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Celiac disease (CD) is a hereditary immune-mediated disorder, which is along with the enormous production of pro-inflammatory cytokines and the reduced level of tight junction proteins. The aim of this study was to determine the expression of TNF-α, IFN-γ, IL-18, Occludin, miR-122-5p and miR-197-3p genes in duodenal biopsies of treated CD patients in comparison to the controls.Biopsy specimens were taken from the duodenum of 50 treated CD patients (36 (72%) females and 14 (28%) males with mean age of 37.06 ± 7.02 years) and 50 healthy controls (17 (34%) females and 33 (66%) males with mean age of 34.12 ± 4.9). Total RNA was isolated, cDNA was synthesized and mRNA expression of TNF-α, IFN-γ, IL-18, Occludin, miR-122-5p and miR-197-3p were quantified by relative qPCR using B2M and U6 as internal control genes. All data were evaluated using SPSS (V.21) and GraphPad Prism (V.5). Our results showed that there was no significant difference between patients and controls for intestinal mRNA expression of TNF-α, IFN-γ, IL-18, Occludin, and miR-122-5p (p 0.05) and the expression of miR-197-3p was significantly increased in CD patients relative to control subjects (p = 0.049).This study suggests that adherence to GFD may have a positive effect on the tight junction (TJ) permeability and in this process, miR-197-3p plays an important role. Increased expression of miR-197-3p with a final protective effect on Occludin expression can be further studied as a complement therapeutic target for Celiac disease.

Introduction: The microRNA-326 (miR-326) gene, by targeting ETS Proto-Oncogene 1 (ETS1), regulates the differentiation and interleukin-17A production of T helper 17 (Th17) cells. Celiac disease (CD) is an intestinal autoimmune disorder, in which the cascade of Th17 cells plays an important role in its pathogenicity. The aim of this study was to evaluate the expression changes of miR-326 and its two target genes ETS1 and IL-17A in celiac disease patients under a gluten-free diet (GFD). We expected the expression of miR-326 and IL-17A gene to decrease, and the expression of the ETS1 gene to increase, following the adherence to GFD. Methods: Peripheral blood samples of 40 CD patients under GFD (for more than 1 year) and 40 healthy individuals were collected. RNA was extracted, cDNA was synthesized and the miR-326, ETS1 and IL-17A gene expressions were evaluated by the quantitative polymerase real-time qPCR method. P-value ˂ 0.05 was considered statistically significant. Results: Although miR-326 mRNA expression was significantly lower in CD patients (P = 0.001), no significant difference was observed in ETS1 mRNA level between the two groups (P = 0.54), but IL-17A was significantly overexpressed in CD patients (P=0.002). No significant correlation was observed between the expression of the studied genes and the patientsʼ symptoms and Marsh classification. Conclusion:Adherence to the GFD for one to two years did not have the expected effect on the expression of genes in this panel. The most important finding that contradicted our hypothesis was the observation of high IL-17A levels in CD patients despite dieting, which may be related to the protective effect of this cytokine on intestinal tight junctions, which needs to be confirmed in further studies.

Background: Non-celiac wheat sensitivity (NCWS) is a poorly understood gluten-related disorder (GRD) and its prominent symptoms can be ameliorated by gluten avoidance. This study aimed to determine the effectiveness of a probiotic mixture in hydrolyzing gliadin peptides (toxic components of gluten) and suppressing gliadin-induced inflammatory responses in Caco-2 cells. Methods: Wheat dough was fermented with a probiotic mix for 0, 2, 4, and 6 h. The effect of the probiotic mix on gliadin degradation was monitored by SDS-PAGE. The expression levels of IL-6, IL-17A, INF-γ, IL-10, and TGF-β were evaluated using ELISA and qRT-PCR methods. Results: According to our findings, fermenting wheat dough with a mix of B. longum, L. acidophilus, and L. plantarum for 6 h was effective in gliadin degradation. This process also reduced levels of IL-6 (p = 0.004), IL-17A (p = 0.004), and IFN-γ (p = 0.01) mRNA, as well as decreased IL-6 (p = 0.006) and IFN-γ (p = 0.0009) protein secretion. 4 h fermentation led to a significant decrease in IL-17A (p = 0.001) and IFN-γ (p = 0.003) mRNA, as well as reduced levels of IL-6 (p = 0.002) and IFN-γ (p < 0.0001) protein secretion. This process was also observed to increase the expression levels of IL-10 (p < 0.0001) and TGF-β (p < 0.0001) mRNA. Conclusions: 4 h fermentation of wheat flour with the proposed probiotic mix might be a good strategy to develop an affordable gluten-free wheat dough for NCWS and probably other GRD patients.

