Pathogenesis Of Celiac Disease Research Articles

FOXP3 expression in duodenal mucosa: Unique role in pathogenesis and differential diagnosis of celiac disease

Forkhead box protein P3 (FOXP3) positive regulatory T lymphocytes are indispensable in the inflammatory homeostasis of the gastrointestinal tract and represent a significant subset of regulatory cells in inflammatory, autoimmune, and neoplastic conditions. This study aimed to elucidate the potential of FOXP3 expression in diagnosing and pathogenesis of celiac disease (CD) by comparing duodenal biopsies of CD cases with non-CD ones, some of which had increased intraepithelial lymphocytes (IELs). Two hundred sixty-one duodenal tissues of patients who applied to adult gastroenterology were reevaluated for immunohistochemical analysis. After excluding patients on a gluten-free diet (n = 44), the CD (n = 97) and non-CD (n = 120) groups were divided based on clinical complaints that could be associated with CD (intestinal or extraintestinal), serologic and histologic findings. The specific threshold was determined by receiver operating characteristic (ROC) analysis, and its relationship with CD diagnosis and clinicopathological data was evaluated. ROC analysis offered a “>14” cut-off value for diagnosing CD, for which AUC (Area Under The Curve): 0.968, p < 0.0001, sensitivity: 92.8, specificity: 91.7, positive and negative predictive values were 90 % and 94 %, respectively. High FOXP3 expression was associated with higher IEL, diagnosis of CD, more severe histologic (higher Marsh score) and endoscopic (scalloping) findings, and higher anti-tissue transglutaminase and anti-endomysium IgA titers (p < 0.001). It also correlates with IEL in CD patients and is unaffected by the increase in IEL and the presence of gastric Helicobacter Pylori in the non-CD group. FOXP3 is a sensitive and specific marker for diagnosing CD despite inflammatory conditions resulting from non-CD causes.

Risk of celiac disease autoimmunity is modified by interactions between CD247 and environmental exposures

Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March–August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3–6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease. ClinicalTrials.gov Identifier: NCT00279318.

Coeliac Disease in Children—A Clinical Review Including Novel Treatment Agents

Coeliac disease (CD) affects almost of 1% of the population, yet remains undiagnosed in the majority. Though the demonstration of enteropathy in duodenal biopsy was traditionally the essential criterion for the diagnosis of coeliac disease, the guidelines published by the European Society of Paediatric Gastroenterology and Nutrition (ESPGHAN) in 2012, and revised in 2020, paved the way to a no-biopsy approach to diagnosis. In a select group of children meeting certain criteria, a definitive diagnosis of CD can now be made without the need for duodenal biopsies. This is being increasingly applied in clinical practice. It is well established that untreated coeliac disease is associated with several chronic adverse health conditions. At present, a strict gluten-free diet remains the only effective treatment for CD. The advances in our understanding of the pathogenesis of CD have led to a search for alternative treatment agents. Several investigational agents are in various phases of clinical trials at present. In this review, we outline the clinical aspects of coeliac disease and summarise various investigational treatment agents.

The Role of Macrophages in the Pathogenesis of Celiac Disease

Aim: to present data on the involvement of macrophages in the pathogenesis of celiac disease and the development of possible treatment methods for this disease aimed at changing the function of macrophages.Key points. Celiac disease is an autoimmune disease with a characteristic serological (antibodies to tissue transglutaminase, endomysium, deamidated gliadin peptides) and histological profile (inflammatory infiltration of the villous epithelium by lymphocytes and their atrophy, crypt hyperplasia) caused by gluten consumption in genetically predisposed individuals. Macrophages, as key cells that provide a link between innate and adaptive immunity, are of significant importance in the pathogenesis of celiac disease. Gliadin peptides stimulate the activation of macrophages according to the proinflammatory phenotype with the production of cytokines, which causes the immune response of T-helpers 1 and T-helpers 17. The result of these processes is the development of an inflammatory reaction and damage to the intestinal mucosa due to the production of matrix metalloproteinases and reactive oxygen species by macrophages. Therapeutic tactics for celiac disease today include a gluten-free diet, which is not so easy to follow. Of interest is the study of the possibility of using polyphenols in celiac disease, which are capable of precipitating gliadins and inhibiting the polarization of macrophages towards a proinflammatory phenotype, while simultaneously stimulating an increase in the population of macrophages of an anti-inflammatory phenotype associated with a decrease in tissue damage.Conclusion. Impaired macrophage function/differentiation results in either inadequate, excessive immune activation or failure to mount effective protective immune responses against pathogens, which may result in the development of gastrointestinal diseases. Studying the involvement of macrophages at different stages of celiac disease progression is important for the development of new treatments for this disease.

