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Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0

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 June 2022) | Viewed by 20284

Special Issue Editors


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Guest Editor
Department of Translational Medical Science, Section of Paediatrics, University Federico II, Via S. Pansini 5, 80131 Naples, Italy
Interests: pediatrics; gastroenterology; chronic inflammation; celiac disease
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Department of Translational Medical Science, University of Naples, Federico II, 80131 Naples, Italy
Interests: pediatrics; gastroenterology; chronic inflammation; celiac disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is the continuation of our previous special issue "Pro-inflammatory Nutrient: Focus on Gliadin and Celiac Disease".

Ingested food can cause tissue inflammation through different mechanisms. Nutrient surplus, for example,  can trigger intracellular stress signals that potentiate pro-inflammatory signaling. In the intestine and particularly in the enterocytes, nutrients are modulators of various cellular functions and can be involved in tissue immune response and inflammation. An example of an intestinal inflammatory and remodeling response of the intestine to food is the small intestinal lesion in Celiac Disease, induced by gluten—an alimentary protein present in wheat and other cereals.

Celiac Disease (CD) is a frequent disease due to a combination of environmental factors and genetic predisposition. Most of the study on the mechanisms of the disease have focused on the T-cell mediated response to gliadin and little has been investigated on the reason why this response happens only in CD subjects. In this special number we would like to encourage papers that focus both on the the peculiar organoleptic characteristic of gliadin, and wheat proteins in general, and on the costitutive alterations of the CD cells that render them more sensitive to inflammatory agents including viruses, gliadin itself and more in general Western Diet and life stiles. 

We will encourage papers (or reviews) focused on:

  • Gliadin and other wheat proteins: digestibility, permanence in biological fluids, structure, mechanisms of entrance in the cells and also biological activity.
  • Differences between normal and celiacs at any level, from cell structure to biological pathway. Biomarkers of CD.
  • Pro-inflammarory agents that can cooperate or potentiate the gliadin effects on cells, including viruses, diet and other environmental factor
  • Models of CD

We hope that the combination of review and original articles selected for this special number could help to deepen the understanding of CD.

Prof. Dr. Maria Vittoria Barone
Prof. Dr. Salvatore Auricchio
Guest Editors

Manuscript Submission Information

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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.

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Keywords

  • Gliadin
  • Celiac Disease
  • intestinal inflammatory
  • T-cell

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Published Papers (7 papers)

