Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA.
Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, 5265601, Israel.
Nat Commun. 2019 Jan 3;10(1):38. doi: 10.1038/s41467-018-07841-3.
Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-αβ integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.
溃疡性结肠炎（UC）的疾病进程和治疗反应的分子机制尚不清楚。在这里，我们使用 RNAseq 技术在 206 名接受标准化治疗的儿科 UC 患者的直肠组织中定义了治疗前的基因表达和粪便微生物组谱。我们在 408 名成人和儿科 UC 患者的队列中验证了我们的主要发现。我们观察到在活动期 UC 中，线粒体基因和功能受到明显抑制，并且疾病严重程度的增加与腺瘤/腺癌和固有免疫基因的富集有关。严重程度基因的一个亚组可改善发现队列中皮质类固醇诱导缓解的预测；该基因特征也与成人中抗 TNFα 和抗 αβ 整合素的反应相关。严重程度和治疗反应基因特征与先前涉及黏膜稳态的微生物的变化有关。我们的数据提供了对 UC 发病机制的深入了解，并可能为目前治疗方法无反应的患者确定未来的治疗方法。
