Development Of Celiac Disease Research Articles

Are there new biomarkers of the gastroduodenal microbiota useful in the diagnosis of coeliac disease in children? A pilot study.

The changing of microbiome could precede the development of coeliac disease (CeD). We compared the bacterial profile of microbiota of tissues collected simultaneously from the stomach and duodenum in newly diagnosed patients with CeD. Biopsies were collected from 60 children and adolescents aged 2-18 years: (1) 40 patients with CeD; (2) 20 children as control group. The evaluation of the bacterial microbiota was carried out by sequencing the V3-V4 regions of the 16S rRNA subunit, using next-generation sequencing (NGS). The composition of bacterial microbiota was correlated with clinical and blood parameters. The beta diversity analysis revealed a significant dissimilarity in the gastric samples between the CeD and control group (Bray-Curtis index, P= 0.008, and weighted UniFrac distance, P= 0.024). At L2 (phylum level), Campylobacterota was only present in the stomach of the CeD group. A comparison of the abundance of bacteria between the stomach and duodenum showed significant differences in 10 OTUs (operational taxonomic units) in the control and 9 OTUs in the CeD group at L6 (genus) and in 8 OTUs and in 6 OTUs, respectively, at L7 (species). A significant correlation was observed between the genus Novosphingobium in stomach of CeD group and possession of the DQ2.5 and DQ 8 allele, and in the duodenum- between the DQ 8 allele and the species Blautia wexlerae. Significant differences in selected, little-known genera of bacteria suggest their potential role as new biomarkers in the development of CeD. To fully understand the mechanism of CeD development in genetically predisposed individuals, it is necessary to take into account not only the abundance of a given genus or species of bacteria, but also the anatomical location of its occurrence.

Bacteria: Potential Make-or-Break Determinants of Celiac Disease.

Celiac disease is an autoimmune disease triggered by dietary gluten in genetically susceptible individuals that primarily affects the small intestinal mucosa. The sole treatment is a gluten-free diet that places a social and economic burden on patients and fails, in some, to lead to symptomatic or mucosal healing. Thus, an alternative treatment has long been sought after. Clinical studies on celiac disease have shown an association between the presence of certain microbes and disease outcomes. However, the mechanisms that underlie the effects of microbes in celiac disease remain unclear. Recent studies have employed disease models that have provided insights into disease mechanisms possibly mediated by bacteria in celiac disease. Here, we have reviewed the bacteria and related mechanisms identified so far that might protect from or incite the development of celiac disease. Evidence indicates bacteria play a role in celiac disease and it is worth continuing to explore this, particularly since few studies, to the best of our knowledge, have focused on establishing a mechanistic link between bacteria and celiac disease. Uncovering host-microbe interactions and their influence on host responses to gluten may enable the discovery of pathogenic targets and development of new therapeutic or preventive approaches.

Investigating the role of iron status in the development of coeliac disease: a Mendelian randomisation study

ObjectiveThe environmental trigger behind the increasing prevalence of coeliac disease is not known. One suggested cause is iron deficiency, which is common in coeliac disease. We aimed to evaluate this...

Non-Host Factors Influencing Onset and Severity of Celiac Disease

Celiac Disease (CeD) is a chronic autoimmune condition driven by gluten ingestion in genetically predisposed individuals, resulting in inflammatory lesions in the proximal small intestine. While the presence of specific human leukocyte antigen (HLA) linked haplotypes and gluten consumption are necessary for disease development, they alone do not account for the variable onset of CeD in susceptible individuals. This review explores the multifaceted role of non-host factors in CeD development, including dietary and microbial influences. We discuss clinical associations and observations highlighting the impact of these factors on disease onset and severity. Furthermore, we discuss studies in CeD-relevant animal models that offer mechanistic insights into how diet, the microbiome, and enteric infections modulate CeD pathogenesis. Finally, we address the clinical implications and therapeutic potential of understanding these cofactors, offering a promising avenue for preventive and therapeutic interventions in CeD management.

Bridging science and accessibility: a tactile journey from gluten through to coeliac disease.