Background: A gluten-free diet (GFD) is the only effective treatment of celiac disease (CD) that is associated with body mass index (BMI) changes. This study aimed to determine how GFD duration affects the BMI of Iranian patients with CD. Methods: In this prospective study, 215 patients with CD, who were on a GFD, were categorized into three groups according to the duration of compliance to GFD: 1. patients with less than 6 months of diet, 2. Patients who had a diet for 6 months to 2 years, and 3. patients with more than 2 years of diet. The BMI changes were assessed before and after adherence to the GFD. Results: Most patients’ weight remains in the same BMI category during different courses of GFD adherence. Patients who were underweight showed significant changes in their BMI following the diet in less than 6 months (P=0.033) and more than 2 years (P

Background and objective: Photobiomodulation (PBM) and Akkermansia muciniphila (A. muciniphila)have been shown to be effective in improving inflammatory conditions with positive effects on increasing the population of anti-inflammatory M2 macrophages. In this study, gliadin stimulated THP-1 derived macrophages were treated with A. muciniphila and PBM to evaluate their effects on promoting the polarization of M2 MQs. Methods and Results: The human monocyte cell line (THP-1) was differentiated to Macrophages (MQ). MQs were stimulated with 200 μg/ml gliadin for 24 h and then were treated with PBM 810 nm alone and along with Akkermansia muciniphila for following 24 h to evaluate their effects on macrophages polarization. THP-1 derived MQs were also treated with PBM and A. muciniphila to evaluate their effects on non-stimulated MQs. CD11b, CD80, and CD206 levels were evaluated by flow cytometry technique. Moreover, the expression of some M1and M2-related cytokines were determined. PBM of gliadin stimulated MQs decreased IL-6 and increased TGF-β, IL-10 and TNF-α expression compared with gliadin exposed MQs. PBM along with A. muciniphila treatment induced IL-6, TNF-α, and IL-10 expression in MQs in comparison to the untreated group and also elevated TGF-β, IL-10 and TNF-α levels in gliadin triggered MQs related to gliadin stimulated MQ cells. Conclusion: The result of this study showed the potential of PBMT and A. muciniphila to be used for modulating inflammatory responses and macrophages polarization, which may open new perspectives to find possible therapeutic target for celiac diseases.

Wheat flour is one of the most important food ingredients containing several essential nutrients including proteins. Gluten is one of the major protein components of wheat consisted of glutenin (encoded on chromosome 1) and gliadin (encoded on chromosome 1 and 6) and there are around hundred genes encoding it in wheat. Gluten proteins have the ability of eliciting the pathogenic immune responses and hypersensitivity reactions in susceptible individuals called “gluten-related disorders (GRDs)”, which include celiac disease (CD), wheat allergy (WA), and non-celiac gluten sensitivity (NCGS). Currently removing gluten from the diet is the only effective treatment for mentioned GRDs and studies for the appropriate and alternative therapeutic approaches are ongoing. Accordingly, several genetic studies have focused on breeding wheat with low immunological properties through gene editing methods. The present review considers genetic characteristics of gluten protein components, focusing on their role in the incidence of gluten-related diseases, and genetic modifications conducted to produce wheat with less immunological properties.

