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Am J Physiol Gastrointest Liver Physiol (March 17, 2005). doi:10.1152/ajpgi.00395.2004
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Submitted on August 31, 2004
Accepted on March 8, 2005

Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a -/- mice

Silvia Resta-Lenert1*, Jane Smitham1, and Kim E. Barrett1

1 Division of Gastroenterology, Department of Medicine, University of California San Diego, School of Medicine, San Diego, California, USA

* To whom correspondence should be addressed. E-mail: srestalenert{at}ucsd.edu.

P-glycoprotein, the product of the multidrug resistance protein 1 (MDR1) gene, is a xenobiotic transporter that may contribute to the physiology of the intestinal barrier. 25% of mdr1a-deficient (-/-) mice spontaneously develop colitis at variable ages when maintained under specific pathogen-free conditions. We hypothesized that this disease would result from epithelial dysfunction and that conventional housing would increase incidence and severity of the colitis phenotype. Wild type congenic FVB (+/+) mice were maintained under the same conditions as controls. Knock out and wild type mice were matched for age and gender, and observed for signs of colitis. Colonic tissues from both groups of mice were examined for macroscopic and microscopic injury and for basal ion transport and transepithelial resistance (TER). Translocation of bacteria across the intestine was assessed by culturing the spleen and mesenteric lymph nodes. Protein analysis was performed by Western blotting. All mdr1a deficient mice developed weight loss and signs of colitis whereas wild type mice never showed such signs. Within the mdr1a deficient group, males consistently developed severe colitis earlier than females. Knock out mice showed increased basal colonic ion transport (Females, 162.7±4.6 vs. 49.7±3.8 µA/cm2; Males, 172.6±5.6 vs. 54.2±3.1 µA/cm2; p<0.01) and decreased TER (Females, 25.4±0.3 vs. 36.4±0.8 {Omega}.cm2; Males, 23.1±.0 vs. 38.3±0.2 {Omega}.cm2; p<0.01) compared to wild type mice. Barrier dysfunction was accompanied by decreased phosphorylation of tight junction proteins. Expression of COX-2 and iNOS in intestinal tissues was increased in the mdr1a -/- group (p<0.01), and correlated with disease severity. Bacterial translocation was greater both in incidence (p<0.01) and severity (p<0.001) for the knock out group. With respect to all indices studied, mdr1a deficient males performed worse than females. Our data support the hypothesis that alterations in the intestinal barrier alone, in the absence of immune dysfunction, may rapidly lead to colitis in the setting of a normal colonic flora.




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