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Molecular Research on Celiac Disease
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Molecular Research on Celiac Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 16795

Special Issue Editor

Dr. Donatella Barisani

E-Mail Website
Guest Editor
Department of Health Sciences, School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy
Interests: celiac disease; liver disease; gastroenterology; immunology; molecular genetics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Throughout the years, our understanding of celiac disease has changed quite dramatically, and the data obtained by several research group have allowed us to better define the pathogenesis of this multifactorial disorder. Celiac disease is now regarded as an autoimmune disorder triggered, in genetically predisposed individuals, by the exposure to gluten.  

Although it is known that a specific HLA is necessary for the development of the disease, the presence of the DQ2.5 or DQ8 heterodimer is not sufficient, and several other genes are involved in the pathogenesis. Genome-wide association studies have identified several loci, mostly harboring genes involved in the immune response, but still about 50% of the genetic predisposition is unknown.

To fill this gap, and to clarify the genes involved in the pathogenesis, different approaches are necessary, also involving the analysis of the epigenetic mechanisms that play an essential role in the regulation of gene expression. In addition, recent research has revealed the extremely important role of noncoding RNAs (ncRNAs). This category includes both short ncRNAs (such as miRNAs) and long ncRNAs, which can exert their function both directly or indirectly, in this latter case acting as competing endogenous RNAs (ceRNAs). Thus, their role in celiac disease could be pivotal, since they could regulate both intestinal permeability as well as the immune response.

Another important issue regards the peptides causing the immune response; several data have demonstrated the role of the 33mer as well as of the 31-43 peptide, but other peptides or even other components of cereals need to be further evaluated in order to define their involvement in the pathogenesis of celiac disease.

Last but not least, we should consider the role of microbiota, which could process the gluten peptides, transforming them into harmless, very short peptides, thus preventing the activation of the immune system. Although some studies have demonstrated variation in the microbiota of celiac patients, we still need data to assess whether these changes are causative or a consequence of the damage of the intestinal mucosa.

Prof. Dr. Donatella Barisani
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Non-coding RNAs
  • Gene expression
  • Gluten peptides
  • Microbiota
  • Adaptive immunity
  • Innate immunity

Published Papers (5 papers)