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Research

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11 pages, 1345 KiB  
Article
Antibody Profile, Gene Expression and Serum Cytokines in At-Risk Infants before the Onset of Celiac Disease
by Renata Auricchio, Martina Galatola, Donatella Cielo, Roberta Rotondo, Fortunata Carbone, Roberta Mandile, Martina Carpinelli, Serena Vitale, Giuseppe Matarese, Carmen Gianfrani, Riccardo Troncone, Salvatore Auricchio and Luigi Greco
Int. J. Mol. Sci. 2023, 24(7), 6836; https://doi.org/10.3390/ijms24076836 - 6 Apr 2023
Cited by 1 | Viewed by 1609
Abstract
Immunological events that precede the development of villous atrophy in celiac disease (CeD) are still not completely understood. We aimed to explore CeD-associated antibody production (anti-native gliadin (AGA), anti-deamidated gliadin (DGP) and anti-tissue transglutaminase (anti-tTG)) in infants at genetic risk for CeD from [...] Read more.
Immunological events that precede the development of villous atrophy in celiac disease (CeD) are still not completely understood. We aimed to explore CeD-associated antibody production (anti-native gliadin (AGA), anti-deamidated gliadin (DGP) and anti-tissue transglutaminase (anti-tTG)) in infants at genetic risk for CeD from the Italian cohorts of the PREVENT-CD and Neocel projects, as well as the relationship between antibody production and systemic inflammation. HLA DQ2 and/or DQ8 infants from families with a CeD case were followed from birth. Out of 220 at-risk children, 182 had not developed CeD by 6 years of age (CTRLs), and 38 developed celiac disease (CeD). The profiles of serum cytokines (INFγ, IL1β, IL2, IL4, IL6, IL10, IL12p70, IL17A and TNFα) and the expression of selected genes (FoxP3, IL10, TGFβ, INFγ, IL4 and IL2) were evaluated in 46 children (20 CeD and 26 CTRLs). Among the 182 healthy CTRLs, 28 (15.3%) produced high levels of AGA-IgA (AGA+CTRLs), and none developed anti-tTG-IgA or DGP-IgA, compared to 2/38 (5.3%) CeD infants (Chi Sq. 5.97, p = 0.0014). AGAs appeared earlier in CTRLs than in those who developed CeD (19 vs. 28 months). Additionally, the production of AGAs in CeD overlapped with the production of DGP and anti-tTG. In addition, gene expression as well as serum cytokine levels discriminated children who developed CeD from CTRLs. In conclusion, these findings suggest that the early and isolated production of AGA-IgA antibodies is a CeD-tolerogenic marker and that changes in gene expression and cytokine patterns precede the appearance of anti-tTG antibodies. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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17 pages, 5682 KiB  
Article
Peculiar Ca2+ Homeostasis, ER Stress, Autophagy, and TG2 Modulation in Celiac Disease Patient-Derived Cells
by Silvia Sposito, Agnese Secondo, Antonio Massimiliano Romanelli, Antonio Montefusco, Merlin Nanayakkara, Salvatore Auricchio, Maria Vittoria Barone, Ivana Caputo and Gaetana Paolella
Int. J. Mol. Sci. 2023, 24(2), 1495; https://doi.org/10.3390/ijms24021495 - 12 Jan 2023
Cited by 2 | Viewed by 1655
Abstract
Celiac disease (CD) is an inflammatory intestinal disease caused by the ingestion of gluten-containing cereals by genetically predisposed individuals. Constitutive differences between cells from CD patients and control subjects, including levels of protein phosphorylation, alterations of vesicular trafficking, and regulation of type 2 [...] Read more.
Celiac disease (CD) is an inflammatory intestinal disease caused by the ingestion of gluten-containing cereals by genetically predisposed individuals. Constitutive differences between cells from CD patients and control subjects, including levels of protein phosphorylation, alterations of vesicular trafficking, and regulation of type 2 transglutaminase (TG2), have been reported. In the present work, we investigated how skin-derived fibroblasts from CD and control subjects responded to thapsigargin, an endoplasmic reticulum ER stress inducer, in an attempt to contribute to the comprehension of molecular features of the CD cellular phenotype. We analyzed Ca2+ levels by single-cell video-imaging and TG2 activity by a microplate assay. Western blots and PCR analyses were employed to monitor TG2 levels and markers of ER stress and autophagy. We found that the cytosolic and ER Ca2+ level of CD cells was lower than in control cells. Treatments with thapsigargin differently activated TG2 in control and CD cells, as well as caused slightly different responses regarding the activation of ER stress and the expression of autophagic markers. On the whole, our findings identified further molecular features of the celiac cellular phenotype and highlighted that CD cells appeared less capable of adapting to a stress condition and responding in a physiological way. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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13 pages, 1787 KiB  
Article
Gliadin Peptide P31-43 Induces mTOR/NFkβ Activation and Reduces Autophagy: The Role of Lactobacillus paracasei CBA L74 Postbiotc
by Mariangela Conte, Federica Nigro, Monia Porpora, Claudia Bellomo, Francesca Furone, Andrea Luigi Budelli, Roberto Nigro, Maria Vittoria Barone and Merlin Nanayakkara
Int. J. Mol. Sci. 2022, 23(7), 3655; https://doi.org/10.3390/ijms23073655 - 26 Mar 2022
Cited by 12 | Viewed by 2690
Abstract
Celiac disease (CD) is an autoimmune disease characterized by an altered immune response stimulated by gliadin peptides that are not digested and cause damage to the intestinal mucosa. The aim of this study was to investigate whether the postbiotic Lactobacillus paracasei (LP) could [...] Read more.