Comparison of the activity of IL-6 and IL22 as more inflammatory cytokines related to the pathogenesis of celiac disease between active and gluten-free diet patient

This study aimed to investigate the activity of anti-inflammatory IL-6 (aIL-6) and pro-regenerative IL-22 in celiac disease patients based on their dietary habits. By comparing cytokine levels between patients on active gluten-containing diets and those on gluten-free diets, we sought to elucidate the potential role of diet in modulating inflammatory responses and clinical outcomes in celiac disease. The study made use of an enzyme-linked immunosorbent assay (ELISA) to evaluate the serum levels of interleukins IL6 and IL22. This was performed on three different groups: Group 1, which consisted of 40 recently identified active celiac patients; Group 2, which included 20 patients following a gluten-free diet; and Group 3, which contained 40 apparently healthy individuals .the individuals included in the study had been previously confirmed as celiac patients through serology, specifically by detecting both anti-IgA and IgG antibodies against tTG and gliadin using indirect immunofluorescence. The findings revealed a notable difference in IL6 levels between the patient and control groups, with a P-value of 0.041. However, when the patient groups were compared using the least significant difference (LSD) method, there were no significant differences between Group 1 (G1) and Group 2 (G2) with a P-value of 0.101, and between Group 1 and Group 3 (G3) with a P-value of 0.720. Yet, a more pronounced difference was observed between Group2 and Group3,with a P-value less than 0.015.Regarding IL22 levels, there was a significant difference between the patient and control groups, with a P-value of 0.002. Further comparisons using the LSD method revealed no significant differences between Group 1 and Group 2, with a P-value less than 0.154. However, a highly significant difference was found between Group 1 and Group 3, with a P-value less than 0.01. Also, significant differences were observed between Group 2 and Group 3, with a P-value less than 0.012. In conclusion, there is important role of the inflammatory cytokines il-6 and il-22 in the inflammation of celiac disease and potential role for these cytokines in the pathogenesis and management of the disease. Adherence to a gluten-free diet appears to have a beneficial effect on modulating the inflammatory response and improving clinical outcomes in celiac disease..

Comparison of the Activity of IL-6 and IL22 as More Inflammatory Cytokines Related to the Pathogenesis of celiac Disease Between Active and Gluten-Free Diet Patient

This study aimed to investigate the activity of anti-inflammatory IL-6 (aIL-6) and pro-regenerative IL-22 in celiac disease patients based on their dietary habits. By comparing cytokine levels between patients on active gluten-containing diets and those on gluten-free diets, we sought to elucidate the potential role of diet in modulating inflammatory responses and clinical outcomes in celiac disease. The study made use of an enzyme-linked immunosorbent assay (ELISA) to evaluate the serum levels of interleukins IL6 and IL22. This was performed on three different groups: Group 1, which consisted of 40 recently identified active celiac patients; Group 2, which included 20 patients following a gluten-free diet; and Group 3, which contained 40 apparently healthy individuals .the individuals included in the study had been previously confirmed as celiac patients through serology, specifically by detecting both anti-IgA and IgG antibodies against tTG and gliadin using indirect immunofluorescence. The findings revealed a notable difference in IL6 levels between the patient and control groups, with a P-value of 0.041. However, when the patient groups were compared using the least significant difference (LSD) method, there were no significant differences between Group 1 (G1) and Group 2 (G2) with a P-value of 0.101, and between Group 1 and Group 3 (G3) with a P-value of 0.720. Yet, a more pronounced difference was observed between Group2 and Group3,with a P-value less than 0.015.Regarding IL22 levels, there was a significant difference between the patient and control groups, with a P-value of 0.002. Further comparisons using the LSD method revealed no significant differences between Group 1 and Group 2, with a P-value less than 0.154. However, a highly significant difference was found between Group 1 and Group 3, with a P-value less than 0.01. Also, significant differences were observed between Group 2 and Group 3, with a P-value less than 0.012. In conclusion, there is important role of the inflammatory cytokines il-6 and il-22 in the inflammation of celiac disease and potential role for these cytokines in the pathogenesis and management of the disease. Adherence to a gluten-free diet appears to have a beneficial effect on modulating the inflammatory response and improving clinical outcomes in celiac disease.

