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INTESTINAL FIBROSIS IN CROHN’S DISEASE: THE ROLE OF IMMUNE RECEPTOR RECOGNITION OF BACTERIAL PRODUCTS
LE Månsson1, GA Grassl2, KSB Bergstrom1, BA Vallance1
1Dept. of Pediatrics, BC’s Children’s Hospital; 2Michael Smith Laboratories, University of British Columbia , Vancouver, British Columbia
Crohn’s disease (CD) leads to significant morbidity caused by chronic inflammation and the associated fibrosis and stricturing that frequently develops in the inflamed bowel segments of CD patients. For reasons that are currently unclear, intestinal tissue repair processes in CD patients can progress uncontrollably, leading to fibroblast proliferation, collagen deposition and stricture formation. Satisfactory therapeutic options for intestinal fibrosis are lacking, in part because the mechanisms underlying these processes are poorly understood.
Studies have shown CD and fibrosis develop in genetically susceptible individuals following bacterial stimulation of the mucosal immune system. To better define the mechanisms underlying intestinal fibrosis, we assessed a new mouse model of chronic intestinal infection and fibrosis caused by the enteric bacterial pathogen Salmonella Typhimurium. Recent studies have implicated the innate immune system, including toll-like receptor 4 and the adaptor protein MyD88 in other forms of tissue remodelling in the intestine. We infected MyD88 deficient (KO) mice and C57BL/6 mice with the attenuated deltaaroA strain of S. Typhimurium and although infection caused significant colitis, there was little sign of fibrosis or fibroblast accumulation in the intestines of MyD88 KO mice, whereas tissues from infected C57BL/6 mice showed numerous fibroblasts, and a 5-6 fold increase in collagen levels. To further address whether the host response to bacterial products was responsible for the fibrosis, wildtype mice were infected with a salmonella mutant deficient in both flagellin genes (deltafliC/deltafljB). While no defects in the resulting colitis were detected, tissue collagen levels in deltafliC/deltafljB infected mice were approximately 50% of that caused by wildtype S. Typhimurium.
Our model offers a unique opportunity to address the host and microbial factors involved in the genesis of intestinal fibrosis. Clarifying the role of bacterial products and their receptors in triggering intestinal fibrosis will ultimately enable therapeutic targeting of these pathways as a means to limit intestinal fibrosis and other disease sequel.