Celiac disease (CD) is a systemic immune-mediated disorder caused by the dietary gluten in individuals who are genetically susceptible to the disease. In fact, CD is a T cell-mediated immune disease in which gluten-derived peptides activate the lamina propria CD4+ Teff cells, and these T-cell subsets can cause the intestinal tissue damages. Also, there are additional subsets of CD4+ T cells with suppressor functions. These subsets express the master transcription factor, FOXP3, and include Tr1 cells and CD4+CD25+ regulatory T cells (Tregs), which are the main population involved in maintaining the peripheral tolerance, preventing the autoimmune diseases and limiting the chronic inflammatory diseases such as CD. The suppressive function of Tregs is important to maintain the immune homeostasis. This paper examined the features and the basic mechanisms used by Tregs to mediate the suppression in CD.

Regulatory T cells (Tregs) have an important role in the control of the immune responses. This study aimed to compare the frequency of peripheral blood (PB) CD4+ CD25+ FoxP3+ Treg cells and PB and duodenal expression levels of pro- and anti-inflammatory mediators in treated celiac disease (CD) patients and healthy controls.Duodenal biopsy specimens and PB samples were collected from 60 treated CD patients and 60 controls. Flow cytometry analysis was conducted on peripheral blood mononuclear cell (PBMC) specimens and relative PB and duodenal mRNA expression levels of CD25, forkhead box P3 (Foxp3), interleukin (IL)-10 and granzyme B (GrzB) were evaluated using quantitative real-time PCR. The levels of serum IL-10 and IL-6 were tested with sandwich enzyme-linked immunosorbent assay kits. p values 0.05 were considered significant. Flow cytometry analysis showed a significant decrease in the number of Tregs in CD patients' PBMC specimens (p = 0.012). CD25 and Foxp3 PB mRNA expressions were also lower in CD patients without reaching the significance level (p 0.05). IL-10 PB mRNA and protein expression did not differ between the groups (p 0.05), and GrzB PB expression was significantly reduced in CD patients (p = 0.001). In duodenal specimens of CD patients, while significantly increased CD25, Foxp3 mRNA expression (p = 0.01 and 0.001, respectively) and decreased IL-10 mRNA expression (p = 0.02) were observed, GrzB mRNA expression did not differ between groups (p 0.05). Moreover, a high serum level of IL-6 was observed in CD patients (p = 0.001).Despite following the gluten free diet, there may still be residual inflammation in the intestine of CD patients. Accordingly, finding a therapeutic approach based on strengthening the function of Treg cells in CD might be helpful.

Gluten proteins are known as immunological triggers for inflammation resulting in mucosal lesions in patients with coeliac disease (CD). Adherence to a strict gluten-free diet (GFD) is currently known as the only effective treatment for CD. In this study, we performed a systematic review and dose-response meta-analysis on data from previous studies to investigate the association between different gluten doses administered and the risk of CD relapse. Electronic databases were systematically searched to retrieve studies that investigated the response of CD patients to different amounts of gluten intake and evaluated the clinical, serologic, and/or histologic evidence to recognize disease relapse. Study-specific relative risks (RRs) were combined using a random effects model. A total of 440 identified published papers were screened, of which 7 records were selected following full-text reviewing and eligibility assessment for dose-response meta-analysis. According to our analysis, the risk of CD relapse is estimated to be 0.2% (RR: 1.002; 95% CI: 1.001 to 1.004) following the consumption of 6 mg gluten/day, which was increased to 7% (RR: 1.07; 95% CI: 1.03 to 1.10), 50% (RR: 1.50; 95% CI: 1.23 to 1.82), 80% (RR: 1.80; 95% CI: 1.36 to 2.38), and 100% (RR: 2.00; 95% CI: 1.43 to 2.78) by the daily intake of 150, 881, 1276, and 1505 mg gluten, respectively. Although good adherence to a GFD can adequately control CD-related symptoms, disease relapse might happen even with a very low dose of gluten, and the duration of exposure to gluten is also an important matter. The current literature has substantial limitations, such as relying on the data from just a few countries that were different in terms of the amount of gluten administered, the duration of the challenge, etc. Therefore, more randomized clinical trials using a standardized gluten challenge protocol are needed to confirm the findings of the present study.

