Deciphering the Transcriptomic Heterogeneity of Duodenal Coeliac Disease Biopsies

Abstract

Coeliac disease (CD) is a clinically heterogeneous autoimmune disease with variable presentation and progression triggered by gluten intake. Molecular or genetic factors contribute to disease heterogeneity, but the reasons for different outcomes are poorly understood. Transcriptome studies of tissue biopsies from CD patients are scarce. Here, we present a high-resolution analysis of the transcriptomes extracted from duodenal biopsies of 24 children and adolescents with active CD and 21 individuals without CD but with intestinal afflictions as controls. The transcriptomes of CD patients divide into three groups—a mixed group presenting the control cases, and CD-low and CD-high groups referring to lower and higher levels of CD severity. Persistence of symptoms was weakly associated with subgroup, but the highest marsh stages were present in subgroup CD-high, together with the highest cell cycle rates as an indicator of virtually complete villous atrophy. Considerable variation in inflammation-level between subgroups was further deciphered into immune cell types using cell type de-convolution. Self-organizing maps portrayal was applied to provide high-resolution landscapes of the CD-transcriptome. We find asymmetric patterns of miRNA and long non-coding RNA and discuss the effect of epigenetic regulation. Expression of genes involved in interferon gamma signaling represent suitable markers to distinguish CD from non-CD cases. Multiple pathways overlay in CD biopsies in different ways, giving rise to heterogeneous transcriptional patterns, which potentially provide information about etiology and the course of the disease.

Gene Expression Signatures Reveal Common Virus Infection Pathways in Target Tissues of Type 1 Diabetes, Hashimoto’s Thyroiditis, and Celiac Disease

“…In the HT dataset GSE138198 ( 8 ), data from 13 HT thyroid samples and three normal thyroid samples were used for analysis. The CD dataset GSE164883 ( 9 ) included intestinal tissues samples from 25 CD patients and 21 normal controls. Two CD patients were sampled twice and all 48 samples were used for further analysis.…”

Celiac disease: From genetics to epigenetics

“…The most common histone modifications are acetylation, phosphorylation, ubiquitination and methylation. Gene expression analysis studies performed on CeD biopsies compared to controls, pointed out a differential regulation of histone-modifying enzymes, thus suggesting the presence of a disease-related epigenetic signature involving histone modifications[ 16 , 17 ].…”

“…An encouraging study that analyzes this aspect has recently been published by Piccialli et al [ 71 ], who tested different models in order to predict the development of an overt CeD in childen with potential CeD. The use of a machine learning approach towards basic science data obtained from duodenal biopsies of CeD patients has recently been published by Wolf et al [ 16 ], who analyzed not only the trascriptomic profiles but also the expression of some lncRNAs and miRNAs. Moreover, the authors focused on gene expression signatures which associate with transcription factor (TF)-activity and chromatin state, as well as DNA and histone methylation pattern, thus providing an indirect measure of epigenetic modifications.…”

Insights from tissue “omics” analysis on intestinal remodeling in celiac disease

“…The first tissue “omics” studies in CeD were performed more than 15 years ago by microarray based transcriptome analysis at a depth of ∼5000 and ∼10,000 genes, respectively (Table 1) [58–72]. By contrast, the first tissue proteomics study from 2010 relied on comparison of protein expression by 2‐dimensional gel electrophoresis followed by mass spectrometry based protein identification.…”

“…Many canonical features of the CeD lesion can be inferred from “omics” analysis of intestinal biopsies from both pediatric and adult patients (Figure 4A) [58–72]. Increased expression of IFNG transcript and IFN‐γ regulated genes such as WARS , STAT1 , TAP , CD74 has been unanimously reported by all studies as well as increased expression of chemokines and adhesion molecules indicative of immune cell migration and infiltration ( CXCL10 , CXCL11 , and ICAM1 ) (Figure 4A).…”