The Role of Viruses in Celiac Disease Pathogenesis: Current Status

The purpose of this review is to present modern data on the correlations between viruses and celiac disease. Some viruses probably have crucial role in celiac disease pathogenesis according to the results of recent studies. However, the virus exposure itself does not lead to the development of autoimmune disease. Number of studies have demonstrated that there are several viruses that can cause celiac disease, and several activation pathways leading to food tolerance loss. Thus far, the role of some reoviruses strains has been proven in the development of celiac disease. Further research is needed for better understanding of the viruses role in the celiac disease development and to improve management and prevention of this disease.

Assessment of the contribution of VDR and VDBP/GC genes in the pathogenesis of celiac disease

Assessment of the contribution of VDR and VDBP/GC genes in the pathogenesis of celiac disease

Expression of MicroRNAs in Adults with Celiac Disease: A Narrative Review.

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of proline- and glutamine-rich proteins, widely termed "gluten", in genetically susceptible individuals. CD induces an altered immune response that leads to chronic inflammation and duodenal mucosal damage. Currently, there are no specific tests for the accurate diagnosis of CD, and no drugs are available to treat this condition. The only available treatment strategy is lifelong adherence to a gluten-free diet. However, some studies have investigated the involvement of microRNAs (miRNAs) in CD pathogenesis. miRNAs are small noncoding ribonucleic acid molecules that regulate gene expression. Despite the growing number of studies on the role of miRNAs in autoimmune disorders, data on miRNAs and CD are scarce. Therefore, this study aimed to perform a literature review to summarize CD, miRNAs, and the potential interactions between miRNAs and CD in adults. This review shows that miRNA expression can suppress or stimulate pathways related to CD pathogenesis by regulating cell proliferation and differentiation, regulatory T-cell development, innate immune response, activation of the inflammatory cascade, focal adhesion, T-cell commitment, tissue transglutaminase synthesis, and cell cycle. Thus, identifying miRNAs and their related effects on CD could open new possibilities for diagnosis, prognosis, and follow-up of biomarkers.

Biological variability of human intraepithelial lymphocytes throughout the human gastrointestinal tract in health and coeliac disease.

Intraepithelial lymphocytes are the first line of defence of the human intestinal immune system. Besides, their composition is altered on patients with coeliac disease (CD), so they are considered as biomarkers with utility on their diagnose and/or monitoring. Our aim is to address their variability through the human gastrointestinal tract in health and characterized them in further depth in the coeliac duodenum. Intraepithelial lymphocytes were isolated from human gastric, duodenal, ileal and colonic biopsies, then stained with specific antibodies and acquired by flow cytometry. Our results confirmed that the profile of Intraepithelial lymphocytes change through the length of the human gastrointestinal tract. Besides and given the central role that Interleukin-15 (IL-15) elicits on CD pathogenesis; we also assessed the expression of its receptor revealing that there was virtually no functional IL-15 receptor on duodenal Intraepithelial lymphocytes. Nevertheless and contrary to our expectations, the active IL-15 receptor was not increased either on Intraepithelial lymphocytes from CD patients. IL-15 might require additional stimulus to activate intraepithelial lymphocytes. These findings may provide novel tools to aid on a CD diagnosis and/or monitoring, at the time that provide the bases to perform functional studies in order of getting a deeper insight in the specific function that Intraepithelial lymphocytes elicit on CD pathogenesis.

The role of tryptophan metabolism and tolerogenic dendritic cells in maintaining immune tolerance: Insights into celiac disease pathogenesis.