As part of the Monash Sensory Science Exhibition, our team guided participants through a multisensory journey unraveling coeliac disease development and pathology. Through tactile and sensory exhibits, we showed how benign dietary gluten can be transformed into a harmful entity for the 1 in 70 Australians with this illness. In contrast to the common misconception of coeliac disease as a food allergy, our exhibits revealed its closer association with autoimmune diseases such as type 1 diabetes, involving genetic susceptibility linked to specific human leukocyte antigens, crucial antigen-specific T- and B-cell responses and autoantibody production. Tactile models underscored the severe consequences of the proinflammatory immune response to gluten on patient health and quality of life. This educational event affirmed to us the value and importance of fostering inclusivity in science education.

Zonulin as a Biomarker for the Development of Celiac Disease.

Increased intestinal permeability seems to be a key factor in the pathogenesis of autoimmune diseases, including celiac disease (CeD). However, it is unknown whether increased permeability precedes CeD onset. This study's objective was to determine whether intestinal permeability is altered before celiac disease autoimmunity (CDA) in at-risk children. We also examined whether environmental factors impacted zonulin, a widely used marker of gut permeability. We evaluated 102 children in the CDGEMM study from 2014-2022. We included 51 CDA cases and matched controls, who were enrolled for 12 months or more and consumed gluten. We measured serum zonulin from age 12 months to time of CDA onset, and the corresponding time point in controls, and examined clinical factors of interest. We ran a mixed-effects longitudinal model with dependent variable zonulin. Children who developed CDA had a significant increase in zonulin in the 18.3 months (range 6-78) preceding CDA compared to those without CDA (slope differential = β = 0.1277, 95% CI: 0.001, 0.255). Among metadata considered, zonulin trajectory was only influenced by increasing number of antibiotic courses, which increased the slope of trajectory of zonulin over time in CDA subjects (P = .04). Zonulin levels significantly rise in the months that precede CDA diagnosis. Exposure to a greater number of antibiotic courses was associated with an increase in zonulin levels in CDA subjects. This suggests zonulin may be used as a biomarker for preclinical CeD screening in at-risk children, and multiple antibiotic courses may increase their risk of CDA by increasing zonulin levels.

The Role of Gluten in Food Products and Dietary Restriction: Exploring the Potential for Restoring Immune Tolerance.

Wheat is extensively utilized in various processed foods due to unique proteins forming from the gluten network. The gluten network in food undergoes morphological and molecular structural changes during food processing, affecting the final quality and digestibility of the food. The present review introduces the formation of the gluten network and the role of gluten in the key steps of the production of several typical food products such as bread, pasta, and beer. Also, it summarizes the factors that affect the digestibility of gluten, considering that different processing conditions probably affect its structure and properties, contributing to an in-depth understanding of the digestion of gluten by the human body under various circumstances. Nevertheless, consumption of gluten protein may lead to the development of celiac disease (CD). The best way is theoretically proposed to prevent and treat CD by the inducement of oral tolerance, an immune non-response system formed by the interaction of oral food antigens with the intestinal immune system. This review proposes the restoration of oral tolerance in CD patients through adjunctive dietary therapy via gluten-encapsulated/modified dietary polyphenols. It will reduce the dietary restriction of gluten and help patients achieve a comprehensive dietary intake by better understanding the interactions between gluten and food-derived active products like polyphenols.

Trends in the prevalence rates and predictive factors of coeliac disease: A long-term nationwide follow-up study.

The prevalence of coeliac disease doubled in Finland from 1980 to 2000. To investigate whether this increase is continuing and if there are specific patient-related factors predicting the development of coeliac disease at a population level. We elicited comprehensive health data in the nationwide Health 2000 and Health 2011 surveys. Serum samples were taken for the measurement of tissue transglutaminase antibodies (TGA); subjects who were seropositive were tested for endomysial antibodies (EmA). Coeliac disease was defined either as a reported diagnosis or as positive TGA and EmA. The surveys comprised, respectively, 6379 and 4056 individuals, forming representative samples for 2,946,057 and 2,079,438 Finnish adults. Altogether 3254 individuals participating in both surveys comprised a prospective follow-up cohort. Prevalence of coeliac disease was 2.12% in 2000 and 2.40% in 2011 (p = 0.156). In the prospective cohort, 16 out of the 3254 (0.49%) subjects developed coeliac disease during follow-up from 2000 to 2011, with an annual incidence rate of 45 per 100,000 persons. Positive TGA without EmA (OR: 133, 95% CI: 30.3-584), TGA values in the upper normal range (51.1, 16.0-163), and after adjusting for TGA, previous autoimmune co-morbidity (8.39, 4.98-35.9) in 2000 increased the likelihood of subsequent coeliac disease. The nationwide prevalence of coeliac disease kept on rising from 2.12% in 2000 to 2.40% in 2011 in Finland. Positive TGA without EmA, TGA titres in the upper normal range and a pre-existing autoimmune disease predisposed to coeliac disease during the 10-year follow-up.

