The correlation between fecal microbiota profiles and intracellular junction genes expression in young Iranian patients with celiac disease.

Celiac disease (CD) is characterized by the disruption of the intestinal barrier integrity and alterations in the microbiota composition. This study aimed to evaluate the changes in the fecal microbiota profile and mRNA expressions of intracellular junction-related genes in pediatric patients with CD compared to healthy controls (HCs). Thirty treated CD patients, 10 active CD, and 40 HCs were recruited. Peripheral blood (PB) and fecal samples were collected. Microbiota analysis was performed using quantitative real-time PCR (qPCR) test. The mRNA expressions of ZO-1, occludin, ß-catenin, E-cadherin, and COX-2 were also evaluated. In active and treated CD patients, the PB expression levels of ZO-1 (p = 0.04 and 0.002, respectively) and ß-catenin (p = 0.006 and 0.02, respectively) were lower than in HCs. PB Occludin's level was upregulated in both active and treated CD patients compared to HCs (p = 0.04 and 0.02, respectively). However, PB E-cadherin and COX-2 expression levels and fecal mRNA expressions of ZO-1, occludin, and COX-2 did not differ significantly between cases and HCs (P˃0.05). Active CD patients had a higher relative abundance of the Firmicutes (p = 0.04) and Actinobacteria (p = 0.03) phyla compared to treated subjects. The relative abundance of Veillonella (p = 0.04) and Staphylococcus (p = 0.01) genera was lower in active patients in comparison to HCs. Researchers should explore the precise impact of the gut microbiome on the molecules and mechanisms involved in intestinal damage of CD. Special attention should be given to Bifidobacteria and Enterobacteriaceae, as they have shown a significant correlation with the expression of tight junction-related genes.

The connection between fatty acids and inflammation in celiac disease; a deep exploring.

The interplay between fatty acids (FAs) and celiac disease (CD) is a burgeoning field of research with significant implications for understanding the pathophysiology and potential therapeutic avenues for this autoimmune disorder. CD, triggered by gluten consumption in susceptible individuals, presents with a range of intestinal and extra-intestinal symptoms impacting various bodily functions. The disruption of intestinal tight junctions (TJs) by gluten proteins leads to increased gut permeability and subsequent inflammatory responses mediated by T-cells. FAs, crucial components of cell membranes, play diverse roles in inflammation and immune regulation. In fact, FAs have been shown to modulate inflammatory processes through various mechanisms. Studies have highlighted alterations in FA profiles in individuals with CD, indicating potential implications for disease pathogenesis and micronutrient deficiencies. Moreover, the exploration of FAs as biomarkers for CD diagnosis offers promising avenues for future research and therapeutic interventions. Understanding the intricate relationship between FAs and CD could lead to novel approaches in managing this complex autoimmune disorder. Therefore, this review article aims to provide an overview of the connection between FAs and inflammation in CD.

Immunomodulatory and Anti-Inflammatory Effects of Vitamin A and Tryptophan on Monocyte-Derived Dendritic Cells Stimulated with Gliadin in Celiac Disease Patients.

Celiac Disease (CeD) is an autoimmune disorder with various symptoms upon gluten exposure. Dendritic cells (DCs) play a crucial role in gliadin-induced inflammation. Vitamin A (retinol; Ret) and its metabolite, retinoic acid (RA), along with tryptophan (Trp) and its metabolite, kynurenic acid (KYNA), are known to influence the immune function of DCs and enhance their tolerogenicity. This research aims to assess the impact of gliadin on DC maturation and the potential of vitamin A and tryptophan to induce immune tolerance in DCs. The monocyte cells obtained from peripheral blood mononuclear cells (PBMCs) of celiac disease patients were differentiated into DCs in the absence or presence of Ret, RA, Trp, KYNA, and then stimulated with peptic and tryptic (PT) digested of gliadin. We used flow cytometry to analyze CD11c, CD14, HLA-DR, CD83, CD86, and CD103 expression. ELISA was carried out to measure TGF-ß, IL-10, IL-12, and TNF-α levels. qRT-PCR was used to assess the mRNA expression of retinaldehyde dehydrogenase 2 (RALDH2) and integrin αE (CD103). The mRNA and protein levels of Indoleamine 2, 3-dioxygenase (IDO) was analyzed by qRT-PCR and Western blot assays, respectively. Our findings demonstrate that PT-gliadin enhances the expression of maturation markers, i.e. CD83, CD86 and HLA-DR and promote the secretion of TNF-α and IL-12 in DCs. Interestingly, vitamin A, tryptophan, and their metabolites increase the expression of CD103, while limiting the expression of HLA-DR, CD83, and CD86. They also enhance RALDH2 and IDO expression and promote the secretion of TGF-ß and IL-10, while limiting IL-12 and TNF-α secretion. These findings suggest that vitamin A and tryptophan have beneficial effects on PT-gliadin-stimulated DCs, highlighting their potential as therapeutic agents for celiac disease. However, further research is needed to fully understand their underlying mechanisms of action in these cells.