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Research

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16 pages, 1590 KiB  
Article
A Combined mRNA- and miRNA-Sequencing Approach Reveals miRNAs as Potential Regulators of the Small Intestinal Transcriptome in Celiac Disease
by Ineke Luise Tan, Donatella Barisani, Roberto Panceri, Rutger Modderman, Marijn Visschedijk, Rinse K. Weersma, Cisca Wijmenga, Iris Jonkers, Rodrigo Coutinho de Almeida and Sebo Withoff
Int. J. Mol. Sci. 2021, 22(21), 11382; https://doi.org/10.3390/ijms222111382 - 21 Oct 2021
Cited by 5 | Viewed by 2546
Abstract
Celiac disease (CeD) is triggered by gluten and results in inflammation and villous atrophy of the small intestine. We aimed to explore the role of miRNA-mediated deregulation of the transcriptome in CeD. Duodenal biopsies of CeD patients (n = 33) and control [...] Read more.
Celiac disease (CeD) is triggered by gluten and results in inflammation and villous atrophy of the small intestine. We aimed to explore the role of miRNA-mediated deregulation of the transcriptome in CeD. Duodenal biopsies of CeD patients (n = 33) and control subjects (n = 10) were available for miRNA-sequencing, with RNA-sequencing also available for controls (n = 5) and CeD (n = 6). Differential expression analysis was performed to select CeD-associated miRNAs and genes. MiRNA‒target transcript pairs selected from public databases that also displayed a strong negative expression correlation in the current dataset (R < −0.7) were used to construct a CeD miRNA‒target transcript interaction network. The network includes 2030 miRNA‒target transcript interactions, including 423 experimentally validated pairs. Pathway analysis found that interactions are involved in immune-related pathways (e.g., interferon signaling) and metabolic pathways (e.g., lipid metabolism). The network includes 13 genes previously prioritized to be causally deregulated by CeD-associated genomic variants, including STAT1. CeD-associated miRNAs might play a role in promoting inflammation and decreasing lipid metabolism in the small intestine, thereby contributing unbalanced cell turnover in the intestinal crypt. Some CeD-associated miRNAs deregulate genes that are also affected by genomic CeD-risk variants, adding an additional layer of complexity to the deregulated transcriptome in CeD. Full article
(This article belongs to the Special Issue Molecular Research on Celiac Disease)
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20 pages, 5204 KiB  
Article
Dietary Nanoparticles Interact with Gluten Peptides and Alter the Intestinal Homeostasis Increasing the Risk of Celiac Disease
by Clara Mancuso, Francesca Re, Ilaria Rivolta, Luca Elli, Elisa Gnodi, Jean-François Beaulieu and Donatella Barisani
Int. J. Mol. Sci. 2021, 22(11), 6102; https://doi.org/10.3390/ijms22116102 - 5 Jun 2021
Cited by 6 | Viewed by 2623
Abstract
The introduction of metallic nanoparticles (mNPs) into the diet is a matter of concern for human health. In particular, their effect on the gastrointestinal tract may potentially lead to the increased passage of gluten peptides and the activation of the immune response. In [...] Read more.
The introduction of metallic nanoparticles (mNPs) into the diet is a matter of concern for human health. In particular, their effect on the gastrointestinal tract may potentially lead to the increased passage of gluten peptides and the activation of the immune response. In consequence, dietary mNPs could play a role in the increasing worldwide celiac disease (CeD) incidence. We evaluated the potential synergistic effects that peptic-tryptic-digested gliadin (PT) and the most-used food mNPs may induce on the intestinal mucosa. PT interaction with mNPs and their consequent aggregation was detected by transmission electron microscopy (TEM) analyses and UV–Vis spectra. In vitro experiments on Caco-2 cells proved the synergistic cytotoxic effect of PT and mNPs, as well as alterations in the monolayer integrity and tight junction proteins. Exposure of duodenal biopsies to gliadin plus mNPs triggered cytokine production, but only in CeD biopsies. These results suggest that mNPs used in the food sector may alter intestinal homeostasis, thus representing an additional environmental risk factor for the development of CeD. Full article
(This article belongs to the Special Issue Molecular Research on Celiac Disease)
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29 pages, 12124 KiB  
Article
Deciphering the Transcriptomic Heterogeneity of Duodenal Coeliac Disease Biopsies
by Johannes Wolf, Edith Willscher, Henry Loeffler-Wirth, Maria Schmidt, Gunter Flemming, Marlen Zurek, Holm H. Uhlig, Norman Händel and Hans Binder
Int. J. Mol. Sci. 2021, 22(5), 2551; https://doi.org/10.3390/ijms22052551 - 4 Mar 2021
Cited by 10 | Viewed by 3252
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Molecular Research on Celiac Disease)
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15 pages, 2552 KiB  
Article
Gliadin, through the Activation of Innate Immunity, Triggers lncRNA NEAT1 Expression in Celiac Disease Duodenal Mucosa
by Elisa Gnodi, Clara Mancuso, Luca Elli, Elisa Ballarini, Raffaella Meneveri, Jean François Beaulieu and Donatella Barisani
Int. J. Mol. Sci. 2021, 22(3), 1289; https://doi.org/10.3390/ijms22031289 - 28 Jan 2021
Cited by 6 | Viewed by 2129
Abstract
Celiac disease (CD) is an autoimmune enteropathy arising in genetically predisposed subjects exposed to gluten, which activates both innate and adaptive immunity. Although the pathogenesis is common to all patients, the clinical spectrum is quite variable, and differences could be explained by gene [...] Read more.
Celiac disease (CD) is an autoimmune enteropathy arising in genetically predisposed subjects exposed to gluten, which activates both innate and adaptive immunity. Although the pathogenesis is common to all patients, the clinical spectrum is quite variable, and differences could be explained by gene expression variations. Among the factors able to affect gene expression, there are lncRNAs. We evaluated the expression profile of 87 lncRNAs in CD vs. healthy control (HC) intestinal biopsies by RT-qPCR array. Nuclear enriched abundant transcript 1 (NEAT1) and taurine upregulated gene 1 (TUG1) were detected as downregulated in CD patients at diagnosis, but their expression increased in biopsies of patients on a gluten-free diet (GFD) exposed to gluten. The increase in NEAT1 expression after gluten exposure was mediated by IL-15 and STAT3 activation and binding to the NEAT1 promoter, as demonstrated by gel shift assay. NEAT1 is localized in the nucleus and can regulate gene expression by sequestering transcription factors, and it has been implicated in immune regulation and control of cell proliferation. The demonstration of its regulation by gluten thus also supports the role of lncRNAs in CD and prompts further research on these RNAs as gene expression regulators. Full article
(This article belongs to the Special Issue Molecular Research on Celiac Disease)
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Review

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25 pages, 1001 KiB  
Review
Molecular Biomarkers for Celiac Disease: Past, Present and Future
by Aarón D. Ramírez-Sánchez, Ineke L. Tan, B.C. Gonera-de Jong, Marijn C. Visschedijk, Iris Jonkers and Sebo Withoff
Int. J. Mol. Sci. 2020, 21(22), 8528; https://doi.org/10.3390/ijms21228528 - 12 Nov 2020
Cited by 15 | Viewed by 5453
Abstract
Celiac disease (CeD) is a complex immune-mediated disorder that is triggered by dietary gluten in genetically predisposed individuals. CeD is characterized by inflammation and villous atrophy of the small intestine, which can lead to gastrointestinal complaints, malnutrition, and malignancies. Currently, diagnosis of CeD [...] Read more.
Celiac disease (CeD) is a complex immune-mediated disorder that is triggered by dietary gluten in genetically predisposed individuals. CeD is characterized by inflammation and villous atrophy of the small intestine, which can lead to gastrointestinal complaints, malnutrition, and malignancies. Currently, diagnosis of CeD relies on serology (antibodies against transglutaminase and endomysium) and small-intestinal biopsies. Since small-intestinal biopsies require invasive upper-endoscopy, and serology cannot predict CeD in an early stage or be used for monitoring disease after initiation of a gluten-free diet, the search for non-invasive biomarkers is ongoing. Here, we summarize current and up-and-coming non-invasive biomarkers that may be able to predict, diagnose, and monitor the progression of CeD. We further discuss how current and emerging techniques, such as (single-cell) transcriptomics and genomics, can be used to uncover the pathophysiology of CeD and identify non-invasive biomarkers. Full article
(This article belongs to the Special Issue Molecular Research on Celiac Disease)
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