Early environmental risk factors and coeliac disease in adolescents: a population-based cohort study in Denmark

ObjectivesOur aim was to investigate the association between early environmental factors and the development of coeliac disease (CeD) in adolescents, recruited from a cohort nested in the Danish National Birth...

S3933 Development of Celiac Disease After Immunotherapy for Psoriasis, Breast Cancer, and Renal Cell Carcinoma: A Case Series

S3933 Development of Celiac Disease After Immunotherapy for Psoriasis, Breast Cancer, and Renal Cell Carcinoma: A Case Series

Atypical manifestation of celiac disease in carriers of HLA mutant gene

Annotation. Celiac disease is an autoimmune disease, which is manifested by enteropathy of the small intestine and is caused by the consumption of gluten-containing foods. According to statistics, the number of patients suffering from this disease has increased by 7.5% recently, which may be due to epigenetic factors and improvements in diagnostic methods of gluten intolerance. Human Leukocyte Antigen (HLA) gene plays a major role in the pathophysiological development of celiac disease. The function of HLA is an autoimmune response to endogenous and exogenous proteins. The pathogenesis of organ damage is based on an autoimmune reaction that occurs as a result of the entry of gliadin – the main component of gluten – into the organism. The influence of circulating immune complexes (CIC) leads to the appearance of typical and numerous atypical manifestations of the disease. This, in turn, significantly complicates the diagnosis and prescription of the correct treatment, which can ensure the restoration of the structure of the affected organs and improve the quality of life for patients. Atypical manifestations of gluten enteropathy are diverse, including chronic fatigue syndrome, damage to joints, bones, liver, male and female infertility, thyroid gland dysfunction, dermatitis, and tooth enamel structure disorders. Taking into account the importance of this issue, we conducted a systematic review and analysis of sources related to this question. The search was conducted in the scientometric databases PubMed, Google Scholar, Web of Science, Scopus, mostly over the last three years. In particular, it was found that screening for the specific HLA gene in first-degree relatives of patients with gluten enteropathy allows for an explanation of the exact etiology of possible atypical symptoms - manifestations of celiac disease, and subsequently prescribing a gluten-free diet that leads to the involution of the negative impact of the immune system on target organs. Moreover, this screening will be useful for identifying risk groups because manifestations of celiac disease could be in different ages and have different symptoms.

The Combined Effect of Infant and Mother Secretor Status on Infant Susceptibility to Viral Gastroenteritis and Celiac Disease

Celiac disease is a prevalent autoimmune disorder with a rising incidence of 7.5% annually during the second half of the 20<sup>th</sup> century and the 21<sup>st</sup> century. Not all genetically susceptible individuals that carry the risk alleles HLA DQ2 and DQ8 go on to develop celiac disease, suggesting that there may be other environmental triggers that contribute to the development of celiac disease in genetically susceptible individuals. Gastroenteritis during infancy has been shown to be associated with increased risk of celiac disease. Secretor status, per the FUT2 genotype, and subsequent alterations in the microbiota, is associated with risk of gastroenteritis in infants. This review investigates the literature from January 2010 to June 2022 to determine the combined effect of secretor status and viral gastroenteritis on the development of celiac disease.<strong> </strong>Mothers with the secretor phenotype and infants with the non-secretor phenotype provided the most protection against particular strains of gastroenteritis and celiac disease. Both the maternal and infant secretor status, as well as the infant’s Lewis status and ABO blood group can influence the infant’s susceptibility to different viral strains, which cause gastroenteritis. Gastroenteritis caused by viral infections can damage intestinal epithelial cells, cause dysbiosis, and affect pro-inflammatory cytokines, which exacerbate celiac disease onset. Understanding the effect of secretor status and gastroenteritis on celiac disease may provide a novel approach to early screening and preventative strategies to reduce risk factors that contribute to the onset of celiac disease.

The prevalence of having coeliac disease in children with type 1 diabetes was not significantly higher during the Swedish coeliac epidemic.

