Conserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification
Conserved transcriptomic profile between mouse and human colitis allows unsupervised patient stratification
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DOI：
10.1038/s41467-019-10769-x
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发表时间：
2019-06-28
影响因子：
16.6
通讯作者：
Villablanca, Eduardo J.
中科院分区：
文献类型：
--
作者：
Czarnewski, Paulo;Parigi, Sara M.;Villablanca, Eduardo J.
溃疡性结肠炎（UC）的临床表现和对治疗的反应是异质性的，但目前缺乏定制治疗的患者分类标准。在这里，我们提出了一个UC患者的无监督分子分类，与独立回顾性队列的治疗反应一致。我们表明，UC患者组织转录组数据集的经典聚类无法识别临床相关特征，这可能是由于相关协变量。为了克服这一点，我们比较横截面人类数据集与新生成的纵向转录组分布的小鼠DSS诱导的结肠炎。我们发现，大多数结肠炎风险相关基因的表达在炎症期达到峰值，而不是在恢复期。此外，我们实现了UC患者聚类成两个不同的转录组学谱，不同的嗜酸性粒细胞相关的基因激活。值得注意的是，UC 1群中87%的患者对两种最广泛使用的生物疗法无反应。这些结果表明，跨物种比较能够对其他分子方法无法区分的患者进行分层。
Clinical manifestations and response to therapies in ulcerative colitis (UC) are heterogeneous, yet patient classification criteria for tailored therapies are currently lacking. Here, we present an unsupervised molecular classification of UC patients, concordant with response to therapy in independent retrospective cohorts. We show that classical clustering of UC patient tissue transcriptomic data sets does not identify clinically relevant profiles, likely due to associated covariates. To overcome this, we compare cross-sectional human data sets with a newly generated longitudinal transcriptome profile of murine DSS-induced colitis. We show that the majority of colitis risk-associated gene expression peaks during the inflammatory rather than the recovery phase. Moreover, we achieve UC patient clustering into two distinct transcriptomic profiles, differing in neutrophil-related gene activation. Notably, 87% of patients in UC1 cluster are unresponsive to two most widely used biological therapies. These results demonstrate that cross-species comparison enables stratification of patients undistinguishable by other molecular approaches.