Biomarkers, Centocor Research & Development, Malvern, Pennsylvania, USA.
Inflamm Bowel Dis. 2012 Aug;18(8):1399-410. doi: 10.1002/ibd.22853. Epub 2012 Jan 4.
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.
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.
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.
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.
肠通透性的改变与溃疡性结肠炎（UC）有关。英夫利昔单抗是一种抗肿瘤坏死因子-α（TNFα）的单克隆抗体，可诱导 UC 患者的临床反应。对英夫利昔单抗应答者和无应答者的结肠活检组织中的基因表达，可以深入了解分子水平上改变的肠通透性的机制。
使用基因表达微阵列分析了 18 例抗 TNFα 初治 UC 患者、8 例正常对照和 80 例 ACT1 患者的结肠活检组织中的 mRNA 表达。应用计算反因果推理构建 UC 及其对治疗反应和无反应的因果网络模型。采用定量逆转录聚合酶链反应（qPCR）验证差异表达基因。
对来自抗 TNFα 初治 UC 和正常样本的 mRNA 表达数据进行反因果推理，提供了 UC 基因表达生物学的机制疾病模型。ACT1 研究中的 mRNA 表达数据可构建一个描述英夫利昔单抗无应答者生物学的机制模型，包括与正常和应答者样本相比，肠道通透性增加的证据。通过 qPCR 分析，在正常、UC 和英夫利昔单抗治疗患者中，鉴定出与肠通透性失调密切相关的基因表达变化。在英夫利昔单抗应答者中，这些基因的表达恢复到正常水平，但在无应答者中则不然。
基因表达分析和因果网络建模相结合表明，参与英夫利昔单抗应答者肠上皮通透性的基因异常 mRNA 表达恢复到正常样本中观察到的水平。英夫利昔单抗无应答者的这些基因表达没有恢复到相应水平。
