Translational Research Center for GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing, Leuven, Belgium.
University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium.
Inflamm Bowel Dis. 2021 Oct 18;27(10):1564-1575. doi: 10.1093/ibd/izab032.
Oncostatin M (OSM) has been implicated in the pathogenesis of inflammatory bowel disease (IBD) and as a marker for nonresponsiveness to anti-tumor necrosis factor (TNF) therapy. We further unraveled the potential of OSM and related receptors as markers of diagnosis, prognosis, and therapy response in IBD.
We collected inflamed mucosal biopsies and serum from patients with Crohn disease (CD) and with ulcerative colitis: (1) newly diagnosed patients who were treatment-naïve, (2) patients initiating anti-TNF or (3) vedolizumab therapy, (4) postoperative patients with CD, and (5) multiple-affected families with IBD including unaffected first-degree relatives (FDRs). We measured the gene expression of mucosal OSM and its receptors OSMR/LIFR and co-receptor IL6ST, and the protein expression of serum OSM. Statistical significance was defined as P < 0.05.
Newly diagnosed patients showed significantly increased mucosal OSM/OSMR compared with control patients, with the highest enrichment for OSM (fold change [FC] >17.9). Likewise, ileal OSM/OSMR were significantly upregulated in postoperative recurrent CD. Serum OSM was increased in newly diagnosed patients and postoperative patients with recurrent CD (FC ≥ 2.6). In families with IBD, higher serum levels were observed in FDRs than in control families (FC = 2.2). Furthermore, elevated colonic OSM/OSMR (but not serum OSM) were associated with the early need for biologic therapy (FC ≥ 1.9), and higher OSM was also predictive of primary nonresponse to both anti-TNF and vedolizumab therapy (FC ≥ 2.4). Immunohistochemistry highlighted mucosal OSM expression in macrophages.
We found that OSM is a diagnostic biomarker in the tissue and serum not only of newly diagnosed patients with IBD and postoperative patients with recurrent CD but also of their FDRs. Higher colonic OSM levels are furthermore associated with poor prognosis and with primary nonresponse to biologic therapies. Therefore, OSM could guide clinical decision-making.
肿瘤坏死因子（OSM）在炎症性肠病（IBD）的发病机制中起作用，并作为抗肿瘤坏死因子（TNF）治疗无反应的标志物。我们进一步揭示了 OSM 及其相关受体作为 IBD 诊断、预后和治疗反应标志物的潜力。
我们收集了克罗恩病（CD）和溃疡性结肠炎患者的炎症性粘膜活检和血清：（1）初诊且未接受治疗的患者，（2）开始接受抗 TNF 或（3）vedolizumab 治疗的患者，（4）术后 CD 患者，以及（5）包括无病一级亲属（FDR）在内的 IBD 多发病家系。我们测量了粘膜 OSM 及其受体 OSMR/LIFR 和共受体 IL6ST 的基因表达，以及血清 OSM 的蛋白表达。统计学意义定义为 P < 0.05。
与对照组相比，新诊断的患者显示出明显增加的粘膜 OSM/OSMR，其中 OSM 的富集程度最高（倍数变化 [FC] >17.9）。同样，术后复发性 CD 的回肠 OSM/OSMR 也显著上调。新诊断患者和术后复发性 CD 患者的血清 OSM 升高（FC ≥ 2.6）。在 IBD 家系中，FDR 的血清水平高于对照组家系（FC = 2.2）。此外，升高的结肠 OSM/OSMR（而非血清 OSM）与早期需要生物治疗相关（FC ≥ 1.9），并且较高的 OSM 还预测对抗 TNF 和 vedolizumab 治疗的原发性无反应（FC ≥ 2.4）。免疫组织化学强调了巨噬细胞中粘膜 OSM 的表达。
我们发现 OSM 不仅是新诊断的 IBD 患者和术后复发性 CD 患者的组织和血清中的诊断生物标志物，也是其 FDR 的诊断生物标志物。较高的结肠 OSM 水平与不良预后以及对生物治疗的原发性无反应相关。因此，OSM 可以指导临床决策。
