BACKGROUND: Alterations in intestinal permeability have been implicated in ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, can induce clinical response in UC. Gene expression in colonic biopsies taken from responders and nonresponders to infliximab can provide insight into the mechanisms of the altered intestinal permeability at a molecular level. METHODS: Colonic biopsies (n = 18 anti-TNFα naïve UC patients; n = 8 normal controls; n = 80 Active Ulcerative Colitis Trial [ACT] 1 patients) were analyzed for mRNA expression using gene expression microarrays. Computational reverse causal reasoning was applied to build causal network models of UC and response and nonresponse of UC to treatment. Quantitative reverse-transcription polymerase chain reaction (qPCR) was used to confirm differentially expressed genes. RESULTS: Reverse causal reasoning on mRNA expression data from anti-TNFα-naïve UC and normal samples provided a mechanistic disease model of the biology of gene expression observed in UC. mRNA expression data from the ACT 1 study enabled construction of a mechanistic model describing the biology of nonresponders to infliximab, including evidence for increased intestinal permeability compared with normal and responder samples. Gene expression changes identified as central to intestinal permeability dysregulation were confirmed in normal, UC, and infliximab-treated patients by qPCR analysis. Gene expression returned toward normal levels in infliximab responders, but not in nonresponders. CONCLUSION: Gene expression analysis and causal network modeling in combination showed that aberrant mRNA expression of genes involved in intestinal epithelial permeability for infliximab responders was restored toward levels observed in normal samples. Infliximab nonresponders showed no equivalent restoration in the expression of these genes. (Inflamm Bowel Dis 2012;).