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P680. The Notch signaling pathway could be involved in the early post-surgical recurrence of Crohn's disease

Y. Zabana1, E. Pedrosa2, J. Mañé3, E. Domènech4, V. Lorén3, M. Mañosa4, M. Piñol5, J. Troya5, J. Boix6, J. Lozano7, E. Cabré4, 1Hospital-Institut Germans Trias i Pujol, Centro de Investigación Biomédica en Red sobre enfermedades hepáticas y digestivas (CIBERehd), Gastroenterology Department and Experimental Digestive Pathology Unit, Badalona, Spain, 2Germans Trias i Pujol Institute, Centro de Investigación Biomédica en Red sobre enfermedades hepáticas y digestivas (CIBERehd), Functional Genetics Unit, Badalona, Spain, 3Germans Trias i Pujol Institute, Centro de Investigación Biomédica en Red sobre enfermedades hepáticas y digestivas (CIBERehd), Experimental Digestive Pathology Unit, Badalona, Spain, 4Hospital Universitari Germans Trias i Pujol, Centro de Investigación Biomédica en Red sobre enfermedades hepáticas y digestivas (CIBERehd), Gastroenterology Department, Badalona, Spain, 5Hospital Universitari Germans Trias i Pujol, General Surgery Department, Badalona, Spain, 6Hospital Universitari Germans Trias i Pujol, Endoscopy Department, Badalona, Spain, 7CIBERehd, Bioinformatic Platform, Barcelona, Spain

Background

Our group previously reported singular molecular phenotypes in the inflamed areas of ileo-cecal resection specimens of patients with Crohn's disease (CD) [Zabana Y, et al. JCC-sup 2012; 6 (1):S186]. However, their accuracy in predicting further post-surgical recurrence (PSR) was limited, possibly due to the predominance of inflammatory features in the studied samples.

Aims: To describe the functional genetic characteristics of non-inflamed intestinal areas of surgical resection specimens from CD patients and their relationship with the development of early PSR.

Methods

Macroscopically non-inflamed and inflamed samples were harvested from the surgical specimens of 15 CD patients undergoing ileo-cecal resection. Follow-up colonoscopies were performed at six, twelve, and eighteen months after surgery. Patients were grouped according to the development (n = 5) or not (n = 10) of endoscopic recurrence within this period. Human whole genome microarray (Codelink) was performed. Transcriptomic profile of surgical samples was compared between recurrent versus non-recurrent patients. LIMA-R package was carried out for normalisation and comparisons. Changes in gene expression were considered significant when they occurred with a Fold Change (FC) of +/-1.5 and p < 0.005. Clustering of genes according to phenotype was done using Qlucore software, and biologic function prediction and genetic update were obtained using GeneCodis, gene set enrichment analysis (GSEA) and informatics database consultation (PubMed).

Results

Macroscopically healthy intestinal tissue of patients with early PSR showed 16 up-regulated (DNAH3, GOLGA1, etc.) and 6 down-regulated genes (MAML2, CABYR, etc.) as compared to patients without PSR. These differently expressed genes are related to ciliar motility, extracellular matrix activity and, particularly, to the Notch pathway. This biological activity was also found in the profile obtained from inflamed ileal tissue (like SAMD4 and NFIC), but was not outstanding probably because the high inflammatory background.

Conclusion

Transcriptomic exploration of macroscopically healthy ileal tissue identified the ciliar motility/Notch pathway axis as a mechanism possibly related to early PSR in CD. Alterations of this biological activity have been recently shown in the development of spontaneous colitis of murine models [Obata, et al, J Immunol, 2012].