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P057. Influence of colitis on ileal epithelial barrier and its environment in a new mouse model of ulcerative colitis

S. Sedghi1, X. Tréton2, Z. Alnabhani3, F. Barreau4, D. Cazals-Hatem5, E. Pédruzzi1, P. Lepage3, E. Ogier-Denis1, F. Daniel1, 1INSERM, U773, Paris, France, 2Beaujon Hospital, Department of Gastroenterology, Clichy la Garenne, France, 3INRA, UMR 1319 Micalis, Jouy-en-Josas, France, 4INSERM, UMR 843, Paris, France, 5Beaujon Hospital, Anatomo-pathologic Department, Clichy la Garenne, France

Background

Unlike Crohn's disease (CD), ulcerative colitis (UC) is characterized by exclusive rectal and colonic inflammation, except in rare cases of backwash ileitis. There are few investigations on the reactivity of ileum against colitis in UC. Some studies have shown changes in the ileum of rats with chemically-induced colitis, or modified Peyer's patches in patients with UC. Our study aims at investigating the effect of colitis on ileal morphology and function in a new mouse model of UC, and in patients with UC.

Methods

We generated a new mouse model named EXCY2, which spontaneously develops colitis with features mimicking the human UC phenotype, i.e. anatomical, histological and immunological characteristics. EXCY2 mice are double knockout (dKO) for interleukin 10 (IL-10) gene and NADPH oxidase 1 (NOX1) gene, a key driver in goblet cells regulation (IL10/Nox1dKO mice). Thus they combined immune abnormalities and epithelial disorders. Clinical signs of colitis occur at 6 weeks of age, and worsen with age. Ileal tissue sections of patients undergoing colectomy and healthy controls are provided by the anatomo-pathologic department of Beaujon hospital. To investigate the effect of colitis on ileal epithelium self-renewal, proliferation was measured by quantification of Ki67 or BrdU-labeled nuclei, and by western blot approaches. The impact of colitis on the integrity of ileal barrier was evaluated in Ussing chamber. Finally the composition of adherent ileal microbiota was determined by pyrosequencing (454-FLX-Titanium).

Results

No inflammation was present in the ileum of EXCY2 mice or UC patients after histological analysis and measurement of cytokine expression. Despite the absence of ileitis, significant increased cryptic proliferation rate occurred in the ileum of 6- and 17-week-old EXCY mice vs. WT mice, associated with an activation of the Wnt/β-catenin and MAPKinase pathways. Interestingly, excess of crypt proliferation was also found in the ileum of UC patients compared to healthy controls. Moreover, disruption of the intestinal barrier was observed in young EXCY2 mice with increased paracellular permeability and bacterial translocation in Peyer's patches and ileal mucosa. Furthermore, a quantitative and qualitative dysbiosis was detected in the ileum of young EXCY2 mice vs. WT mice.

Conclusion

We report here that colonic inflammation has a remote effect on the ileal epithelial barrier and its environment. Despite dysbiosis and increased permeability, ileal epithelial homeostasis is not compromised. These data contribute to a greater understanding of ileal resistance to inflammation in UC, and may help determine the pathogenesis of ileal involvement in CD.