New entity of adult ultra-short coeliac disease: the first international cohort and case-control study.

BACKGROUND: Ultra-short coeliac disease (USCD) is defined as villous atrophy only present in the duodenal bulb (D1) with concurrent positive coeliac serology. We present the first, multicentre, international study of patients with USCD. METHODS: Patients with USCD were identified from 10 tertiary hospitals (6 from Europe, 2 from Asia, 1 from North America and 1 from Australasia) and compared with age-matched and sex-matched patients with conventional coeliac disease. FINDINGS: Patients with USCD (n=137, median age 27 years, IQR 21-43 years; 73% female) were younger than those with conventional coeliac disease (27 vs 38 years, respectively, p<0.001). Immunoglobulin A-tissue transglutaminase (IgA-tTG) titres at index gastroscopy were lower in patients with USCD versus conventional coeliac disease (1.8×upper limit of normal (ULN) (IQR 1.1-5.9) vs 12.6×ULN (IQR 3.3-18.3), p<0.001).Patients with USCD had the same number of symptoms overall (median 3 (IQR 2-4) vs 3 (IQR 1-4), p=0.875). Patients with USCD experienced less iron deficiency (41.8% vs 22.4%, p=0.006).Both USCD and conventional coeliac disease had the same intraepithelial lymphocytes immunophenotype staining pattern; positive for CD3 and CD8, but not CD4.At follow-up having commenced a gluten-free diet (GFD) (median of 1181 days IQR: 440-2160 days) both USCD and the age-matched and sex-matched controls experienced a similar reduction in IgA-tTG titres (0.5 ULN (IQR 0.2-1.4) vs 0.7 ULN (IQR 0.2-2.6), p=0.312). 95.7% of patients with USCD reported a clinical improvement in their symptoms. INTERPRETATION: Patients with USCD are younger, have a similar symptomatic burden and benefit from a GFD. This study endorses the recommendation of D1 sampling as part of the endoscopic coeliac disease diagnostic workup.

Evaluating CD4 and Foxp3 mRNA Expression in Tissue Specimens of Celiac Disease and Colorectal Cancer Patients.

OBJECTIVE: Celiac disease (CD) and colorectal cancer (CRC) are distinct gastrointestinal conditions with a debated association. This study aimed to evaluate the mRNA expression of CD4 and Foxp3 in tissue specimens of CD and CRC patients. The findings can provide valuable insights into the complex connection between these different gastrointestinal conditions. METHODS: Tissue samples from 100 CRC patients, 50 CD patients, and 50 healthy controls (HCs) were collected. RNA extraction, cDNA synthesis, and quantitative real-time PCR were performed. Statistical analysis was conducted using ANOVA and Pearson's correlation test. RESULT: CD4 mRNA expression was significantly higher in CRC patients compared to CD patients and HCs (P<0.0001 for both). Foxp3 mRNA expression was significantly higher in CD patients compared to CRC patients and HCs (P<0.0001 for both). Clinicopathological characteristics did not correlate significantly with gene expression levels. CONCLUSION: This study reveals differential expression patterns of CD4 and Foxp3 mRNA in CRC and CD patients. Upregulated CD4 mRNA suggests its potential role in promoting tumor growth, while increased Foxp3 mRNA expression may reflect an immunosuppressive mechanism in CD pathogenesis. These findings provide insights into the molecular and immunological aspects of CRC and CD, warranting further studies for potential therapeutic strategies.

Metabolomics and lipidomics signature in celiac disease: a narrative review.

