682 Investigating the Pathogenesis of Ulcerative Colitis Through Meta-Analysis of Gene Expression Omnibus Data

Abstract

INTRODUCTION: Ulcerative colitis (UC) is an inflammatory bowel disease that causes inflammation of the colon and rectum, alongside extra-colonic manifestations. The etiology is unclear but is thought to include such factors as genetic predisposition, immune regulation, microbiome, and environmental triggers. Though strides have been made in treatment, the failure of anti-IL13 drugs demonstrates our limited knowledge of UC pathology. Here we use meta-analysis to dissect UC pathogenesis. METHODS: We employed our STARGEO platform to search Gene Expression Omnibus and performed meta-analysis on 465 colon samples from active UC patients, using 326 healthy colon samples as a control. We then analyzed the signature in Ingenuity Pathway Analysis. RESULTS: Our analysis identified granulocyte adhesion and diapedesis, TREM1 signaling, and communication between innate and adaptive immune cells as top canonical pathways. TNF, IFNγ, and IL1 were top upstream regulators with predicted activation. We noted upregulation of the DUOX/DUOXA2 enzyme system, responsible for generating reactive oxygen species. We also found upregulation of calprotectin S100A8, which defines UC severity, and downregulation of the E3 ubiquitin ligase RNF5 responsible for controlling S100A8 expression. Impaired epithelial integrity was suggested by upregulation of matrix metalloproteinases MMP1 and MMP3 and down regulation of claudin 8. Furthermore, downregulation of aquaporin 8 and guanylin suggests loss of absorption. Upregulation of the amino acid transporter SLC6A14 and aldolase B may represent a compensation for loss of absorptive function. We also found metabolic dysfunction through downregulation of phosphoenolpyruvate carboxykinase 1, and UDP-glucuronosyltransferases UGT1A7/A5/A3. Lastly, we found downregulation of several miRNAs including mir-188, 192, 200a/b, 215, and 320. CONCLUSION: UC pathogenesis represents a multifactorial disease process that remains elusive. Here we suggest several mechanisms that may underpin UC development and susceptibility. In a recent study, inverse expression of RNF5 and S100A8 was found to coincide with UC severity and our results give credence to this correlation. Our results also demonstrate the parts that DUOX/DUOXA2 system and loss of epithelial and metabolic integrity have in UC. Lastly, miRNAs have an emerging role in UC and mimic therapy of the downregulated miRNAs we identified may prove efficacious. These results provide novel insights into UC pathophysiology and potential therapeutic avenues.