The multidrug resistance gene, Mdr1a, encodes a transmembrane protein that is expressed in many tissues including intestinal epithelial cells, a subset of lymphoid cells and hematopoietic cells1-3. It is reported that Mdr1a knockout (Mdr1a-/-) mice are susceptible to developing a severe, spontaneous intestinal inflammation when maintained under pathogen free animal facility conditions. The intestinal inflammation seen in Mdr1a knockout mice fully develops around 12-16 weeks of life, is pathologically similar to that of human inflammatory bowel disease, and is defined by dysregulated epithelial cell growth and leukocytic infiltration into the lamina propria of the large intestine1-3. There is increasing evidence that the intestinal microflora is an important cofactor in the pathogenesis of intestinal inflammation. The development of spontaneous colitis in many mouse models can be prevented if mice are generated and maintained in a germ-free environment or treated with oral antibiotics, highlighting the central role for bacterial colonization in the initiation and/or perpetuation of experimental IBD. This model of spontaneous colitis may provide new insight into the pathogenesis of IBD, the nature of a dysregulated immune system, and the potential to screen therapeutic compounds in a chronic IBD setting that does not require a chemical or immunomodulatory induction1-5.
Diseased animals (Mdr1a mice) may be administered up to 5×10^7 Colony Forming Units (CFUs) of Helicobacter bilis. This bacterium is administered at the beginning of a study to aid in disease synchronization.
At the time of arrival, mice will be acclimated for one week prior to the study initiation. On study day 0, mice will be randomized into treatments groups based on body weight and endoscopy or Disease Activity Index (DAI) scores, and treatment will begin.
The endpoints of the study include, colon length, colon weight, colon weight/length, and degenerative changes and microscopic evaluation of the colon for inflammation and epithelial loss/damage to determine the potential amelioration of disease by test articles.
Route of administration: SC, PO, IP, IV
Disease-specific signs of possible pain and distress will be decreased activity, decreased food consumption, hunching, piloerection, anogenital staining, prolapsed rectum and fecal impaction. DAI and Endoscopy can also be included to evaluate the clinical state of the animals. Any animals that lose more than 20% body weight within 1 week will be enrolled in the animal health assessment program and monitored daily. Animals that lose more than 30% of their body weight from the start of a study will be euthanized. 16. Unlike other mouse models of IBD, the incidence of prolapsed rectum is a component of the spontaneous disease in Mdr1a mice.