Celiac disease (CD) is a chronic immune-mediated inflammatory disease of the small intestine caused by aberrant immune responses to consumed gluten proteins. CD is diagnosed by a combination of the patients reported symptoms, serologic and endoscopic biopsy evaluation of the small intestine; and adherence to a strict gluten-free diet (GFD) is considered the only available therapeutic approach for this disorder. Novel approaches need to be considered for finding new biomarkers to help this disorder diagnosis and finding a new alternative therapeutic method for this group of patients. Metabolomics and lipidomics are powerful tools to provide highly accurate and sensitive biomarkers. Previous studies indicated a metabolic fingerprint for CD deriving from alterations in gut microflora or intestinal permeability, malabsorption, and energy metabolism. Moreover, since CD is characterized by increased intestinal permeability and due to the importance of membrane lipid components in controlling barrier integrity, conducting lipidomics studies in this disorder is of great importance. In the current study, we tried to provide a critical overview of metabolomic and lipidomic changes in CD.

Alterations in the gut microbiota and their metabolites in human intestinal epithelial cells of patients with colorectal cancer.

BACKGROUND: The gut microbiota has become one of the main risk factors for the formation and development of colorectal cancer (CRC). CRC intensification may be due to the microbial pathogens' colonization and their released metabolites. Here, we analyzed Bacteroidetes and Clostridia bacteria in CRC patients and studied bacterial metabolome in cancerous tissues compared to their adjacent normal tissues. METHODS AND RESULTS: The population of selected bacteria in biopsy specimens of 30 patients with CRC was studied by RT-qPCR. The mutagenicity and cytotoxicity effects of microbiota metabolites were evaluated by Ames test and MTT Assay, respectively. Moreover, gene expression in carcinogenic pathways was studied by RT-qPCR, and genes with different expressions in tumor and non-tumor tissues were diagnosed. Based on microbiota analysis, the relative abundance of Clostridia and C. difficile was significantly higher in CRC tissue, whereas C. perfringens showed higher relative abundance in normal tissue. AIMES test confirmed the proliferation and mutagenicity effects of the bacterial metabolites in CRC patients. Significant upregulation of C-Myc, GRB2, IL-8, EGFR, PI3K, and AKT and downregulation of ATM were observed in CRC samples compared to the control. CONCLUSIONS: The influence of bacterial metabolites on inflammation and altered expression of genes in the cell signaling pathways was observed. The findings confirm the role gut microbiota composition and bacterial metabolites as key players in CRC onset and development.

Intestinal mRNA expression analysis of polarity-related genes identified the discriminatory ability of CRB3 as a diagnostic marker for celiac disease.

BACKGROUND: Celiac disease (CD) is a chronic autoimmune disorder characterized by an abnormal immune response to gluten, a protein found in wheat, barley, and rye. It is well established that the integrity of epithelial tight junctions (TJs) and adherens junctions (AJs) plays a crucial role in the pathogenesis of CD. These junctional complexes contribute to the apical-basal polarity of the intestinal epithelial cells, which is crucial for their proper functioning. METHODS: Sixty CD subjects, and 50 controls were enrolled in the current study. Mucosal samples were obtained from the distal duodenum, total RNA was extracted and complementary DNA was synthesized. The relative expression levels of the desired genes were evaluated by quantitative real-time polymerase chain reaction based on ΔΔCt method. The gene-gene interaction network was also constructed using GeneMANIA. RESULTS: CRB3 (p = .0005), LKB1 (p < .0001), and SCRIB (p = .0005) had lower expression in CD patients compared to controls, while PRKCZ expression did not differ between groups (p > .05). CRB3 represented a significant diagnostic value for differentiating CD patients from the control group (p = .02). CONCLUSION: The aim of the current study was to evaluate the changes in the mRNA expression levels of SCRIB, PRKCZ, LKB1, and CRB3 genes in the small intestinal biopsy samples of CD patients in comparison to the healthy control subjects. Our data uncover the importance of polarity-related genes (especially CRB3) in CD pahtomechanism, that may facilitate the planning of the future studies looking for finding innovative diagnostic and therapeutic strategies for CD.

Investigating the Impact of Vitamin A and Amino Acids on Immune Responses in Celiac Disease Patients.

