DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome,Gastroenterology

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DNA Methylation and Transcription Patterns in Intestinal Epithelial Cells From Pediatric Patients With Inflammatory Bowel Diseases Differentiate Disease Subtypes and Associate With Outcome
Gastroenterology ( IF 25.7 ) Pub Date : 2017-10-12 , DOI: 10.1053/j.gastro.2017.10.007
Kate Joanne Howell ₁ , Judith Kraiczy ₂ , Komal M Nayak ₂ , Marco Gasparetto ₃ , Alexander Ross ₄ , Claire Lee ₃ , Tim N Mak ₂ , Bon-Kyoung Koo ₅ , Nitin Kumar ₆ , Trevor Lawley ₆ , Anupam Sinha ₇ , Philip Rosenstiel ₇ , Robert Heuschkel ₈ , Oliver Stegle ₉ , Matthias Zilbauer ₁₀

Affiliation

University Department of Paediatrics, University of Cambridge, UK; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
University Department of Paediatrics, University of Cambridge, UK.
University Department of Paediatrics, University of Cambridge, UK; Department of Paediatric Gastroenterology, University of Cambridge and Addenbrooke's Hospital, Cambridge, UK.
University Department of Paediatrics, University of Cambridge, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.
Institute of Clinical Molecular Biology (IKMB), Kiel University, Kiel, Germany.
Department of Paediatric Gastroenterology, University of Cambridge and Addenbrooke's Hospital, Cambridge, UK.
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
University Department of Paediatrics, University of Cambridge, UK; Department of Paediatric Gastroenterology, University of Cambridge and Addenbrooke's Hospital, Cambridge, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.

Background & Aims

We analyzed DNA methylation patterns and transcriptomes of primary intestinal epithelial cells (IEC) of children newly diagnosed with inflammatory bowel diseases (IBD) to learn more about pathogenesis.

Methods

We obtained mucosal biopsies (N = 236) collected from terminal ileum and ascending and sigmoid colons of children (median age 13 years) newly diagnosed with IBD (43 with Crohn’s disease [CD], 23 with ulcerative colitis [UC]), and 30 children without IBD (controls). Patients were recruited and managed at a hospital in the United Kingdom from 2013 through 2016. We also obtained biopsies collected at later stages from a subset of patients. IECs were purified and analyzed for genome-wide DNA methylation patterns and gene expression profiles. Adjacent microbiota were isolated from biopsies and analyzed by 16S gene sequencing. We generated intestinal organoid cultures from a subset of samples and genome-wide DNA methylation analysis was performed.

Results

We found gut segment-specific differences in DNA methylation and transcription profiles of IECs from children with IBD vs controls; some were independent of mucosal inflammation. Changes in gut microbiota between IBD and control groups were not as large and were difficult to assess because of large amounts of intra-individual variation. Only IECs from patients with CD had changes in DNA methylation and transcription patterns in terminal ileum epithelium, compared with controls. Colon epithelium from patients with CD and from patients with ulcerative colitis had distinct changes in DNA methylation and transcription patterns, compared with controls. In IECs from patients with IBD, changes in DNA methylation, compared with controls, were stable over time and were partially retained in ex-vivo organoid cultures. Statistical analyses of epithelial cell profiles allowed us to distinguish children with CD or UC from controls; profiles correlated with disease outcome parameters, such as the requirement for treatment with biologic agents.

Conclusions

We identified specific changes in DNA methylation and transcriptome patterns in IECs from pediatric patients with IBD compared with controls. These data indicate that IECs undergo changes during IBD development and could be involved in pathogenesis. Further analyses of primary IECs from patients with IBD could improve our understanding of the large variations in disease progression and outcomes.

中文翻译：

炎症性肠病儿科患者肠上皮细胞的 DNA 甲基化和转录模式可区分疾病亚型并与结果相关

背景与目标

我们分析了新诊断为炎症性肠病 (IBD) 的儿童的原代肠上皮细胞 (IEC) 的 DNA 甲基化模式和转录组，以了解有关发病机制的更多信息。

方法

我们获得了从回肠末端、升结肠和乙状结肠收集的黏膜活检样本（N = 236），这些儿童（中位年龄 13 岁）新诊断为 IBD（43 例克罗恩病 [CD]、23 例溃疡性结肠炎 [UC]）和 30没有 IBD 的儿童（对照）。从 2013 年到 2016 年，患者在英国的一家医院招募和管理。我们还获得了后期从一部分患者收集的活检样本。纯化并分析了 IEC 的全基因组 DNA 甲基化模式和基因表达谱。从活组织检查中分离出相邻的微生物群，并通过 16S 基因测序进行分析。我们从一部分样本中生成了肠道类器官培养物，并进行了全基因组 DNA 甲基化分析。

结果

我们发现 IBD 儿童与对照组在 DNA 甲基化和 IEC 转录谱中的肠道片段特异性差异；有些与黏膜炎症无关。IBD 组和对照组之间肠道微生物群的变化没有那么大，并且由于个体内部存在大量差异而难以评估。与对照组相比，只有来自 CD 患者的 IEC 在末端回肠上皮中的 DNA 甲基化和转录模式发生了变化。与对照组相比，来自 CD 患者和溃疡性结肠炎患者的结肠上皮在 DNA 甲基化和转录模式上有明显的变化。在来自 IBD 患者的 IEC 中，与对照组相比，DNA 甲基化的变化随着时间的推移保持稳定，并且部分保留在离体类器官培养物中。上皮细胞谱的统计分析使我们能够将患有 CD 或 UC 的儿童与对照组区分开来。概况与疾病结果参数相关，例如对生物制剂治疗的要求。