In mammals, amino acid metabolism has evolved to control immune responses. Tryptophan (Trp) is the rarest essential amino acid found in food and its metabolism has evolved to be a primary regulatory node in the control of immune responses. Celiac disease (CeD) is a developed immunological condition caused by gluten intolerance and is linked to chronic small intestine enteropathy in genetically predisposed individuals. Dendritic cells (DCs), serving as the bridge between innate and adaptive immunities, can influence immunological responses in CeD through phenotypic alterations. This review aims to highlight the connection between Trp metabolism and tolerogenic DCs, and the significance of this interaction in the pathogenesis of CeD. It is been recognized that various DC subtypes contribute to the pathogenesis of CeD. Tolerogenic DCs, in particular, are instrumental in inducing immune tolerance, leading to T-reg differentiation that helps maintain intestinal immune tolerance against inflammatory responses in CeD patients and those with other autoimmune disorders. T-regs, a subset of T-cells, play a crucial role in maintaining intestinal immunological homeostasis by regulating the activities of other immune cells. Notably, Trp metabolism, essential for T-reg function, facilitates T-reg differentiation through microbiota-mediated degradation and the kynurenine pathway. Therefore, alterations in Trp metabolism could potentially influence the immune response in CeD, affecting both the development of the disease and the persistence of symptoms despite adherence to a gluten-free diet.

Circulating MicroRNAs and Cytokines Associated with Celiac Disease.

The current research examines the molecular terrain of celiac disease (CD) through microRNA (miRNA) and cytokines as potential new diagnostic and therapeutic markers. Gluten-appropriate immune response is a key feature of an autoimmune clinical entity known as CD that leads to inflammation and degeneration of small intestine mucosa. However, the mechanisms responsible for this remain unclear. Quantitative reverse transcription polymerase chain reaction (RT-qPCR ) was carried out on serum samples obtained from patients with CD and control groups to unravel their pathogenesis. Assessing miR-155, miR-15b, interleukin (IL)-2, IL-7, IL-35and IL-37 levels in expression might be useful in diagnosing or treating the disorder. A significant dysregulation of these molecular players in patients with CD compared with healthy controls has been evidenced by results from this study. For instance, miR-155 was up-regulated, whereas miR-15b was significantly down-regulated in CD, illustrating their roles in immune responses and inflammation-mediated processes. Besides, there was an over-expression of IL-2 and an under-expression of IL-37 in patients with CD, indicating these biomolecules' role in immuno-dysregulation and inflammatory process underlying CD. In addition, a positive correlation between IL-2 and miRNA 155 expression levels was observed in patients with CD, suggesting that they could be involved together with other cytokines, showing the interplay between immune response pathways and inflammatory cascades during CD pathogenesis. These molecular signature discoveries might result in new and revolutionary diagnostic modalities and molecular-targeted therapies for CD pathogenesis. When used with the scientific understanding of miRNAs and cytokines associated with CD pathophysiology, it creates a basis for personalized medicine based on the individualized molecular profile of all patients. This will undoubtedly increase the efficacy of CD treatment strategies. In brief, more research on molecular pathways' workings should be done to harness their potential in CD diagnosis and treatment.

Transcriptomic analysis of intestine following administration of a transglutaminase 2 inhibitor to prevent gluten-induced intestinal damage in celiac disease

Transglutaminase 2 (TG2) plays a pivotal role in the pathogenesis of celiac disease (CeD) by deamidating dietary gluten peptides, which facilitates antigenic presentation and a strong anti-gluten T cell response. Here, we elucidate the molecular mechanisms underlying the efficacy of the TG2 inhibitor ZED1227 by performing transcriptional analysis of duodenal biopsies from individuals with CeD on a long-term gluten-free diet before and after a 6-week gluten challenge combined with 100 mg per day ZED1227 or placebo. At the transcriptome level, orally administered ZED1227 effectively prevented gluten-induced intestinal damage and inflammation, providing molecular-level evidence that TG2 inhibition is an effective strategy for treating CeD. ZED1227 treatment preserved transcriptome signatures associated with mucosal morphology, inflammation, cell differentiation and nutrient absorption to the level of the gluten-free diet group. Nearly half of the gluten-induced gene expression changes in CeD were associated with the epithelial interferon-γ response. Moreover, data suggest that deamidated gluten-induced adaptive immunity is a sufficient step to set the stage for CeD pathogenesis. Our results, with the limited sample size, also suggest that individuals with CeD might benefit from an HLA-DQ2/HLA-DQ8 stratification based on gene doses to maximally eliminate the interferon-γ-induced mucosal damage triggered by gluten.

