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P820 Molecular changes in non-inflamed terminal ileum in patients with ulcerative colitis

H-S. Lee*1,2, M. Vancamelbeke3, S. Verstockt1, B. Verstockt3,4, G. Van Assche3,4, M. Ferrante3,4, S. Vermeire3,4, I. Cleynen1

1KU Leuven, Department of Human Genetics, Laboratory of Complex Genetics, Leuven, Belgium, 2University of Ulsan College of Medicine, Department of Biochemistry and Molecular Biology, Seoul, South Korea, 3KU Leuven, Department Chronic Diseases, Metabolism & Ageing (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium, 4University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium

Background

Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine, typically confined to the mucosal layer of the colon. Small intestinal dysfunction has, however, been described in patients with UC, although the underlying mechanisms of these alterations in apparently intact ileum are currently unknown. We here evaluated molecular changes and biological networks in non-inflamed terminal ileum in UC, and their association with colonic inflammation.

Methods

Terminal ileum biopsies were obtained during endoscopy from 36 patients with UC (7 active (Mayo endoscopic subscore ≥2) and 29 inactive) and 16 healthy controls. Subjects with endoscopic or histological (backwash) ileitis were not included. Single-end RNA sequencing was performed using Illumina HiSeq4000. Gene expression differences were analysed using DESeq2, and corrected for age and gender. Weighted gene co-expression network analysis (WGCNA) was performed to find biological networks of genes that correlate with UC activity. Pathways and upstream regulators were identified using IPA.

Results

When we compared ileal expression levels of active UC (71% male, median age 52 years) with controls (44% male, median age 57 years), we found 20 differentially expressed (adj. p ≤ 0.05 and fold change (FC)≥2) genes, with DUOXA2 being the most significant (FC=4.9, adj. p = 0.009). The 20 genes were involved in free radical scavenging, molecular transport, cell-to-cell signalling, and cellular proliferation. Cytokines IL1A, IFNG, and TNF were predicted as upstream regulators. Comparison of inactive UC (59% male, median age 52 years) with controls only found 2 dysregulated genes (CEBPD and REG1B). REG1B was also one of the 20 dysregulated genes in active UC (active UC: FC=4.1, adj. p = 0.02; inactive UC: FC=2.7, adj. p = 0.04). WGCNA analysis found 38 co-expression modules, 3 of which were positively correlated (adj. p ≤ 0.2) with active UC, and with the enclosed genes mainly involved in immune functions (e.g. interferon and cytokine signalling, and antigen presentation). One module was positively correlated with inactive UC (enriched for genes involved in mitochondrial translation), and one was negatively correlated (enriched in signal regulatory protein (SIRP) family interactions and NF-kB activation genes).

Conclusion

Our transcriptome analysis identified significant alterations in non-inflamed ileum of UC patients, depending on colonic inflammation. Ileal changes in active UC are mainly related to immune function, but the causal and temporal relationship with colonic inflammation is unclear. Ileal changes in inactive UC on the other hand seem to be functioning to maintain the intestinal barrier with increased mitochondrial functions and dampened immune functions.