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17 pages, 3025 KiB

Open AccessArticle

The Combination of Gold and Silver Food Nanoparticles with Gluten Peptides Alters the Autophagic Pathway in Intestinal Crypt-like Cells

by Clara Mancuso, Eric Tremblay, Elisa Gnodi, Steve Jean, Jean-François Beaulieu and Donatella Barisani

Int. J. Mol. Sci. 2023, 24(17), 13040; https://doi.org/10.3390/ijms241713040 - 22 Aug 2023

Viewed by 799

Abstract

Metallic nanoparticles (mNPs) are widely used as food additives and can interact with gliadin triggering an immune response, but evaluation of the effects on crypts, hypertrophic in celiac subjects, is still lacking. This study evaluated the effects of gold and silver mNPs in [...] Read more.

Metallic nanoparticles (mNPs) are widely used as food additives and can interact with gliadin triggering an immune response, but evaluation of the effects on crypts, hypertrophic in celiac subjects, is still lacking. This study evaluated the effects of gold and silver mNPs in combination with gliadin on crypt-like cells (HIEC-6). Transmission electron microscopy (TEM) was used to evaluate gliadin-mNP aggregates in cells. Western blot and immunofluorescence analysis assessed autophagy-related molecule levels (p62, LC3, beclin-1, EGFR). Lysosome functionality was tested with acridine orange (AO) and Magic Red assays. TEM identified an increase in autophagic vacuoles after exposure to gliadin + mNPs, as also detected by significant increments in LC3-II and p62 expression. Immunofluorescence confirmed the presence of mature autophagosomes, showing LC3 and p62 colocalization, indicating an altered autophagic flux, further assessed with EGFR degradation, AO and Magic Red assays. The results showed a significant reduction in lysosomal enzyme activity and a modest reduction in acidity. Thus, gliadin + mNPs can block the autophagic flux inducing a lysosomal defect. The alteration of this pathway, essential for cell function, can lead to cell damage and death. The potential effects of this copresence in food should be further characterized to avoid a negative impact on celiac disease subjects. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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14 pages, 5708 KiB

Open AccessArticle

Gene Expression Profiling in Coeliac Disease Confirmed the Key Role of the Immune System and Revealed a Molecular Overlap with Non-Celiac Gluten Sensitivity

by Michele Sallese, Konstantinos Efthymakis, Michele Marchioni, Benedetto Neri, Beatrice Dufrusine, Enrico Dainese, Marta Di Nicola and Matteo Neri

Int. J. Mol. Sci. 2023, 24(9), 7769; https://doi.org/10.3390/ijms24097769 - 24 Apr 2023

Cited by 2 | Viewed by 1732

Abstract

Coeliac disease (CeD) is an immune-mediated disorder triggered by the ingestion of gluten and an as yet unidentified environmental factor in genetically predisposed individuals. The disease involves a major autoimmune component that primarily damages the intestinal mucosa; although, it also has systemic involvement. [...] Read more.

Coeliac disease (CeD) is an immune-mediated disorder triggered by the ingestion of gluten and an as yet unidentified environmental factor in genetically predisposed individuals. The disease involves a major autoimmune component that primarily damages the intestinal mucosa; although, it also has systemic involvement. The Th1 inflammatory response is one of the main events leading to mucosal damage; although, enterocytes and the innate immune response also participate in the pathological mechanism. In this study, we performed an analysis of the gene expression profile of the intestinal mucosa of patients with active disease and compared it with that of patients who do not suffer from gluten-related disorders but report dyspeptic symptoms. This analysis identified 1781 differentially expressed (DE) genes, of which 872 were downregulated and 909 upregulated. Gene Ontology and pathway analysis indicated that the innate and adaptive immune response, in particular the Th1 pathway, are important pathogenetic mechanisms of CeD, while the key cytokines are IL27, IL21, IL2, IL1b, TNF, CSF2 and IL7, as well as type I (IFNA1, IFNA2) and type II (IFNG) interferons. Finally, the comparison between the DE genes identified in this study and those identified in our previous study in the intestinal mucosa of patients with non-celiac gluten sensitivity (NCGS) revealed a high degree of molecular overlap. About 30% of the genes dysregulated in NCGS, most of which are long non-coding RNAs, are also altered in CeD suggesting that these diseases may have a common root (dysregulated long non-coding RNAs) from which they develop towards an inflammatory phenotype of variable degree in the case of CeD and NCGS respectively. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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18 pages, 8359 KiB