Amino acids (AAs) and vitamin imbalances are observed in celiac disease (CD). This study evaluated the plasma profile of vitamin A and AAs and the expression level of IL-2, IL-4, IL-10, IL-12 and TGFß in CD patients. A total of 60 children and adults with CD and 40 healthy controls (HCs) were included. The plasma profile of Vitamin A and AAs and the mRNA expression levels of target genes were assessed. Active adult patients exhibited a decrease in Vitamin A levels (p = 0.04) and an increase in IL-2 (p = 0.008) and IL-12 (p = 0.007) mRNA expression compared to the HCs. The treated adult patients showed elevated Serine (p = 0.003) and Glycine (p = 0.04) levels, as well as increased IL-12 (p < 0.0001) mRNA expression, and a decrease in Tryptophan (p = 0.04) levels relative to the controls. Additionally, the treated adult patients had higher plasma levels of Threonine compared to both the active (p = 0.04) and control (p = 0.02) subjects, and the increased mRNA expression of IL-4 (p = 0.01) in comparison to the active patients. In active children with CD, the IL-2 mRNA level was found to be higher than in the controls (p < 0.0001) and in the treated children (p = 0.005). The treated children with CD exhibited decreased plasma levels of Tryptophan (p = 0.01) and Isoleucine (p = 0.01) relative to the controls, and the increased mRNA expression of TGFß (p = 0.04) relative to the active patients. Elevated levels of specific AAs (Serine, Glycine, Threonine) in the treated CD patients suggested their potential to improve intestinal damage and inflammation, while decreased levels of Tryptophan and Isoleucine highlighted the need for dietary intervention.

Overview of the compromised mucosal integrity in celiac disease.

Intestinal epithelium is a dynamic cellular layer that lines the small-bowel and makes a relatively impenetrable barrier to macromolecules. Intestinal epithelial cell polarity is crucial in coordinating signalling pathways within cells and mainly regulated by three conserved polarity protein complexes, the Crumbs (Crb) complex, partitioning defective (PAR) complex, and Scribble (Scrib) complex. Polarity proteins regulate the proper establishment of the intercellular junctional complexes including tight junctions (TJs), adherence junctions (AJs), and desmosomes which hold epithelial cells together and play a major role in maintaining intestinal barrier integrity. Impaired intestinal epithelial cell polarity and barrier integrity result in irreversible immune responses, the host- microbial imbalance and intestinal inflammatory disorders. Disassembling the epithelial tight junction and augmented paracellular permeability is a conspicuous hallmark of celiac disease (CD) pathogenesis. There are several dietary components that can improve intestinal integrity and function. The aim of this review article is to summarize current information about the association of polarity proteins and AJC damages with pathogenesis of CD.

Introducing Critical Genes in Response to Photodynamic Therapy: A Network Analysis.

Introduction: Photodynamic therapy (PDT) is applied as an efficient method for preventing the progress of cancers. Light and a photosensitive compound which is known as photosensitizer (PS) are the main parts of PDT. In the present study, molecular events after using PDT in the presence of a super lethal dose of a PS were assessed via protein-protein interaction (PPI) analysis. Methods: Data were extracted from Gene Expression Omnibus (GEO). The gene expression profiles of the treated human Sk-Cha1 cells via PDT were compared with the control cells. Expressed change analysis and PPI network analysis were administrated via Cytoscape software v 3.7.2 to find the critical differentially expressed genes (DEGs). Regulatory relationships between the central DEGs were evaluated and the highlighted genes were identified. Results: The significant amounts of gene expression values were grouped and a few DEGs characterized by tremendously expressed values were identified. EGFR, CANX, HSPA5, MYC, JUN, ITGB1, APP, and CDH1 were highlighted as hub-bottleneck DEGs. EGFR, CDH1, and JUN appeared as a set of SEGs, which play a crucial role in response to PDT in the treated Sk-Cha1 cells. Conclusion: In conclusion, regulatory relationships between EGFR, CDH1, and JUN, which have an effect on the regulation of cellular survival, differentiation, and proliferation, were highlighted in the present investigation.

Long and Short-terms Effects of Ablative Fractional Laser Therapy on Human Skin: A Network Analysis.

