30) pg/mg vs 106.93 (SE 17.51) pg/ml in controls, p<0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alberta, Walter C Mackenzie Health Science Ctre, Edmonton, AB, Canada.

ABSTRACT

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 interleukin 10 (IL10) 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 dependent 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: IL10 gene-deficient (IL10(-)/(-)) mice) were treated with AT-1001 (a zonulin peptide inhibitor), a small peptide previously demonstrated to reduce small intestinal permeability. Small intestinal permeability was measured, in vivo, weekly from 4 to 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 (SE 0.08) in controls vs 3.97 (SE 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, secretion of tumour necrosis factor alpha (TNFalpha) from a colonic explant was significantly lower in the treated group (25.33 (SE 4.30) pg/mg vs 106.93 (SE 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 which demonstrated that AT-1001 was functionally active only in the small intestine.

Conclusions: This work suggests that increased intestinal permeability may be an important aetiological event in the development of colitis in IL10(-)/(-) mice.

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Related in: MedlinePlus

Small intestinal permeability is reduced with a zonulin antagonist AT-1001. (A) Small intestinal permeability was measured in IL10−/− mice treated with high dose AT-1001 (open squares), low dose (open circles) or placebo (closed circles) from 4 to 17 weeks of age. The shaded area represents the mean (3 SD) of the lactulose/mannitol ratios observed in wild-type mice. Mice treated with the high dose of AT-1001 eventually reached the wild-type range. (B) Statistical analysis of the areas under the curve of small intestinal permeabilities for each group. The permeabilities of the groups treated with AT-1001 differed significantly from the placebo group; p<0.05 (low dose), p<0.01 (high dose), n = 10–13.
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GUT-58-01-0041-f02: Small intestinal permeability is reduced with a zonulin antagonist AT-1001. (A) Small intestinal permeability was measured in IL10−/− mice treated with high dose AT-1001 (open squares), low dose (open circles) or placebo (closed circles) from 4 to 17 weeks of age. The shaded area represents the mean (3 SD) of the lactulose/mannitol ratios observed in wild-type mice. Mice treated with the high dose of AT-1001 eventually reached the wild-type range. (B) Statistical analysis of the areas under the curve of small intestinal permeabilities for each group. The permeabilities of the groups treated with AT-1001 differed significantly from the placebo group; p<0.05 (low dose), p<0.01 (high dose), n = 10–13.

Mentions: To determine whether the increased small intestinal permeability was zonulin dependent the animals were treated with AT-1001. When given daily in the drinking water the zonulin antagonist AT-1001 was effective in decreasing small intestinal permeability in the IL10−/− mice (fig 2). After 4 weeks of treatment, high-dose AT-1001 reduced small intestinal permeability to levels observed in control animals. This was evident from 8 weeks of age (fig 2A). The animals treated with low dose AT-1001 showed a significant reduction in overall permeability (as expressed as the area under the permeability curve) as compared to the placebo group (fig 2B), but this dose did not quite return small intestinal permeability to normal levels (fig 2A).


Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse.

Arrieta MC, Madsen K, Doyle J, Meddings J - Gut (2008)

Small intestinal permeability is reduced with a zonulin antagonist AT-1001. (A) Small intestinal permeability was measured in IL10−/− mice treated with high dose AT-1001 (open squares), low dose (open circles) or placebo (closed circles) from 4 to 17 weeks of age. The shaded area represents the mean (3 SD) of the lactulose/mannitol ratios observed in wild-type mice. Mice treated with the high dose of AT-1001 eventually reached the wild-type range. (B) Statistical analysis of the areas under the curve of small intestinal permeabilities for each group. The permeabilities of the groups treated with AT-1001 differed significantly from the placebo group; p<0.05 (low dose), p<0.01 (high dose), n = 10–13.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2597688&req=5

GUT-58-01-0041-f02: Small intestinal permeability is reduced with a zonulin antagonist AT-1001. (A) Small intestinal permeability was measured in IL10−/− mice treated with high dose AT-1001 (open squares), low dose (open circles) or placebo (closed circles) from 4 to 17 weeks of age. The shaded area represents the mean (3 SD) of the lactulose/mannitol ratios observed in wild-type mice. Mice treated with the high dose of AT-1001 eventually reached the wild-type range. (B) Statistical analysis of the areas under the curve of small intestinal permeabilities for each group. The permeabilities of the groups treated with AT-1001 differed significantly from the placebo group; p<0.05 (low dose), p<0.01 (high dose), n = 10–13.
Mentions: To determine whether the increased small intestinal permeability was zonulin dependent the animals were treated with AT-1001. When given daily in the drinking water the zonulin antagonist AT-1001 was effective in decreasing small intestinal permeability in the IL10−/− mice (fig 2). After 4 weeks of treatment, high-dose AT-1001 reduced small intestinal permeability to levels observed in control animals. This was evident from 8 weeks of age (fig 2A). The animals treated with low dose AT-1001 showed a significant reduction in overall permeability (as expressed as the area under the permeability curve) as compared to the placebo group (fig 2B), but this dose did not quite return small intestinal permeability to normal levels (fig 2A).

Bottom Line: Treated animals showed a marked reduction in small intestinal permeability.At 8 weeks of age there was a significant reduction of colonic mucosal permeability and increased electrical resistance.By 17 weeks of age, secretion of tumour necrosis factor alpha (TNFalpha) from a colonic explant was significantly lower in the treated group (25.33 (SE 4.30) pg/mg vs 106.93 (SE 17.51) pg/ml in controls, p<0.01).

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Alberta, Walter C Mackenzie Health Science Ctre, Edmonton, AB, Canada.

ABSTRACT

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 interleukin 10 (IL10) 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 dependent 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: IL10 gene-deficient (IL10(-)/(-)) mice) were treated with AT-1001 (a zonulin peptide inhibitor), a small peptide previously demonstrated to reduce small intestinal permeability. Small intestinal permeability was measured, in vivo, weekly from 4 to 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 (SE 0.08) in controls vs 3.97 (SE 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, secretion of tumour necrosis factor alpha (TNFalpha) from a colonic explant was significantly lower in the treated group (25.33 (SE 4.30) pg/mg vs 106.93 (SE 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 which demonstrated that AT-1001 was functionally active only in the small intestine.

Conclusions: This work suggests that increased intestinal permeability may be an important aetiological event in the development of colitis in IL10(-)/(-) mice.

Show MeSH
Related in: MedlinePlus