Open AccessArticle

Altered Posttranslational Modification of Microtubules Contributes to Disturbed Enterocyte Morphology in Celiac Disease

by Sebastian Stricker, Manuel Müller, Klaus-Peter Zimmer and Ralf Jacob

Int. J. Mol. Sci. 2023, 24(3), 2635; https://doi.org/10.3390/ijms24032635 - 30 Jan 2023

Cited by 3 | Viewed by 1431

Abstract

Celiac disease (CD) represents a frequent autoimmune disease triggered by the ingestion of gliadin in genetically predisposed individuals. The alteration of enterocytes and brush border membrane morphology have been repetitively demonstrated, but the underlying mechanisms remain unclear. Microtubules represent a major element of [...] Read more.

Celiac disease (CD) represents a frequent autoimmune disease triggered by the ingestion of gliadin in genetically predisposed individuals. The alteration of enterocytes and brush border membrane morphology have been repetitively demonstrated, but the underlying mechanisms remain unclear. Microtubules represent a major element of the cytoskeleton and exert multiple functions depending on their tyrosination status. The aim of our study was to investigate whether posttranslational modification of microtubules was altered in the context of CD and whether this mechanism contributed to morphological changes of CD enterocytes. We examined the expression of tubulin tyrosine ligase (TTL) and vasohibin-2 (VASH2) and the level of detyrosinated and acetylated tubulin in duodenal biopsies and Caco-2 cells by immunoblot and immunofluorescence microcopy. Electron microscopy was performed to investigate the subcellular distribution of detyrosinated tubulin and brush border membrane architecture in CD biopsies and Madin–Darby Canine Kidney type II (MDCK) cells lacking TTL. CD enterocytes and Caco-2 cells stimulated with digested gliadin or IFN-y displayed a flattened cell morphology. This disturbed cellular architecture was accompanied by an increased amount of detyrosinated and acetylated tubulin and corresponding high expression of VASH2 and low expression of TTL. The altered posttranslational modification of tubulin was reversible after the introduction of the gluten-free diet. CD enterocytes and MDCK cells deficient in TTL displayed a reduced cell height along with an increased cell width and a reduced number of apical microvilli. Our results provide a functional explanation for the observed morphological alterations of the enterocytes observed in CD and provide diagnostic potential of the tyrosination status of microtubules as an early marker of villous atrophy and CD inflammation. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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Review

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21 pages, 727 KiB

Open AccessReview

Old and New Adjunctive Therapies in Celiac Disease and Refractory Celiac Disease: A Review

by Marco Valvano, Stefano Fabiani, Sabrina Monaco, Mauro Calabrò, Antonio Mancusi, Sara Frassino, Claudia Rolandi, Marta Mosca, Susanna Faenza, Emanuele Sgamma, Nicola Cesaro and Giovanni Latella

Int. J. Mol. Sci. 2023, 24(16), 12800; https://doi.org/10.3390/ijms241612800 - 15 Aug 2023

Cited by 4 | Viewed by 2795

Abstract

Celiac disease (CD) is a chronic enteropathy caused by the ingestion of gluten in a genetically susceptible individual. Currently, a gluten-free diet (GFD) is the only recommended treatment. However, unintentional gluten ingestion or a persistent villous atrophy with malabsorption (regardless of a strict [...] Read more.

Celiac disease (CD) is a chronic enteropathy caused by the ingestion of gluten in a genetically susceptible individual. Currently, a gluten-free diet (GFD) is the only recommended treatment. However, unintentional gluten ingestion or a persistent villous atrophy with malabsorption (regardless of a strict GFD) as in the case of Refractory Celiac Disease (RCD) represents a major issue. In this review, we have analysed and discussed data from both randomized controlled trials and observational studies concerning adjunctive therapies as well as novel therapies for the treatment of CD and RCD. The literature search was carried out through Medline and Scopus. In total, 2268 articles have been identified and 49 were included in this review (36 studies resulting from the search strategy and 13 from other sources). Today, GFD remains the only effective treatment, although steroids, mesalamine, and more recently biological therapies have found space in the complex management of RCD. Currently, studies evaluating the effectiveness of novel therapies are still limited and preliminary results have been controversial. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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20 pages, 696 KiB