Introduction: Time-dependent effects of laser radiation have been investigated by researchers. An understanding of the molecular mechanism of the time course effect of the laser needs molecular assessment and function evaluation of the related genes. In the present study, the importance of repetition of treatment after 4 weeks and gene expression alteration after 7 days of laser radiation versus one day on the human skin was evaluated via protein-protein interaction (PPI) network analysis and gene ontology enrichment. Methods: The differentially expressed genes (DEGs) were extracted from Gene Expression Omnibus (GEO) and assessed via PPI network analysis. The critical DEGs were enriched via gene ontology. The related biological processes and biochemical pathways were retrieved from "GO-Biological process" and "Kyoto Encyclopedia of Genes and Genomes" (KEGG) respectively. Results: The repetition of laser therapy after 4 weeks of the first treatment did not have a significant effect on treatment efficacy. Sixty-three significant DEGs and six classes of biological terms discriminated the samples seven days after the treatment from individuals one day after the treatment. The studied DEGs were organized into two clusters with certain functions. Conclusion: Based on the findings after laser therapy, several days are required to complete the critical processes such as DNA biosynthesis and skin cornification.

Impact of probiotics on gut microbiota composition and clinical symptoms of coeliac disease patients following gluten-free diet.

Coeliac disease (CD) is associated with alterations in gut microbiota composition. This study evaluated the effects of probiotics on gut microbiota composition and clinical symptoms of treated CD patients. In this double-blind, placebo-controlled trial study, 31 CD patients that were randomly classified as probiotics (n = 15) and placebo (n = 16) groups received 109 colony-forming units/capsule for 12 weeks. Fecal samples were collected before and after probiotics, or placebo administration and the changes in intestinal microbiota were assessed by quantitative real-time PCR. Probiotic administration improved the patients' clinical symptoms when compared to the placebo group. Fatigue score was significantly reduced by the intake of probiotic supplements (P = 0.02). Except for Staphylococcus spp., the relative abundances of Bacteroidetes, Lactobacillus spp., Bifidobacterium spp., Clostridium cluster I, Enterobacteriaceae, and Firmicutes were higher in probiotics group. Accordingly, a 12-week multi-strain probiotic treatment regimen may modify the composition of intestinal microbiota and improve GI symptoms in CD patients.

Long non-coding RNAs ANRIL, THRIL, and NEAT1 as potential circulating biomarkers of SARS-CoV-2 infection and disease severity.

The current outbreak of coronavirus disease 2019 (COVID-19) is a global emergency, as its rapid spread and high mortality rate, which poses a significant threat to public health. Innate immunity plays a crucial role in the primary defense against infections, and recent studies have highlighted the pivotal regulatory function of long non-coding RNAs (lncRNAs) in innate immune responses. This study aims to assess the circulating levels of lncRNAs namely ANRIL, THRIL, NEAT1, and MALAT1 in the blood of moderate and severe SARS-CoV-2 infected patients, in comparison to healthy individuals. Additionally, it aims to explore the potential of these lncRNAs as biomarkers for determining the severity of the disease. The blood samples were collected from a total of 38 moderate and 25 severe COVID-19 patients, along with 30 healthy controls. The total RNA was extracted and qPCR was performed to evaluate the blood levels of the lncRNAs. The results indicate significantly higher expression levels of lncRNAs ANRIL and THRIL in severe patients when compared to moderate patients (P value = 0.0307, P value = 0.0059, respectively). Moreover, the expression levels of lncRNAs ANRIL and THRIL were significantly up-regulated in both moderate and severe patients in comparison to the control group (P value < 0.001, P value < 0.001, P value = 0.001, P value < 0.001, respectively). The expression levels of lncRNA NEAT1 were found to be significantly higher in both moderate and severe COVID-19 patients compared to the healthy group (P value < 0.001, P value < 0.001, respectively), and there was no significant difference in the expression levels of NEAT1 between moderate and severe patients (P value = 0.6979). The expression levels of MALAT1 in moderate and severe patients did not exhibit a significant difference compared to the control group (P value = 0.677, P value = 0.764, respectively). Furthermore, the discriminative power of ANRIL and THRIL was significantly higher in the severe patient group than the moderate group (Area under curve (AUC) = 0.6879; P-value = 0.0122, AUC = 0.6947; P-value = 0.0093, respectively). In conclusion, the expression levels of the lncRNAs ANRIL and THRIL are correlated with the severity of COVID-19 and can be regarded as circulating biomarkers for disease progression.

Relationship between anxiety and quality of life in the presence of other factors in adult celiac patients; a nationwide study.

