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P683. Gene expression profiles of ileal inflammatory bowel disease provide insights on disease immunopathology

S. Ben-Shachar1, H. Yanai2, L. Baram2, H. Elad2, E. Mehirovihtz2, A. Ofer2, H. Tulchinsky3, M. Psamnik-Shor4, I. Dotan2, 1Tel Aviv Medical Center, Genetic Institute, Tel Aviv, Israel, 2Tel Aviv Medical Center, 2. IBD center, Department of Gastroenterology and Liver Diseases, Tel Aviv, Israel, 3Tel Aviv Medical Center, 3. Department of Surgery, Tel Aviv, Israel, 4Tel Aviv University, 3. Bioinformatics unit, G.S.W. Faculty of Life Sciences, Tel Aviv, Israel

Background

The etiology of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) is yet unknown. About a quarter of UC patients may undergo total proctocolectomy and the creation of an ileal pouch due to intractable or complicated disease. Inflammation of the pouch (pouchitis) may develop de novo in approximately half of those UC pouch patients, but not in familial adenomatous polyposis (FAP) patients suggesting different genetic and environmental factors. We hypothesized that pouch inflammation may serve as a model for IBD.

Methods

Biopsies were taken from the ileal pouch of UC or FAP patients and from the ileum of UC and CD patients and normal controls. Pouch disease behavior was defined as normal, acute/recurrent acute, chronic, or Crohn's-like disease of the pouch (CLDP) based on clinical, endoscopic and histologic criteria. RNA was extracted for array-based expression analyses, and validated by RT-PCR. Alterations of ≥2 fold-change with corrected P values <0.05 (FDR) were considered significant.

Results

Sixty-six participants were prospectively recruited. While the ileal mucosa of unoperated UC patients did not show any significant alterations in gene expression and FAP and UC patients with a normal pouch had 54 and 168 significant alterations respectively, those with chronic pouchitis and CLDP had more than ∼500, and 1000 alterations, respectively. In CD patients 358 alterations were noted and more than 90% of them were shared with the different pouchitis groups. The magnitude of mucosal gene alterations correlated with pouch disease behavior. Moreover, a higher magnitude of alterations was noticed in patients with pouchitis compared to CD. Functional and pathway analyses of the gene alterations revealed multiple biological processes associated with ileal inflammation, including the immune system, defense responses and metabolic processes, as well as various infections including Staphylococcus aureus, and mycobacterium.

Conclusion

Ileal inflammation in IBD may be triggered by an external trigger causing a spectrum of molecular phenotypes characterized by an increasing number and magnitude of alterations from none in normal controls and UC patients to ∼1000 in CLDP patients. The ileal pouch may be a model of human early IBD, providing a better understanding of IBD immunopathogenesis, and a platform to evaluate therapeutic approaches for early IBD.