From 1986 to 1996, there was a four-fold increase in coeliac disease among young Swedish children, known as the Swedish coeliac epidemic. Children with type 1 diabetes have an increased risk of developing coeliac disease. We studied whether the prevalence of coeliac disease differed in children with type 1 diabetes born during and after this epidemic. We compared national birth cohorts of 240 844 children born in 1992-1993 during the coeliac disease epidemic and 179 530 children born in 1997-1998 after the epidemic. Children diagnosed with both type 1 diabetes and coeliac disease were identified by merging information from five national registers. There was no statistically significant difference in the prevalence of coeliac disease among children with type 1 diabetes between the two cohorts: 176/1642 (10.7%, 95% confidence interval 9.2%-12.2%) in the cohort born during the coeliac disease epidemic versus 161/1380 (11.7%, 95% confidence interval 10.0%-13.5%) in the post-epidemic cohort. The prevalence of having both coeliac disease and type 1 diabetes was not significantly higher in children born during, than after, the Swedish coeliac epidemic. This may support a stronger genetic disposition in children who develop both conditions.

Two-Sample Mendelian Randomization detects bidirectional causality between gut microbiota and celiac disease in individuals with high genetic risk.

Celiac Disease (CeD) is an autoimmune disorder triggered by gluten intake in genetically susceptible individuals. Highest risk individuals are homozygous for the Human Leucocyte Antigen (HLA) DQ2.5 haplotype or DQ2.5/DQ2.2 heterozygous. Both the HLA-DQ2-positive high genetic risk individuals and those that have developed the disease have altered intestinal microbiota, but it remains unclear whether these alterations are a cause or a consequence of CeD. To investigate a potential bidirectional causality between gut microbiota (GM) and CeD in HLA-DQ2 high genetic risk individuals. We performed a bidirectional Two-Sample Mendelian Randomization (2SMR) test using summary statistics from the largest publicly available Genome-Wide Association Study (GWAS) of GM and the summary statistics of the Immunochip CeD study of those individuals with the HLA-DQ2 high-risk haplotype. To test whether changes in GM composition were causally linked to CeD, GM data were used as exposure and CeD data as outcome; to test for reverse causation, the exposure and outcome datasets were inverted. We identified several bacteria from Ruminococcaceae and Lachnospiraceae families of the Firmicutes phylum as potentially causal in both directions. In addition, our results suggest that changes in the abundance of Veillonellaceae family might be causal in the development of CeD, while alterations in Pasteurellaceae family might be a consequence of the disease itself. Our results suggest that the relationship between GM and HLA-DQ2 high risk individuals is highly complex and bidirectional.

A gut commensal protist protects against virus-mediated loss of oral tolerance

Abstract Loss of oral tolerance (LOT) to gluten, characterized by a T helper 1 (Th1) gluten-specific immune response, is a hallmark of celiac disease (CeD) and can be triggered by enteric viral infections. We hypothesized that certain gut microbes have the capacity to protect against virus-mediated LOT. By using our previously defined reovirus-mediated LOT CeD model, we discovered that the gut colonizing protist Tritrichomonas promotes oral tolerance and protects against reovirus-mediated LOT by suppressing the reovirus-induced proinflammatory program of dietary-antigen-presenting CD103+ dendritic cells. Importantly, Tritrichomonas-mediated protection against T1L-induced LOT is not attributable to differences in antiviral host responses and is independent of the microbiota. Mechanistically, we show that Tritrichomonas colonization restrains reovirus-induced inflammatory responses in dendritic cells and thus limit their ability to promote Th1 immune responses. Finally, our studies using human stool samples support a role for Tritrichomonas sp. colonization in protecting against development of CeD. Supported by grants from NIH (T32 AI089443)

Helicobacter pylori kolonizasyon yoğunluğu çölyak hastalığının gelişmesinde önemli rol oynayabilir