Open AccessReview

Celiac Disease Genetics, Pathogenesis, and Standard Therapy for Japanese Patients

by Tasuku Tamai and Kenji Ihara

Int. J. Mol. Sci. 2023, 24(3), 2075; https://doi.org/10.3390/ijms24032075 - 20 Jan 2023

Cited by 7 | Viewed by 3992

Abstract

Celiac disease is an autoimmune disease primarily affecting the small intestine that is caused by the ingestion of gluten in genetically susceptible individuals. The development of celiac disease is based on a complex immune response to gluten proteins. The global average prevalence in [...] Read more.

Celiac disease is an autoimmune disease primarily affecting the small intestine that is caused by the ingestion of gluten in genetically susceptible individuals. The development of celiac disease is based on a complex immune response to gluten proteins. The global average prevalence in the general population is about 1%. In recent years, it has become clear that celiac disease is not less common in Asian countries than in Western countries but often remains undiagnosed. Although the number of patients with celiac disease in Asia is expected to increase with improving disease recognition and advances in diagnostic techniques, there remain few reports of celiac disease in the Far East region of Asia, especially in Japan. In this paper, we outline the epidemiology, diagnosis, and treatment of celiac disease. In addition, we summarize the reported Japanese cases of celiac disease with an overview in Japan. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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17 pages, 2466 KiB

Open AccessReview

Meta-Analysis and Systematic Review of HLA DQ2/DQ8 in Adults with Celiac Disease

by Sara Aboulaghras, Daniela Piancatelli, Khalid Taghzouti, Abdelaali Balahbib, Mohammed Merae Alshahrani, Ahmed Abdullah Al Awadh, Khang Wen Goh, Long Chiau Ming, Abdelhakim Bouyahya and Khadija Oumhani

Int. J. Mol. Sci. 2023, 24(2), 1188; https://doi.org/10.3390/ijms24021188 - 7 Jan 2023

Cited by 8 | Viewed by 3162

Abstract

Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the [...] Read more.

Although people with human leukocyte antigens (HLA) DQ2 and/or DQ8 are more likely to develop celiac disease (CD), the condition cannot be fully explained by this genetic predisposition alone. Multiple, as yet unidentified, factors contribute to the genesis of CD, including genetics, the environment, and the immune system. In order to provide insight into a prospective possibility and an expanded screening technique, we aim to undertake a comprehensive and meta-analytical study of the assessment and distribution of HLA class II (HLA-DQ2/DQ8) in adult CD patients. A systematic review was conducted using an electronic search of databases (PubMed, Google Scholar, Embase, and Direct Science) from January 2004 to February 2022. DQ2/DQ2 homozygotes have the highest risk of developing CD. DQ2/DQ8 typing is an effective test to exclude CD from the differential diagnosis of a patient with CD symptoms. Although other non-HLA genes have been associated with CD, they are rarely considered at diagnosis because they account for only a small proportion of the heritability of CD. This finding, together with the information gathered previously, may be useful in considering widely available and economically feasible screening options for celiac disease in young people. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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17 pages, 363 KiB

Open AccessReview

New Developments in Celiac Disease Treatment

by Mariana Verdelho Machado

Int. J. Mol. Sci. 2023, 24(2), 945; https://doi.org/10.3390/ijms24020945 - 4 Jan 2023

Cited by 11 | Viewed by 9330

Abstract

Celiac disease (CD) is a common autoimmune disease affecting around 1% of the population. It consists of an immune-mediated enteropathy, triggered by gluten exposure in susceptible patients. All patients with CD, irrespective of the presence of symptoms, must endure a lifelong gluten-free diet [...] Read more.