A bispecific antibody targeting HLA-DQ2.5-gluten peptides potently blocks gluten-specific T cells induced by gluten ingestion in patients with celiac disease

The gluten-free diet for celiac disease (CeD) is restrictive and often fails to induce complete symptom and/or mucosal disease remission. Central to CeD pathogenesis is the gluten-specific CD4+ T cell that is restricted by HLA-DQ2.5 in over 85% of CeD patients, making HLA-DQ2.5 an attractive target for suppressing gluten-dependent immunity. Recently, a novel anti-HLA-DQ2.5 antibody that specifically recognizes the complexes of HLA-DQ2.5 and multiple gluten epitopes was developed (DONQ52). ObjectiveTo assess the ability of DONQ52 to inhibit CeD patient-derived T-cell responses to the most immunogenic gluten peptides that encompass immunodominant T cell epitopes. MethodsWe employed an in vivo gluten challenge model in patients with CeD that affords a quantitative readout of disease-relevant gluten-specific T-cell responses. HLA-DQ2.5+ CeD patients consumed food containing wheat, barley, or rye for 3 days with collection of blood before (D1) and 6 days after (D6) commencing the challenge. Peripheral blood mononuclear cells were isolated and assessed in an interferon (IFN)-γ enzyme-linked immunosorbent spot assay (ELISpot) testing responses to gluten peptides encompassing a series of immunodominant T cell epitopes. The inhibitory effect of DONQ52 (4 or 40 μg/mL) was assessed and compared to pan-HLA-DQ blockade (SPVL3 antibody). ResultsIn HLA-DQ2.5+ CeD patients, DONQ52 reduced T cell responses to all wheat gluten peptides to an equivalent or more effective degree than pan-HLA-DQ antibody blockade. It reduced T cell responses to a cocktail of the most immunodominant wheat epitopes by a median of 87% (IQR 72–92). Notably, DONQ52 also substantially reduced T-cell responses to dominant barley hordein and rye secalin derived peptides. DONQ52 had no effect on T-cell responses to non-gluten antigens. ConclusionDONQ52 can significantly block HLA-DQ2.5-restricted T cell responses to the most highly immunogenic gluten peptides in CeD. Our findings support in vitro data that DONQ52 displays selectivity and broad cross-reactivity against multiple gluten peptide:HLA-DQ2.5 complexes. This work provides proof-of-concept multi-specific antibody blockade has the potential to meaningfully inhibit pathogenic gluten-specific T-cell responses in CeD and supports ongoing therapeutic development.

The role of HLA-DQ8 and B cells on CD8 IEL activation in celiac disease pathogenesis

The role of HLA-DQ8 and B cells on CD8 IEL activation in celiac disease pathogenesis

A microbiota derived metabolite and pediatric celiac disease pathogenesis

Abstract Celiac Disease (CD) is an autoimmune condition triggered by gluten ingestion and defined by small intestine inflammation leading to villous atrophy in genetically predisposed individuals. 20-40% of the general population possess the predisposing HLA-DQ2 or HLA-DQ8 alleles, however only 1-2% of the population develops CD, indicating that there are additional environmental factors at play in the pathogenesis of the disease. In a prospective cohort study using fecal and plasma samples from children at ages 2.5 and 5 years, before the onset of celiac disease (CD progressors), we found that CD progressors have an altered gut microbiome, plasma metabolome and cytokine profile years before diagnosis. IgA sequencing revealed an increased IgA response and unique microbial targets of IgA. One metabolite increased in CD progressors is taurodeoxycholic acid (TDCA), a secondary bile acid produced by gut microbes. Treating C57BL/B6 mice with TDCA caused villous atrophy as well as upregulated CD4+T-cells in intraepithelial lymphocytes and natural killer cells in the lamina propria (LP). TDCA increased the expression of Qa-1 and NKG2D on T-cells. The DQ8-Dd-villin-IL-15tg mouse model of CD possesses the predisposing HLA-DQ8 molecule and overexpresses IL-15 in the LP. Treating these mice with TDCA caused the villi/crypt ratio to decrease in the treatment group of pooled villi. Our results indicate that TDCA and TDCA-producing bacteria could potentially contribute to the pathogenesis of CD.

