KU Leuven Department of Chronic Diseases, Metabolism and Ageing, Translational Research Center for Gastrointestinal Disorders (TARGID), IBD group, KU Leuven, Leuven, Belgium.
Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium.
BMJ Open Gastroenterol. 2023 Feb;10(1). doi: 10.1136/bmjgast-2022-001003.
To infer potential mechanisms driving disease subtypes among patients with inflammatory bowel disease (IBD), we profiled the transcriptome of purified circulating monocytes and CD4 T-cells.
RNA extracted from purified monocytes and CD4 T-cells derived from the peripheral blood of 125 endoscopically active patients with IBD was sequenced using Illumina HiSeq 4000NGS. We used complementary supervised and unsupervised analytical methods to infer gene expression signatures associated with demographic/clinical features. Expression differences and specificity were validated by comparison with publicly available single cell datasets, tissue-specific expression and meta-analyses. Drug target information, druggability and adverse reaction records were used to prioritise disease subtype-specific therapeutic targets.
Unsupervised/supervised methods identified significant differences in the expression profiles of CD4 T-cells between patients with ileal Crohn's disease (CD) and ulcerative colitis (UC). Following a pathway-based classification (Area Under Receiver Operating Characteristic - AUROC=86%) between ileal-CD and UC patients, we identified MAPK and FOXO pathways to be downregulated in UC. Coexpression module/regulatory network analysis using systems-biology approaches revealed mediatory core transcription factors. We independently confirmed that a subset of the disease location-associated signature is characterised by T-cell-specific and location-specific expression. Integration of drug-target information resulted in the discovery of several new (, , ) and repurposable drug targets (, ) for ileal CD as well as novel targets (, ) for UC.
Transcriptomic profiling of circulating CD4 T-cells in patients with IBD demonstrated marked molecular differences between the IBD-spectrum extremities (UC and predominantly ileal CD, sandwiching colonic CD), which could help in prioritising particular drug targets for IBD subtypes.
为了推断炎症性肠病（IBD）患者疾病亚型的潜在机制，我们对纯化的循环单核细胞和 CD4 T 细胞的转录组进行了分析。
使用 Illumina HiSeq 4000NGS 对来自 125 例内镜活动期 IBD 患者外周血中纯化的单核细胞和 CD4 T 细胞的 RNA 进行测序。我们使用互补的监督和非监督分析方法来推断与人口统计学/临床特征相关的基因表达特征。通过与公开的单细胞数据集、组织特异性表达和荟萃分析进行比较，验证了表达差异和特异性。药物靶点信息、药物可及性和不良反应记录用于优先考虑疾病亚型特异性治疗靶点。
非监督/监督方法鉴定出 CD4 T 细胞在回肠克罗恩病（CD）和溃疡性结肠炎（UC）患者之间的表达谱存在显著差异。在基于途径的分类（接受者操作特征曲线下面积-AUROC=86%）之后，我们发现 MAPK 和 FOXO 途径在 UC 中下调。使用系统生物学方法的共表达模块/调控网络分析揭示了中介核心转录因子。我们独立证实了疾病位置相关特征的子集具有 T 细胞特异性和位置特异性表达的特征。药物靶点信息的整合导致发现了几个新的（、、）和可再利用的药物靶点（、）用于回肠 CD，以及用于 UC 的新靶点（、）。
对 IBD 患者循环 CD4 T 细胞的转录组分析显示，IBD 谱两端（UC 和主要回肠 CD，夹在结肠 CD 之间）之间存在显著的分子差异，这有助于为 IBD 亚型优先选择特定的药物靶点。