Background and Aims: The aim of this study was to investigate the relationship between celiac disease and Helicobacter pylori infection and to compare the severity of celiac disease and Helicobacter pylori infection in adults according to the modified Marsh score.
 Materials and Methods: This study included 148 patients with celiac disease and 240 control patients without celiac disease who underwent endoscopy for various reasons in a tertiary hospital. Age, gender, endoscopy indications, descriptive characteristics, complaints, serological, endoscopic and histopathological findings of the patients were recorded and analyzed. Results: Helicobacter pylori colonization in the celiac disease patients was 43.9% and in control group was 57.5% (p = 0.009). Helicobacter pylori positivity rate was significantly lower in Marsh 2, 3A, 3B, 3C groups ( p = 0.04). Pearson correlation analysis revealed a significant but weak negative relationship between the severity of Helicobacter pylori and celiac disease (r = -.109, p = 0.031). When Marsh score was increasing, Helicobacter pylori grade decreased. Conclusion: The current study indicated that the incidence of Helicobacter pylori infection was lower in adults with celiac disease compared to control patients, and Helicobacter pylori colonization density was associated with milder duodenal lesions in celiac patients. Helicobacter pylori colonization may have a protective role in the development of celiac disease.

Pregnancy- and birth-related risk factors for the development of childhood celiac disease.

To evaluate whether pregnancy and birth-related factors are associated with celiac disease (CD) in a large, United States (US)-based mother-child cohort. We analysed data gathering from the Massachusetts General Hospital Maternal Child Cohort (MMCC) of children born between 1998 and 2016. Data included the mode of delivery, maternal pregnancy and their offspring characteristics. We searched for CD cases by using diagnosis billing codes. Cox proportional hazard regression models were created to identify variables associated with CD. We identified 44 539 mother-child pairs who had at least one encounter by 5 years old and identified 173 children (0.4%) with CD diagnosis; median age at the diagnosis was 6 years. Overall, the adjusted hazard ratio (aHR) of caesarean delivery for CD was 1.39 (95% CI: 0.99, 1.96, p= 0.06) when compared to children born vaginally. After stratifying for the presence of labour, children born by Caesarean delivery without labour had a higher risk of CD (aHR 1.56; 95%CI: 1.01, 2.41; p=0.046) while infants born by Caesarean delivery with labour did not (aHR 1.26; 95% CI: 0.83, 1.93; p=0.28). Being born by Caesarean delivery without labour may be associated with an increased risk for CD in the US children.

Profiling of peripheral blood B-cell transcriptome in children who developed coeliac disease in a prospective study

BackgroundIn coeliac disease (CoD), the role of B-cells has mainly been considered to be production of antibodies. The functional role of B-cells has not been analysed extensively in CoD. MethodsWe conducted a study to characterize gene expression in B-cells from children developing CoD early in life using samples collected before and at the diagnosis of the disease. Blood samples were collected from children at risk at 12, 18, 24 and 36 months of age. RNA from peripheral blood CD19+ cells was sequenced and differential gene expression was analysed using R package Limma. FindingsOverall, we found one gene, HNRNPL, modestly downregulated in all patients (logFC −0·7; q = 0·09), and several others downregulated in those diagnosed with CoD already by the age of 2 years. InterpretationThe data highlight the role of B-cells in CoD development. The role of HNRPL in suppressing enteroviral replication suggests that the predisposing factor for both CoD and enteroviral infections is the low level of HNRNPL expression. FundingEU FP7 grant no. 202063, EU Regional Developmental Fund and research grant PRG712, The Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) 2012–2017, grant no. 250114) and, AoF Personalized Medicine Program (grant no. 292482), AoF grants 292335, 294337, 319280, 31444, 319280, 329277, 331790) and grants from the Sigrid Jusélius Foundation (SJF).

Why are western diet and western lifestyle pro-inflammatory risk factors of celiac disease?

The prevalence of celiac disease increased in recent years. In addition to the genetic and immunological factors, it appears that environmental determinants are also involved in the pathophysiology of celiac disease. Gastrointestinal infections impact the development of celiac disease. Current research does not directly confirm the protective effect of natural childbirth and breastfeeding on celiac disease. However, it seems that in genetically predisposed children, the amount of gluten introduced into the diet may have an impact on celiac disease development. Also western lifestyle, including western dietary patterns high in fat, sugar, and gliadin, potentially may increase the risk of celiac disease due to changes in intestinal microbiota, intestinal permeability, or mucosal inflammation. Further research is needed to expand the knowledge of the relationship between environmental factors and the development of celiac disease to define evidence-based preventive interventions against the development of celiac disease. The manuscript summarizes current knowledge on factors predisposing to the development of celiac disease including factors associated with the western lifestyle.

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

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.