Colonic epithelial miR-31 associates with the development of Crohn's phenotypes
Colonic epithelial miR-31 associates with the development of Crohn's phenotypes
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DOI：
10.1172/jci.insight.122788
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发表时间：
2018-10-04
期刊：
影响因子：
8
通讯作者：
Sheikh, Shehzad Z.
中科院分区：
文献类型：
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作者：
Keith, Benjamin P.;Barrow, Jasmine B.;Sheikh, Shehzad Z.
背景。克罗恩病 (CD) 具有高度异质性，这在很大程度上是由于 CD 自然史的细胞过程的变异性，从而影响了有效的治疗。迫切需要加深对驱动 CD 异质性的细胞机制的理解。方法。我们对 CD 和 NIBD 对照的成人结肠组织进行了小 RNA 测序。从结肠组织中分离结肠上皮细胞和免疫细胞，并测量 microRNA-31 (miR-31) 的表达。在对照和 CD 患者产生的结肠培养物中测量 miR-31 表达。我们对未经治疗的 CD 儿科患者和对照患者的福尔马林固定石蜡包埋的结肠和回肠活检组织进行了小 RNA 测序，并收集了有关疾病特征和结果的数据。 结果。结肠中的小 RNA 测序和 microRNA 分析揭示了 2 种不同的分子亚型，每种亚型具有不同的临床关联。值得注意的是，我们发现 miR-31 表达是这两种亚型的驱动因素，此外，miR-31 表达在上皮细胞中尤其明显。 Colonoids 揭示，在该离体系统中保留了 miR-31 表达差异。在成年患者中，手术时结肠 miR-31 表达水平低与更差的疾病结果相关，这通过回肠末端造口的需要和新末端回肠疾病的复发来衡量。在儿科患者中，诊断时较低的 miR-31 表达与未来需要手术治疗的纤维狭窄回肠 CD 相关。这些发现代表了设计更有效的临床试验和开发个性化 CD 疗法的重要一步。
BACKGROUND. Crohn's disease (CD) is highly heterogeneous, due in large part to variability in cellular processes that underlie the natural history of CD, thereby confounding effective therapy. There is a critical need to advance understanding of the cellular mechanisms that drive CD heterogeneity.METHODS. We performed small RNA sequencing of adult colon tissue from CD and NIBD controls. Colonic epithelial cells and immune cells were isolated from colonic tissues, and microRNA-31 (miR-31) expression was measured. miR-31 expression was measured in colonoid cultures generated from controls and patients with CD. We performed small RNA-sequencing of formalin-fixed paraffin-embedded colon and ileum biopsies from treatment-naive pediatric patients with CD and controls and collected data on disease features and outcomes.RESULTS. Small RNA-sequencing and microRNA profiling in the colon revealed 2 distinct molecular subtypes, each with different clinical associations. Notably, we found that miR-31 expression was a driver of these 2 subtypes and, further, that miR-31 expression was particularly pronounced in epithelial cells. Colonoids revealed that miR-31 expression differences are preserved in this ex vivo system. In adult patients, low colonic miR-31 expression levels at the time of surgery were associated with worse disease outcome as measured by need for an end ileostomy and recurrence of disease in the neoterminal ileum. In pediatric patients, lower miR-31 expression at the time of diagnosis was associated with future development of fibrostenotic ileal CD requiring surgeryCONCLUSIONS. These findings represent an important step forward in designing more effective clinical trials and developing personalized CD therapies.