Celiac disease (CD) is an autoimmune disease characterized by an altered immune response stimulated by gliadin peptides that are not digested and cause damage to the intestinal mucosa. The aim of this study was to investigate whether the postbiotic Lactobacillus paracasei (LP) could prevent the action of gliadin peptides on mTOR, autophagy, and the inflammatory response. Most of the experiments performed were conducted on intestinal epithelial cells Caco-2 treated with a peptic-tryptic digest of gliadin (PTG) and P31-43. Furthermore, we pretreated the Caco-2 with the postbiotic LP before treatment with the previously described stimuli. In both cases, we evaluated the levels of pmTOR, p70S6k, and p4EBP-1 for the mTOR pathway, pNFkβ, and pERK for inflammation and LC 3 and p62 for autophagy. For autophagy, we also used immunofluorescence analysis. Using intestinal organoids derivate from celiac (CD) patients, we analyzed the effect of gliadin after postbiotic pretreatment with LP on inflammation marker NFkβ. Through these experiments, we showed that gliadin peptides are able to induce the increase of the inflammatory response in a more complex model of intestinal epithelial cells. LP postbiotic was able to induce autophagy in Caco-2 cells and prevent gliadin effects. In conclusion, postbiotic pretreatment with LP could be considered for in vivo clinical trials. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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14 pages, 3478 KiB  
Article
Tissue Transglutaminase but Not Microbial Transglutaminase Is Inhibited by Exogenous Oxidative Substances in Celiac Disease
by Sebastian Stricker, Silvia Rudloff, Jan De Laffolie and Klaus-Peter Zimmer
Int. J. Mol. Sci. 2022, 23(4), 2248; https://doi.org/10.3390/ijms23042248 - 17 Feb 2022
Cited by 3 | Viewed by 2597
Abstract
Enzymatic modification of gliadin peptides by human transglutaminase 2 (TG2) is a central step in celiac disease (CD) pathogenesis. Microbial transglutaminase (mTG) mimics the enzymatic function of TG2 and might play a role in CD. TG2 is inhibited by endogenous oxidative endoplasmic reticulum-resident [...] Read more.
Enzymatic modification of gliadin peptides by human transglutaminase 2 (TG2) is a central step in celiac disease (CD) pathogenesis. Microbial transglutaminase (mTG) mimics the enzymatic function of TG2 and might play a role in CD. TG2 is inhibited by endogenous oxidative endoplasmic reticulum-resident protein 57 (ERp57), but data about mTG are lacking. We investigated the localization of ERp57 in duodenal biopsies and examined inhibition of TG2, and mTG by competitive, and oxidative molecules. Localization of ERp57 was investigated in duodenal biopsies from CD, and control patients by electron microcopy. Inhibition of TG2 and mTG was analyzed on an in vitro level using a photometric assay. ERp57 was observed within the lamina propria and its abundance within the endoplasmic reticulum (ER) was reduced in CD patients. TG2 was oxidatively inhibited by up to 95% by PX12 (p < 0.001) and L-cystine (p < 0.001), whereas mTG remained unaffected. The reduced presence of ERp57 within the ER of CD biopsies suggests a regulatory function of this protein within CD pathogenesis. PX12 and L-cystine oxidatively inhibit TG2 and might serve as treatment options in CD. mTG is poorly regulated and could contribute to the accumulation of immunogenic peptides within the gut with potential pathogenic effects. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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17 pages, 3993 KiB  
Article
Inflammation Is Present, Persistent and More Sensitive to Proinflammatory Triggers in Celiac Disease Enterocytes
by Monia Porpora, Mariangela Conte, Giuliana Lania, Claudia Bellomo, Luciano Rapacciuolo, Fernando Gabriel Chirdo, Renata Auricchio, Riccardo Troncone, Salvatore Auricchio, Maria Vittoria Barone and Merlin Nanayakkara
Int. J. Mol. Sci. 2022, 23(4), 1973; https://doi.org/10.3390/ijms23041973 - 10 Feb 2022
Cited by 22 | Viewed by 2409
Abstract
Celiac disease (CD) is a chronic inflammatory disease caused by a genetic predisposition to an abnormal T cell-mediated immune response to the gluten in the diet. Different environmental proinflammatory factors can influence and amplify the T cell-mediated response to gluten. The aim of [...] Read more.
Celiac disease (CD) is a chronic inflammatory disease caused by a genetic predisposition to an abnormal T cell-mediated immune response to the gluten in the diet. Different environmental proinflammatory factors can influence and amplify the T cell-mediated response to gluten. The aim of this manuscript was to study the role of enterocytes in CD intestinal inflammation and their response to different proinflammatory factors, such as gliadin and viruses. Intestinal biopsies from CD patients on a gluten-containing (GCD-CD) or a gluten-free diet (GFD-CD) as well as biopsies from potential CD patients (Pot-CD) before the onset of intestinal lesions and controls (CTR) were used to investigate IL-1β and IL-6 mRNA levels in situ. Organoids from CD patients were used to test the levels of NF-κB, ERK, IL-6, and IL-1β by Western blot (WB), ELISA, and quantitative PCR. The Toll-like receptor ligand loxoribine (Lox) and gliadin peptide P31-43 were used as proinflammatory stimuli. In CD biopsies inflammation markers IL-1β and IL-6 were increased in the enterocytes, and also in Pot-CD before the onset of the intestinal lesion and in GFD-CD. The inflammatory markers pNF-κB, pERK, IL-1β, and IL-6 were increased and persistent in CD organoids; these organoids were more sensitive to P31-43 and Lox stimuli compared with CTR organoids. Taken together, these observations point to constitutive inflammation in CD enterocytes, which are more sensitive to inflammatory stimuli such as food components and viruses. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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Review