Celiac disease (CeD) and inflammatory bowel disease (IBD) are accompanied by impaired immune responses. To study the immune regulation of these diseases, we evaluated the expression levels of pro-inflammatory (IL-8 and IL-17 A) and anti-inflammatory (IL-10) cytokines in intestinal biopsy specimens of CeD and IBD patients in comparison to healthy subjects.Intestinal biopsies were collected from 33 patients with IBD, 47 patients with CeD, and 20 healthy individuals. Total RNA was extracted and mRNA expression levels of IL-8, IL-17 A and IL-10 were assessed by qPCR. P-value 0.05 was considered statistically significant. The expression levels of IL-8 and IL-17 A were higher in biopsies of IBD (UC and CD) and CeD patients compared to the control group (P 0.05). IBD patients (UC and CD) had higher IL-8 intestinal level than CeD patients (P 0.0001 and P = 0.0007, respectively). The expression of IL-10 was significantly down-regulated in intestinal biopsies of CeD and IBD patients compared with controls (P 0.001). In addition, the expression level of this cytokine was significantly lower in IBD patients (P 0.001 for UC patients and P 0.0001 for CD patients) than CeD group.The three selected pro- and anti-inflammatory cytokines showed a similar expression pattern in both IBD and CeD patients. As IBD and CeD are immune-mediated disorders and are accompanied by inflammatory events, the understanding of the similarities and differences among them can help researchers to find out useful candidate therapeutic protocols. We suggest that larger cohort studies be organized to achieve more insights into this regulation.

The cultivation of gluten-containing grains, which started in the Middle East about 10,000 years ago, along with the growth of civilizations, has led to a broad spectrum of gluten-related disorders (GRDs). While numerous studies concerning different aspects of GRDs have been published, a comprehensive integrating book that brings together all this clinical information was lacking. We have the honor to present this new book, which brings together all five categories of GRDs in different areas of knowledge, in order to integrate necessary and wide apart information.

This study aimed to evaluate the prevalence and outcome of COVID-19 among Iranian celiac disease patients.Patients with celiac disease (CD) might be at greater risk for opportunistic viral infections. Coronavirus disease-2019 (COVID-19) is a new coronavirus (SARS-CoV-2) cause of respiratory disorder which spread around the world at the end of 2019. The question is does COVID-19 infection increase the risk of severe outcome and/or a higher mortality in treated celiac disease?.Data regarding demographic details, clinical history, and COVID-19 infection symptoms among treated celiac disease patients was collected from July 2020 to January 2021 and analyzed using SPSS version 25.A total of 455 celiac disease patients were included in this study. The prevalence of Covid-19 infection among celiac disease patients was 2.4%. Infection among women (72.7%) was higher than the men, and only one overweight man who smoked was hospitalized. Among COVID-19 infected celiac disease patients, the most common symptoms were myalgia 90.9% (10/11), fever, body trembling, headache, shortness of breath, loss of smell and taste, and anorexia (72.7%). Treatments for COVID-19, included antibiotics (90.9%), pain analgesics (54.5%), antihistamines (27.3%), antivirals (9.1%) and hydroxychloroquine (9.1%).This study shows that treated celiac disease is not a risk factor for severity or higher mortality in patients infected with COVID-19. Women, however, might need extra-protection to prevent COVID-19 infection.

BACKGROUND: Inflammatory cytokines play roles in the pathogenesis of celiac disease. To introduce new diagnostic markers in patients with celiac disease for easy, fast, low cost, and non-invasive diagnosis, we evaluated the peripheral blood expression levels of interleukin-15 (IL-15), interleukin-17A (IL-17A), interleukin23A (IL-23A), granzyme B (GzmB), T-box transcription factor 21 (TBX21), and tumor necrosis factor alpha-induced protein 3 (TNFAIP3) of patients compared with the healthy controls, which were extracted from public databases organized in a protein-protein interaction network, in this group. METHODS: Peripheral blood mononuclear cells were collected from 30 patients with celiac disease and 30 healthy subjects. Total RNA was extracted, and mRNA expression levels of targeted genes were investigated by the quantitative real-time polymerase chain reaction (PCR) method. SPSS software was used for statistical analysis. Receiver operating characteristic (ROC) curve analysis was performed to characterize the diagnostic ability of the studied genes. RESULTS: The expression of IL-15, IL-17A, IL-23A, GzmB, TBX21, and TNFAIP3 genes in peripheral blood mononuclear cells of patients with celiac disease showed a significant increase compared with the control group. Among them, TNFAIP3, IL23A, and GzmB have better resolution and diagnostic value in differentiating patients with celiac disease from healthy controls. CONCLUSION: Our results suggest that TNFAIP3, IL23A, and GzmB could be useful and sensible markers in differentiating patients with celiac disease from healthy controls. However, the diagnostic relevance of other genes recognized by pathway analysis needs to be further investigated.

