W1228 Genes Associated With Reduced Epithelial Permeability and Epithelial-Mesenchymal Transition: Changes in Expression Following Infliximab Therapy in Ulcerative Colitis

Abstract

Background:Changes in intestinal permeability have been implicated in the pathology of ulcerative colitis (UC). Objectives: To investigate mechanismsmodulating intestinal permeability and epithelial-mesenchymal transition (EMT) following infliximab (IFX)treatment, we analyzed mRNA expression in colonic biopsies obtained from UC patients(pts), normal healthy subjects, and UC pts enrolled in the ACT1 study. ACT1 evaluated safety and efficacy of IFX in pts with UC. Methods: Colonic biopsies (n=17 UC anti-TNFα naive; n=8 nonIBD normal; n=113 from ACT1) were analyzed for mRNA expression using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays followed by quantitative polymerase chain reaction (qPCR) confirmation of the differentially expressed genes. Causal network modeling was utilized to generate models describing the biological signaling pathways that drive changes observed in the mRNA expression data. Results: mRNA expression results from anti-TNFα naive UC and normal samples analyzed using network modeling determined that genes known to affect intestinal permeability were deregulated in UC pts. Analysis of the ACT1 sample expression data demonstrated that treatment with IFX restored gene expression toward, but not completely to, normal in IFX-responder pts. Pts in ACT1 who were non-responders or placebo treated (including those diagnosed as clinical responders) did not restore these functions. qPCR analysis of the identified genes (Table) confirmed the changes in gene expression observed in IFX treated pts from the ACT1 study. Conclusion: Using the combination of expression analysis and network modeling, we found that responders to IFX restore mRNA expression levels in genes involved in intestinal epithelial permeability and fibrotic processes leading to EMT to levels comparable with those seen in normal subjects. IFX non-responders and placebo treated pts have no equivalent restoration in gene expression involved in these functions.