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19 pages, 379 KiB  
Review
Celiac Disease and Possible Dietary Interventions: From Enzymes and Probiotics to Postbiotics and Viruses
by Sandip K. Wagh, Karen M. Lammers, Manohar V. Padul, Alfonso Rodriguez-Herrera and Veronica I. Dodero
Int. J. Mol. Sci. 2022, 23(19), 11748; https://doi.org/10.3390/ijms231911748 - 4 Oct 2022
Cited by 9 | Viewed by 5772
Abstract
Celiac Disease (CeD) is a chronic small intestinal immune-mediated enteropathy caused by the ingestion of dietary gluten proteins in genetically susceptible individuals. CeD is one of the most common autoimmune diseases, affecting around 1.4% of the population globally. To date, the only acceptable [...] Read more.
Celiac Disease (CeD) is a chronic small intestinal immune-mediated enteropathy caused by the ingestion of dietary gluten proteins in genetically susceptible individuals. CeD is one of the most common autoimmune diseases, affecting around 1.4% of the population globally. To date, the only acceptable treatment for CeD is strict, lifelong adherence to a gluten-free diet (GFD). However, in some cases, GFD does not alter gluten-induced symptoms. In addition, strict adherence to a GFD reduces patients’ quality of life and is often a socio-economic burden. This narrative review offers an interdisciplinary overview of CeD pathomechanism and the limitations of GFD, focusing on current research on possible dietary interventions. It concentrates on the recent research on the degradation of gluten through enzymes, the modulation of the microbiome, and the different types of “biotics” strategies, from probiotics to the less explored “viromebiotics” as possible beneficial complementary interventions for CeD management. The final aim is to set the context for future research that may consider the role of gluten proteins and the microbiome in nutritional and non-pharmacological interventions for CeD beyond the sole use of the GFD. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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17 pages, 1020 KiB  
Review
Pivotal Role of Inflammation in Celiac Disease
by Maria Vittoria Barone, Renata Auricchio, Merlin Nanayakkara, Luigi Greco, Riccardo Troncone and Salvatore Auricchio
Int. J. Mol. Sci. 2022, 23(13), 7177; https://doi.org/10.3390/ijms23137177 - 28 Jun 2022
Cited by 12 | Viewed by 2823
Abstract
Celiac disease (CD) is an immune-mediated enteropathy triggered in genetically susceptible individuals by gluten-containing cereals. A central role in the pathogenesis of CD is played by the HLA-restricted gliadin-specific intestinal T cell response generated in a pro-inflammatory environment. The mechanisms that generate this [...] Read more.
Celiac disease (CD) is an immune-mediated enteropathy triggered in genetically susceptible individuals by gluten-containing cereals. A central role in the pathogenesis of CD is played by the HLA-restricted gliadin-specific intestinal T cell response generated in a pro-inflammatory environment. The mechanisms that generate this pro-inflammatory environment in CD is now starting to be addressed. In vitro study on CD cells and organoids, shows that constant low-grade inflammation is present also in the absence of gluten. In vivo studies on a population at risk, show before the onset of the disease and before the introduction of gluten in the diet, cellular and metabolic alterations in the absence of a T cell-mediated response. Gluten exacerbates these constitutive alterations in vitro and in vivo. Inflammation, may have a main role in CD, adding this disease tout court to the big family of chronic inflammatory diseases. Nutrients can have pro-inflammatory or anti-inflammatory effects, also mediated by intestinal microbiota. The intestine function as a crossroad for the control of inflammation both locally and at distance. The aim of this review is to discuss the recent literature on the main role of inflammation in the natural history of CD, supported by cellular fragility with increased sensitivity to gluten and other pro-inflammatory agents. Full article
(This article belongs to the Special Issue Pro-inflammatory Nutrients: Focus on Gliadin and Celiac Disease 2.0)
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