Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
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DOI：
10.1038/s41467-018-07841-3
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发表时间：
2019-01-03
影响因子：
16.6
通讯作者：
Denson, Lee A.
中科院分区：
文献类型：
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作者：
Haberman, Yael;Karns, Rebekah;Denson, Lee A.
溃疡性结肠炎（UC）病程和治疗反应的分子机制尚不清楚。在这里，我们使用RNAseq来定义206名接受标准化治疗的儿童UC患者的治疗前直肠基因表达和粪便微生物群谱。我们在408名参与者的成人和儿童UC队列中验证了我们的关键发现。我们观察到在活动性UC的队列中线粒体基因和功能的显著抑制，并且疾病严重程度的增加对于腺瘤/腺癌和先天免疫基因的富集是显著的。在发现队列中，一个严重性基因子集改善了对皮质类固醇诱导缓解的预测;该基因特征也与成人中抗TNF α和抗α（4）β（7）整联蛋白的应答相关。严重程度和治疗反应基因特征反过来与先前参与粘膜稳态的微生物的变化相关。我们的数据提供了对UC发病机制的见解，并可能优先考虑未来对当前方法无应答者的治疗。
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-TNF alpha and anti-alpha(4)beta(7) 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.