Helicobacter pylori infection in pediatric patients with celiac disease: A single-center experience

Aim: There are numerous studies investigating the relationship between celiac disease (CD) and Helicobacter pylori (H. pylori). In this study, we aimed to compare the prevalence of coexisting H. pylori infection and CD in pediatric patients diagnosed with celiac disease at our clinic versus an age-matched control group. Materials and Methods: A total of 198 patients with celiac disease and 131 sex and age -matched controls undergoing upper gastrointestinal endoscopy due to dyspeptic complaints were included in this study. The prevalence of H. pylori was compared between the groups. Results: Of the 198 patients with CD included in the study, 66 (33.3%) were male and 132 (66.7%) were female, while in the control group, 36 (27.5%) were male, and 95 (72.5%) were female. 89 (44%) of the patients with CD and 70 (53.4%) of the controls were H. pylori-positive. There was no statistically significant difference in the distribution of Marsh scores between the H. pylori-negative and -positive groups. Conclusion: The association between celiac disease and H. pylori remains controversial. Thus, multicenter studies are warranted to evaluate the role of H. pylori in the pathogenesis of celiac disease.

How Future Pharmacologic Therapies for Celiac Disease Will Complement the Gluten-Free Diet

The only proven treatment for celiac disease is adherence to a strict, lifelong, gluten free diet. However, complete dietary gluten avoidance is challenging and a substantial number of patients do not respond fully, clinically or histologically, despite their best efforts. As celiac disease is common and its central pathophysiology is well elucidated, it has become attractive for drug development to address the limitations of dietary treatment. Most efforts address non-responsive celiac disease, defined as continued symptoms and/or signs of disease activity despite a gluten free diet, including the more severe forms of refractory celiac disease type 1 and 2. An increasing spectrum of therapeutic approaches target defined mechanisms in celiac disease pathogenesis, and some currently advance to phase 2-3 clinical studies. We discuss these approaches in terms of potential efficiency, practicability, safety and need as defined by patients, regulatory authorities, health care providers and payors.

Relationship between vitamin D levels and pediatric celiac disease: a systematic review and meta-analysis

BackgroundThe relationship between Vitamin D levels and pediatric celiac disease (CD) remains controversial. In this study, we conducted a systematic review and meta-analysis to examine the relationship between Vitamin D and pediatric CD. Methods: We screened relevant studies from PubMed, EMBASE, and Web of Science published in English from January 1, 2000, to August 1, 2023. The included studies were assessed according to the STROBE checklist. Heterogeneity was quantified by Cochran’s Q test and the I2 statistic. Publication bias was estimated by Begg’s test and Egger’s test. Meta‐regression was used to detect potential sources of heterogeneity. Results: A total of 26 studies were included in the meta-analysis. Nineteen articles compared 25(OH)D3 levels between CD patients and control groups, average 25-hydroxyvitamin D3 [25(OH)D3 or calcidiol], and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3 or calcitriol] levels, as the main forms of Vitamin D, there was a significant difference in CD patients and healthy controls (weighted mean difference (WMD) = − 5.77, 95% confidence interval (CI) = [− 10.86, − 0.69] nmol/L). Meanwhile, eleven articles reported the numbers of patients and controls with Vitamin D deficiency, there was a significant difference in the incidence of 25(OH)D3 deficiency between CD patients and healthy controls (odds ratio 2.20, 95% CI= [1.19, 4.08]). Nine articles reported changes in 25(OH)D3 levels before and after administering a GFD in patients with CD, the result of this study revealed the increase of 25(OH)D3 levels in CD patients after a gluten-free diet (GFD) (WMD = − 6.74, 95% CI = [− 9.78, − 3.70] nmol/L). Conclusions: Vitamin D levels in pediatric CD patients were lower than in healthy controls, and 25(OH)D3 deficiency was more prevalent in CD patients. We found that 25(OH)D3 levels were elevated in CD patients after GFD, which is consistent with previous research. Further well-designed, longitudinal, prospective cohort studies focusing on the role of Vitamin D in the pathogenesis of CD are therefore needed.

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

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. 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. 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). 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.