Abstract
Abstract Background The aim of the study is to dissect the mechanisms associated with the evolution of Inflammatory Bowel Disease (IBD), including Crohn’s Disease (CD) and Ulcerative Colitis (UC) in both pediatric and adult patients, along with the severity of the disease and the risk to develop malignancy. Methods A multiomics approach, including miRNA (N=700), gene expression (N=800 genes) (nCounter platform; Nanostring) and methylation (Infinium Methylation Epic Bead Chip kit, Illumina), was utilized to characterize the gut tissue biopsies from pediatric (N=20) and adult (N=18) IBD patients. Moreover, a cohort of patients with gut malignancies with history of IBD were also enrolled in the study. Additionally, the role of Natural Killer Group 2D ligands (NKG2DLs) along with different stages of IBD (remission, mild, moderate and severe) were investigated. Results Differential miRNA and gene signatures were found by the comparison of tissues from pediatric and adult patients with different stages of the disease. N=83 miRs were significantly differentially detected between pediatric and adult patients (P<0.05). miR-630, miR-493-3p and miR-370-3p were found over-expressed in adult vs. pediatric gut tissues. These miRs are involved in epithelial-to-mesenchymal transition (EMT) through the WNT/β-catenin pathway. These miRNAs can also regulate cell proliferation, cell adhesion and migration and cancer development. Interestingly, miR-20a and miR-34a, which are known modulators of NKG2DLs expression were upregulated in tissues from severe vs. mild disease. The gene expression analysis highlighted, among multiple differentially detected pathways in tissues with different grades of IBD, genes, such as SMAD4, EGR1, CHUCK and JAG1, associated with inflammation, stemness, immune regulation, cell proliferation and migration. Through qPCR analyses, the higher expression of the NKG2DLs MICB was detected in tissues from left or right sides, respectively for both pediatric and adult patients while similar observation occurred for MICA only in adult patients. Soluble NKG2DLs were also detected in the plasma of IBD patients, with in some cases differences (P<0.05) in patients vs. healthy donors. sULBP3 correlated with the presence of active inflammation in adult IBD tissues. Confocal imaging of IBD tissues showed upregulation of stemness-associated markers (e.g., LGR5) and NKG2DLs (ULBP-1 and ULBP-3) in adult vs. pediatric patients. Conclusion The ongoing integration of data from multi-omics and the expression of immune-related molecules can lead to the identification of candidate molecular mechanisms associated with the evolution of IBD.
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