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P044. MicroRNA expression in ileal inflammatory bowel disease correlates with disease behavior

S. Ben-Shachar1, H. Yanai2, H. Elad2, L. Baram2, H. Sherman Horev2, A. Ofer2, E. Brazowski3, H. Tulchinsky4, M. Pasmanik-Chor5, N. Shomron6, I. Dotan2, 1Tel Aviv Medical Center affiliated to Sackler Faculty of Medicine, Tel Aviv university, Genetic institute, Tel Aviv, Israel, 2Tel Aviv Medical Center, affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Department of Gastroenterology and Liver Diseases, Tel Aviv, Israel, 3Tel Aviv Sourasky Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Department of Pathology, Tel Aviv, Israel, 4Tel Aviv Medical Center, affiliated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Proctology Unit, Department of Surgery, Tel Aviv, Israel, 5Tel Aviv University, Tel Aviv, Israel, Bioinformatics unit, G.S.W. Faculty of Life Sciences, Tel Aviv, Israel, 6Tel Aviv University, Sackler Faculty of Medicine, Tel Aviv, Israel

Background

The etiology of inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC) is yet unknown. Inflammation in UC is limited to the large bowel mucosa, thus large bowel resection was expected to be curative. Nonetheless, about 50% of patients undergoing total proctocolectomy with the creation of an ileal pouch (pouch surgery) develop small intestinal inflammation (pouchitis). We have previously shown that gene expression profiles are associated with ileal inflammation and disease behavior in IBD. One mechanism of regulating gene and protein expression is by MicroRNAs (miRNAs). Altered expression of a limited number of miRNAs was previously noted in IBD. We aimed to evaluate global miRNAs expression in ileal IBD, and its correlation with inflammation, and possible mode of action.

Methods

Patients with CD ileitis, UC patients (unoperated and after pouch surgery) and normal controls (NC) were recruited. Pouch patients were stratified according to disease behavior into 3 groups: normal pouch (NP), chronic pouchitis (CP), and Crohn's-like disease of the pouch (CLDP). miRNAs expression in Ileal and pouch biopsies was analyzed by parallel massive sequencing (next generation sequencing). Bioinformatics tools were applied for clustering and detection of potential targets.

Results

Fifty-Six subjects (10 CD, 12 NP, 12 CP, 4 CLDP and 11 unoperated UC, as well as 7 NC) were recruited. The ileum of unoperated UC patients was comparable to NC. Significant miRNAs alterations (fold change >2, corrected p-value <0.05) were noticed in NP (n = 8), CP (n = 25), and CLDP (n = 124) patients compared to NC. However, only 2 alterations were noticed in CD. Highly overlap of alterations in pouch patients was noticed. The magnitude of alteration change correlated with disease behavior. More than 95% of the altered miRNAs showed increased expression. The magnitude of maximal increase was 47 folds-more pronounced compared with the magnitude of maximal decrease which was only 4 folds. miR-449b, miR-549, and miR-412 had the greatest increase in expression: 47, 44 and 19 fold change in CLDP, respectively. Interestingly, most miRNAs with increased expression were predicted to target mRNA transcripts that were significantly decreased in pouchitis. miRNAs alterations and phenotype clustered in the pouch groups, while no such clustering was noticed among CD patients.

Conclusion

Increased expression of multiple miRNAs occurs in pouchitis and correlates with disease behavior. Thus, miRNAs may have a role in down regulation of mRNA transcripts in IBD. The absence of clustering of miRNAs expression in CD ileitis may reflect the heterogeneity of CD and explain the limited previous findings regarding miRNAs expression alteration in CD.