Determination of the activation phenotype at the molecular level in inflammatory bowel diseases

Objective: Inflammatory bowel diseases(IBD) are chronic inflammatory diseases of the gastrointestinal tract with relapses and remissions. Genetic predisposition, environmental factors, microbiota and immunological factors are thought to be effective in the development of the disease. There are insufficient data on the factors that trigger disease activation in patients in remission. In our study, we aimed to determine the factors that cause activation in IBD and to elucidate the molecular mechanisms of these factors. In addition, it was aimed to identify genes and proteins that may be associated with IBD and the pathways in which these genes are involved, and to identify new diagnostic and therapeutic targets for IBD. Material and Method: A questionnaire was applied to the patients to determine the factors affecting IBD activation, and the questionnaire data were analyzed by SPSS. Logistic regression analysis was performed for significant results. p <0.05 was considered statistically significant. In addition, microarray datasets of patients with IBD and healthy colon tissue samples were downloaded from the GEO (Gene Expression Omnibus) database. The datasets were processed in the RStudio program to identify genes with differentiated expression (DEG). Enriched pathway analyzes of these DEGs were made with the Kyoto Encyclopedia of Genes and Genomes (KEGG). The protein-protein interaction of the detected DEGs was analyzed with the STRING database, and the protein-protein interaction network was visualized with CYTOSCAPE. Results: When the factors that can cause activation in inflammatory bowel disease are evaluated; A statistically significant relationship was found between disease activation and female gender (p=0.015), winter season (p=0.022), alcohol consumption (p=0.002), frequency of antibiotic use (p=0.017), physical activity (p=0.013), stress (p=0.015), seasonal change (p=0.007), sleep quality (p=0.001), pickle-vinegar consumption (p=0.016), and fiber-rich food consumption (p=0.035). Not doing physical activity (p=0.005) (OR:5.43, 95% confidence interval, 1.6-18.43), poor sleep quality (p=0.005) (OR:3.49, 95% confidence interval 1.44 -8.44), NSAID use (p=0.05) (OR:2.89 95% confidence interval 1-8.39), seasonal change effect (p=0.008) (OR:5.11 95% confidence interval 1.5-17) were identified as independent variables related to disease activation. By performing gene expression analysis in IBD, the ten DEGs with the highest expression increase; LCN2, MMP1, MMP3, CHI3L1, DEFA6, DUOX2, SLC6A14, REG1B, DEFA5, REG1A were detected. When the enrichment analysis of DEGs with KEGG pathways was performed, it was observed that the most association with IBD was in the IL-17 signaling pathway, rheumatoid arthritis pathway and TNF signaling pathway. Conclusion: Physical activity, seasonal change, NSAID use, and poor sleep quality were found to be significant as independent variables for the activation of IBD. The molecular mechanisms of these factors were examined, and the TPH1 gene in the serotonergic synapse pathway, which is thought to be associated with sleep, showed decreased expression in IBD. The arachidonic acid metabolism pathway, which is thought to be related to NSAID use, was investigated. A decrease in the expression of the EPHX2 gene, one of the genes involved in this pathway, and an increase in the expression of the PTDGS and PLA2G2A genes were observed. The molecular mechanisms of the effects of other factors on IBD activation have not been determined. Ten genes whose expression is differentiated in IBD have been identified. Further studies and molecular analyzes of these genes will contribute to the identification of genes and proteins that can be used as biomarkers in the diagnosis of IBD and to the determination of new therapeutic targets. Keywords: Inflammatory bowel disease (IBD), ulcerative colitis (UC), Crohn's disease (CD), disease activation