Aim: This study aimed to detect relationships among quality of life (QoL) and anxiety and demographic factors in patients with celiac disease (CD). Background: CD is a type of autoimmune small intestine diseases caused by gluten ingestion. In Iran, the prevalence of CD is considered to be 1% in the general population. As physical problems and behavioral disorders of CD can lead to a reduction in QoL. Methods: This cross-sectional study was performed on 533 patients with Celiac Disease from 9 cities of Iran. Data collected were analyzed by SPSS version 22. Quality of life and anxiety respectively evaluated by (GHQ-28) and SAS questionnaires. Predictors of quality of life (sex, age, age of diagnosis, city of life, education level, family history of celiac, occupation and anxiety) were tested by multiple linear regression. Results: Our results showed a significant relationship between poor quality of life and anxiety (correlation= -0.143, P=0.001). The mean of the quality of life index in celiac diseases was 126.2±30.4 and women had a lower quality of life than men (P=0.003) importantly in emotions and worries scores. There was no significant difference between male and female in terms of anxiety level. Conclusion: According to the results, both quality of life and anxiety correlated together and women seem to suffer more than men from celiac disease. Therefore, greater attention to women who have celiac disease are suggested.

Evaluating Serum Proteome in Women with Obsessive-Compulsive Disorder/Bipolar Disorder Compared to Pure Obsessive- Compulsive Disorder Subjects and Healthy Controls.

Objectives: The present study aimed to evaluate the serum proteome of women with obsessive-compulsive disorder (OCD)/bipolar disorder (BP) compared to pure OCD subjects and healthy controls. Materials & Methods: Serum proteome of women with OCD/BP, pure OCD individuals, and healthy controls were subjected to 2DE-based proteomics accompanied with MALDI-TOF-TOF mass spectrometry. Further evaluation of the identified protein spots with the significance of p<0.05 and fold≥1.5 was done by applying protein interaction mapping via Cytoscape v. 5.3.1 and its plugins. Results: The results indicate that vitamin D binding protein (GC) and haptoglobin spots (HP) significantly changed expression in OCD and OCD/BP with different expression patterns. These identified spots may contribute to OCD/BP and act as differentially recognized biomarkers comparing pure OCD and OCD/BP. Conclusion: The Findings imply that these proteins in the serum of the patients could be potential distinguishable biomarkers in clinical usage after related validation experiments. Therefore, this study provides a preliminary evaluation to understand OCD/BP proteome behavior better.

The Gliadin Hydrolysis Capacity of B. longum, L. acidophilus, and L. plantarum and Their Protective Effects on Caco-2 Cells against Gliadin-Induced Inflammatory Responses.

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-ß 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-ß (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.

Expression analysis of IL-2, TBX21 and SOCS1 in peripheral blood cells of celiac disease patients reveals the diagnostic potential of IL-2.

BACKGROUND: Celiac disease (CD) is a chronic immune-mediated enteropathy and a cytokine network is involved in its pathogenesis. Interleukin-2 (IL-2) has a key role in the adaptive immune pathogenesis of CD and has been reported to be one of the earliest cytokines to be elicited after gluten exposure by CD patients. This study aimed at investigating the expression level of IL-2 and functionally related genes SOCS1 and TBX21 in active and treated CD patients compared to controls. METHODS AND RESULTS: Peripheral blood (PB) samples were collected from 40 active CD (ACD), 100 treated CD, and 100 healthy subjects. RNA was extracted, cDNA was synthesized and mRNA expression levels of the desired genes were investigated by Real-time PCR. The gene-gene interaction network was also constructed by GeneMANIA. Our results showed a higher PB mRNA expression of IL-2 in ACD patients compared to controls (p = 0.001) and treated CD patients (p˂0.0001). The mRNA expression level of TBX21 was also significantly up-regulated in ACD patients compared to controls (P = 0.03). SOCS1 mRNA level did not differ between active and treated CD patients and controls (p˃0.05) but showed a significant correlation with the patient's aphthous stomatitis symptom (r = 0.37, p = 0.01). ROC curve analysis suggested that the use of IL-2 levels can reach a high specificity and sensitivity in discriminating active CD patients. CONCLUSIONS: The PB level of IL-2 has the potential to be introduced as a diagnostic biomarker for CD. Larger cohort studies, including pediatric patients, are needed to achieve more insights in this regard.

Systematic Review and Dose-Response Meta-Analysis on the Relationship between Different Gluten Doses and Risk of Coeliac Disease Relapse.

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.