The aim of this study was to introduce biomarkers commonly involved in pancreatic cancer metastasis to the liver.The liver is affected by metastatic disease in pancreatic cancer.Two cancer biomarkers were distinguished through a STRING database protein query. The dysregulated proteins of the two cancers were included in 2 networks drawn by Cytoscape software v 3.2.7. 20 top nodes and achieved by the Network analyzer application of Cytoscape based on degree value. The common hub nodes were determined, and action maps were analyzed.Among 20 hubs of each studied cancer, 18 common hub nodes (90% of hubs) were identified and screened by action maps. Four proteins, AKT1, CDKN2A, ERBB2, and IL6, were identified as common central proteins related to the two studied diseases.AKT1, CDKN2A, ERBB2, and IL6 are common protein core of liver and pancreatic cancers, while STAT3, CASP3, NOTCH1, and CTNNB1 are possible differential proteins to discriminate these cancers.

Background. Celiac disease (CeD) is an autoimmune intestinal disorder caused by gluten protein consumption in genetically predisposed individuals. As biopsy sampling is an invasive procedure, finding novel noninvasive serological markers for screening of at-risk CeD population is a priority. Metabolomics is helpful in monitoring metabolite changes in body fluids and tissues. In the present study, we evaluated serum metabolite levels of CeD patients relative to healthy controls with the aim of introducing new biomarkers for population screening. Method. We compared the serum metabolic profile of CeD patients ( n = 42 ) and healthy controls ( n = 22 ) using NMR spectroscopy and multivariate analysis. Result. 25 metabolites were identified by serum metabolic profiling. Levels of 3-hydroxyisobutyric acid and isobutyrate showed significant differences in CeD patients’ samples compared with healthy controls ( p < 0.05 ). According to pathway analysis, our data demonstrated that changes in nine metabolic pathways were significantly disrupted/affected in patients with CeD. These enriched pathways are involved in aminoacyl-tRNA biosynthesis; primary bile acid biosynthesis; nitrogen metabolism; glutamine and glutamate metabolism; valine, leucine, and isoleucine biosynthesis and degradation; taurine and hypotaurine metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and arginine biosynthesis. Conclusion. In summary, our results demonstrated that changes in the serum level of 25 metabolites may be useful in distinguishing CeD patients from healthy controls, which have the potential to be considered candidate biomarkers of CeD.

Aim: Evaluating the expression level of CD4+ FoxP3+ CD25+ T cells and IL-6 in peripheral blood samples of hospitalized COVID-19 patients. Background: COVID-19 is an emerging disease with worldwide distribution. However, there is a little data about the correlation between the disease and the host immune responses. Methods: Whole blood samples of 30 COVID-19 patients and eight healthy people were collected during March to June 2020. Total RNA was extracted from the samples, cDNA synthesis was performed, and the expression level of targeted genes was evaluated using quantitative real-time PCR. Results: The expression level of CD4, CD25, and Foxp3 was significantly downregulated 5-, 2-, and 3-fold, respectively, among COVID-19 patients in comparison to healthy controls (P-value < 0.0001). The expression level of IL-6 represented almost 18-fold increase in COVID-19 patients compared to healthy controls. Conclusion: Our findings indicated the expression profile analysis of CD4+ FoxP3+ CD25+ T cells could be a potential marker for the assessment of severity of COVID-19 patients.