Table2_Improved diagnosis of inflammatory bowel disease and prediction and monitoring of response to anti-TNF alpha treatment based on measurement of signal transduction pathway activity.XLSX

Objective: Ulcerative colitis (UC) and Crohn’s disease (CD) are two subtypes of chronic inflammatory bowel disease (IBD). Differential diagnosis remains a challenge. Anti-TNFα treatment is an important treatment for IBD, yet resistance frequently occurs and cannot be predicted. Consequently, many patients receive ineffective therapy with potentially adverse effects. Novel assays are needed to improve diagnosis, and predict and monitor response to anti-TNF-α compounds.
Design: Signal transduction pathway (STP) technology was used to quantify activity of STPs (androgen and estrogen receptor, PI3K, MAPK, TGFβ, Notch, Hedgehog, Wnt, NFκB, JAK-STAT1/2, and JAK-STAT3 pathways) in colon mucosa samples of CD and UC patients, based on transcriptome analysis. Previously described STP assay technology is based on computational inference of STP activity from mRNA levels of target genes of the STP transcription factor.
Results: Results show that NFκB, JAK-STAT3, Wnt, MAPK, and androgen receptor pathways were abnormally active in CD and UC. Colon and ileum-localized CD differed with respect to STP activity, the JAK-STAT1/2 pathway being abnormally active in ileal CD. High activity of NFκB, JAK-STAT3, and TGFβ pathways was associated with resistance to anti-TNFα treatment in UC and colon-located CD, but not in ileal CD. Abnormal STP activity decreased with successful treatment.
Conclusion: We believe that measuring mucosal STP activity provides clinically relevant information to improve differential diagnosis of IBD and prediction of resistance to anti-TNFα treatment in patients with colon-localized IBD, and provides new targets for treatment and overcoming anti-TNFα resistance.

研究目的：溃疡性结肠炎（Ulcerative colitis, UC）与克罗恩病（Crohn’s disease, CD）均为慢性炎症性肠病（chronic inflammatory bowel disease, IBD）的两大亚型，二者的鉴别诊断仍是临床难题。抗TNFα治疗是慢性炎症性肠病的重要治疗手段，但常出现治疗耐药且无法提前预测，导致大量患者接受无效治疗并面临潜在不良反应。因此亟需开发新型检测方法，以优化炎症性肠病的诊断，并实现对抗TNFα类药物治疗响应的预测与监测。
研究设计：本研究基于转录组分析，采用信号转导通路（Signal transduction pathway, STP）检测技术，对克罗恩病与溃疡性结肠炎患者结肠黏膜样本中的信号转导通路活性进行定量分析，涵盖雄激素受体通路、雌激素受体通路、PI3K通路、MAPK通路、TGFβ通路、Notch通路、Hedgehog通路、Wnt通路、NFκB通路、JAK-STAT1/2通路及JAK-STAT3通路。本研究所用的信号转导通路检测技术，此前已被报道可通过计算推断转录因子靶基因的mRNA水平，进而反推信号转导通路的活性。
研究结果：结果显示，NFκB通路、JAK-STAT3通路、Wnt通路、MAPK通路及雄激素受体通路在克罗恩病与溃疡性结肠炎患者中均呈现异常活化。位于结肠与回肠的克罗恩病患者，其信号转导通路活性存在显著差异：回肠克罗恩病患者的JAK-STAT1/2通路呈现异常活化。在溃疡性结肠炎及结肠型克罗恩病患者中，NFκB、JAK-STAT3及TGFβ通路的高活性与抗TNFα治疗耐药相关，但回肠克罗恩病患者未观察到此关联。经有效治疗后，异常活化的信号转导通路活性可出现下降。
研究结论：本研究认为，检测黏膜组织的信号转导通路活性可提供具有临床价值的信息，有助于优化慢性炎症性肠病的鉴别诊断，并实现结肠型炎症性肠病患者对抗TNFα治疗耐药性的预测，同时可为慢性炎症性肠病的治疗靶点开发及抗TNFα治疗耐药的逆转提供新方向。