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CHRONIC ADHERENT INVASIVE ESCHERICHIA COLI INFECTION IN MICE LEADS TO PERSISTENT COLONIZATION AND FIBROSIS
C Small, B CoombesMcMaster University, Hamilton, ON
Aims: Crohn's disease (CD) is a chronic inflammatory bowel disease (IBD), which primarily affects the ileum and colon. CD is characterized by chronic inflammation and severe intestinal pathology, which can extend throughout the intestinal wall causing symptoms of diarrhea, abdominal pain and nausea. Several genetic and environmental factors are implicated in CD pathogenesis, including the composition of the enteric microbiota. Of particular interest is a pathotype of E. coli known as adherent-invasive E. coli (AIEC) that is frequently isolated from the ileal mucosa of CD patients. However, the potential role of AIEC in the initiation or progression of CD is unclear. To address this, we have developed a mouse model of chronic AIEC-induced colitis that leads to intestinal fibrosis and immunopathology.
Methods: Various mouse strains were pre-treated with streptomycin prior to infection with the human clinical AIEC isolate NRG857c. At several times after colonization, colonic and cecal tissues were assessed for maintenance of AIEC colonization, tissue pathology, inflammation and fibrosis.
Results: AIEC infection in mice led to chronic and persistent colonization and reduction in size of the cecum, which was not indicative of body weight loss. The duration and severity of tissue colonization differed among mouse strains. Chronic AIEC infection in mice was associated with severe crypt hyperplasia, massive epithelial sloughing, cellular infiltration, desquamation as well as transmural inflammation. Extensive submucosal edema was primarily evident in the cecum, while mucosal ulceration was only observed in the colon of mice by day 7 and was still present by day 63. Heavy and extensive extracellular matrix deposition indicative of fibrosis was detected by day 7 in the mucosa and extending throughout the submucosa and muscularis mucosa. Moreover, increased number of fibrils in submucosal and muscularis mucosal collagen could be observed in the cecum of all mouse strains except C57BL/6 mice.
Conclusions: Our new animal model of AIEC-induced colitis and intestinal fibrosis will facilitate understanding of the role of AIEC in chronic gut inflammation and help to uncover the bacterial and host genetic determinants underlying the observed pathology.