Ramírez-Sánchez Aarón D, Zühlke Stephanie, Aguirre-Gamboa Raúl, Vochteloo Martijn, Franke Lude, Lundin Knut E A, Withoff Sebo, Jonkers Iris H
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
K.G. Jebsen Coeliac Disease Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Genes Immun. 2025 Sep 9. doi: 10.1038/s41435-025-00356-0.
In coeliac disease (CeD), the epithelial lining (EL) of the small intestine is severely damaged by a complex auto-inflammatory response, leading intraepithelial lymphocytes to attack epithelial cells. To understand the intestinal changes and genetic regulation in CeD, we investigated the heterogeneity in the transcriptomic profile of the duodenal EL using RNA-seq and eQTL analysis on predicted cell types. The study included duodenal biopsies from 82 patients, grouped into controls, gluten-free diet treated CeD and untreated CeD. We identified 1 862 differential expressed genes, which clustered into four sets. Two sets, one upregulated for cell cycle function (n = 366) and one downregulated for digestion, transmembrane transport, and laminin pathways (n = 543), defined three sample groups based on inflammation status: non-inflamed, mild inflammation or severe inflammation. The remaining two sets of genes were enriched for immune (n = 458) and extracellular matrix and barrier functions (n = 495) and were sufficient to classify samples into their disease conditions. Finally, deconvoluting eQTL effects from epithelial and immune cells identified 6 and 15 cell-type-mediated eQTL genes, respectively. In sum, we identified genes expressed in the duodenal EL whose expression reflect heterogeneity in CeD and that may be used as biomarkers to assess CeD condition and its mucosal and immune status.
在乳糜泻（CeD）中，小肠上皮内层（EL）会因复杂的自身炎症反应而受到严重损伤，导致上皮内淋巴细胞攻击上皮细胞。为了解CeD中的肠道变化和基因调控，我们使用RNA测序和对预测细胞类型的表达数量性状基因座（eQTL）分析，研究了十二指肠EL转录组图谱的异质性。该研究纳入了82例患者的十二指肠活检样本，分为对照组、接受无麸质饮食治疗的CeD患者组和未治疗的CeD患者组。我们鉴定出1862个差异表达基因，这些基因聚为四组。其中两组，一组细胞周期功能上调（n = 366），另一组消化、跨膜转运和层粘连蛋白途径下调（n = 543），根据炎症状态定义了三个样本组：非炎症、轻度炎症或重度炎症。其余两组基因分别富集于免疫（n = 458）以及细胞外基质和屏障功能（n = 495），并且足以将样本分类到各自的疾病状态。最后，从上皮细胞和免疫细胞中解卷积eQTL效应，分别鉴定出6个和15个细胞类型介导的eQTL基因。总之，我们鉴定出了在十二指肠EL中表达的基因，其表达反映了CeD中的异质性，并且可用作评估CeD病情及其黏膜和免疫状态的生物标志物。