Celiac disease (CD) is a common autoimmune disease affecting around 1% of the population. It consists of an immune-mediated enteropathy, triggered by gluten exposure in susceptible patients. All patients with CD, irrespective of the presence of symptoms, must endure a lifelong gluten-free diet (GFD). This is not an easy task due to a lack of awareness of the gluten content in foods and the extensive incorporation of gluten in processed foods. Furthermore, a GFD imposes a sense of limitation and might be associated with decreased quality of life in CD patients. This results in gluten contamination in the diet of four out of five celiac patients adhering to a GFD. Furthermore, one in three adult patients will report persistent symptoms and two in three will not achieve full histological recovery when on a GFD. In recent years, there has been extensive research conducted in the quest to find the holy grail of pharmacological treatment for CD. This review will present a concise description of the current rationale and main clinical trials related to CD drug therapy. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

24 pages, 723 KiB

Open AccessReview

Toll-like Receptors and Celiac Disease

by Diana Talipova, Aiganym Smagulova and Dimitri Poddighe

Int. J. Mol. Sci. 2023, 24(1), 265; https://doi.org/10.3390/ijms24010265 - 23 Dec 2022

Cited by 8 | Viewed by 2089

Abstract

Celiac disease (CD) is an immune-mediated disorder triggered by dietary gluten intake in some genetically predisposed individuals; however, the additional non-HLA-related genetic factors implicated in CD immunopathogenesis are not well-defined. The role of the innate immune system in autoimmunity has emerged in the [...] Read more.

Celiac disease (CD) is an immune-mediated disorder triggered by dietary gluten intake in some genetically predisposed individuals; however, the additional non-HLA-related genetic factors implicated in CD immunopathogenesis are not well-defined. The role of the innate immune system in autoimmunity has emerged in the last few years. Genetic polymorphisms of some pattern-recognition receptors, including toll-like receptors (TLRs), have been associated with several autoimmune disorders. In this review, we summarize and discuss the evidence from basic research and clinical studies as regards the potential role of TLRs in CD immunopathogenesis. The evidence supporting the role of TLRs in CD immunopathogenesis is limited, especially in terms of basic research. However, differences in the expression and activation of TLRs between active CD patients from one side, and controls and treated CD patients from the other side, have been described in some clinical studies. Therefore, TLRs may be part of those non-HLA-related genetic factors implicated in CD etiopathogenesis, considering their potential role in the interaction between the host immune system and some environmental factors (including viral infections and gut microbiota), which are included in the list of candidate agents potentially contributing to the determination of CD risk in genetically predisposed individuals exposed to dietary gluten intake. Further basic research and clinical studies focused on TLRs in the context of CD and other gluten-related disorders are needed. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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16 pages, 320 KiB

Open AccessReview

Replacing the Burden of the Gluten Free Diet: Then, Now, and the Future

by Roxana Nemteanu, Irina Ciortescu, Corina Elena Hincu, Andreea Clim, Liliana Gheorghe, Anca Trifan and Alina Plesa

Int. J. Mol. Sci. 2022, 23(23), 15108; https://doi.org/10.3390/ijms232315108 - 1 Dec 2022

Cited by 2 | Viewed by 2050

Abstract

Without a doubt, a majority of diseases are food-pattern-related. However, one disease stands out as an increasingly more common autoimmune-mediated enteropathy triggered by the ingestion of gluten. Celiac disease (CD) is an old disease, with changing clinical patterns, affecting any age, including infancy [...] Read more.

Without a doubt, a majority of diseases are food-pattern-related. However, one disease stands out as an increasingly more common autoimmune-mediated enteropathy triggered by the ingestion of gluten. Celiac disease (CD) is an old disease, with changing clinical patterns, affecting any age, including infancy and adolescence, and becoming more frequent among the elderly. The gluten-free diet (GFD) has been the sole provider of clinical, serological, and histological improvement for patients with CD for more than seven decades. Nowadays, complete avoidance of dietary gluten is rarely possible because of the wide availability of wheat and other processed foods that contain even more gluten, to the detriment of gluten-free products. Undeniably, there is a definite need for replacing the burdensome GFD. An add-on therapy that could control the dietary transgressions and inadvertent gluten consumption that can possibly lead to overt CD should be considered while on GFD. Nevertheless, future drugs should be able to provide patients some freedom to self-manage CD and increase food independence, while actively reducing exposure and mucosal damage and alleviating GI symptoms. Numerous clinical trials assessing different molecules have already been performed with favorable outcomes, and hopefully they will soon be available for patient use. Full article

(This article belongs to the Special Issue Celiac Disease: Genetics, Pathogenesis and Therapy)

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