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Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.

ABSTRACT: P-glycoprotein (P-gp), the product of the multidrug resistance gene (MDR), is an ATP-dependent transmembrane pump, which is expressed in multiple cell lineages including epithelial and hematopoetic cells. The human MDR gene is located on chromosome 7 (7q21.1), a susceptibility loci for inflammatory bowel disease (IBD). A significant number of IBD patients carry mutations in this gene and P-gp-deficient FVB/N mice develop a severe spontaneous colitis, characterized by impaired intestinal barrier function and immune reactivity to intestinal bacterial antigens.In this work we explored the role of mouse strain, as well as environmental insults, on the development of colonic inflammation in the absence of P-gp. Among the induction methods utilized, dextran sodium sulfate (DSS) disrupts the intestinal epithelium, while piroxicam is a nonsteroidal antiinflammatory (NSAID) drug that inhibits prostaglandin production and initiates colitis in IL10-deficient animals. Helicobacter bilis is a known mediator of bacterial-induced colitis.We demonstrate that crossing this mutation onto the C57BL/6 strain confers protection from spontaneous colitis. C57BL/6.mdr1a-deficient animals demonstrated increased histological inflammation, colonic shortening, fecal blood, and reduced body weight after 7 days of treatment with 2.25% DSS. C57BL/6.mdr1a-deficient mice treated with piroxicam or infected with H. bilis showed no weight loss, or alterations in colonic histology.These data indicate that the effects of P-gp deficiency are significantly modulated by background strain influences, but that the epithelium continues to have increased susceptibility to chemical injury in the C57BL/6 model.

SUBMITTER: Staley EM

PROVIDER: S-EPMC2887754 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.

Staley Elizabeth M EM Schoeb Trenton R TR Lorenz Robin G RG

Inflammatory bowel diseases 20090501 5

<h4>Background</h4>P-glycoprotein (P-gp), the product of the multidrug resistance gene (MDR), is an ATP-dependent transmembrane pump, which is expressed in multiple cell lineages including epithelial and hematopoetic cells. The human MDR gene is located on chromosome 7 (7q21.1), a susceptibility loci for inflammatory bowel disease (IBD). A significant number of IBD patients carry mutations in this gene and P-gp-deficient FVB/N mice develop a severe spontaneous colitis, characterized by impaired ...[more]

PMID: 19067430

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Project description:Crohn's disease (CD) represents a chronic inflammatory disorder of the intestinal tract. Several susceptibility genes have been linked to CD, though their precise role in the pathogenesis of this disorder remains unclear. Immunity-related GTPase M (IRGM) is an established risk allele in CD. We have shown previously that conventionally raised (CV) mice lacking the IRGM ortholog, Irgm1 exhibit abnormal Paneth cells (PCs) and increased susceptibility to intestinal injury. In the present study, we sought to utilize this model system to determine if environmental conditions impact these phenotypes, as is thought to be the case in human CD. To accomplish this, wild-type and Irgm1-/- mice were rederived into specific pathogen-free (SPF) and germ-free (GF) conditions. We next assessed how these differential housing environments influenced intestinal injury patterns, and epithelial cell morphology and function in wild-type and Irgm1-/- mice. Remarkably, in contrast to CV mice, SPF Irgm1-/- mice showed only a slight increase in susceptibility to dextran sodium sulfate-induced inflammation. SPF Irgm1-/- mice also displayed minimal abnormalities in PC number and morphology, and in antimicrobial peptide expression. Goblet cell numbers and epithelial proliferation were also unaffected by Irgm1 in SPF conditions. No microbial differences were observed between wild-type and Irgm1-/- mice, but gut bacterial communities differed profoundly between CV and SPF mice. Specifically, Helicobacter sequences were significantly increased in CV mice; however, inoculating SPF Irgm1-/- mice with Helicobacter hepaticus was not sufficient to transmit a pro-inflammatory phenotype. In summary, our findings suggest the impact of Irgm1-deficiency on susceptibility to intestinal inflammation and epithelial function is critically dependent on environmental influences. This work establishes the importance of Irgm1-/- mice as a model to elucidate host-environment interactions that regulate mucosal homeostasis and intestinal inflammatory responses. Defining such interactions will be essential for developing novel preventative and therapeutic strategies for human CD.

Dataset Information

Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.

Publications

Differential susceptibility of P-glycoprotein deficient mice to colitis induction by environmental insults.

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