Molecular Patterns in Human Ulcerative Colitis and Correlation with Response to Infliximab

Background:As a T cell-mediated disease of the colonic epithelium, ulcerative colitis (UC) is likely to share pathogenic elements with other T cell-mediated inflammatory diseases. Recently, microarray analysis revealed large-scale molecular changes in T cell-mediated rejection of kidney and heart transplants. We hypothesized that similar disturbances might be operating in UC and could provide insights into responsiveness to therapy.Methods:We studied 56 colon biopsies from patients with colitis characterizing the clinical and histological features and using microarrays to define the messenger RNA phenotype. We expressed the microarray results using previously defined pathogenesis-based transcript sets. We also studied 48 published microarray files from human colon biopsies downloaded from the Gene Expression Omnibus database, classified by response to infliximab therapy, to examine whether the molecular measurements derived from our studies correlated with nonresponsiveness to treatment.Results:UC biopsies manifested coordinate transcript changes resembling rejecting transplants, with effector T cell, IFNG-induced, macrophage, and injury transcripts increasing while parenchymal transcripts decreased. The disturbance in gene expression, summarized as principal component 1 (PC1), correlated with conventional clinical and histologic assessments. When assessed in microarray results from published studies, the disturbance (PC1) predicted response to infliximab: patients with intense disturbance did not achieve clinical response, although quantitative improvement was seen even in many clinical nonresponders. Similar changes were seen in Crohn's colitis.Conclusions:The molecular phenotype of UC manifests a large-scale coordinate disturbance reflecting changes in inflammatory cells and parenchymal elements that correlates with conventional features and predicts response to infliximab.