Decreasing incidence of celiac disease in Southern Sweden.

BACKGROUND: The incidence of celiac disease (CD) has increased rapidly in the late 20th and early 21st centuries, but there are recent reports of rates levelling off in countries with a high prevalence. The aim of this study was to investigate current trends in CD in southern Sweden. PATIENTS AND METHODS: Children and adults diagnosed with CD by biopsy or serology in the region of Skåne, southern Sweden, from 2010-2022 were included. The home address was identified through registers to analyze temporal and geographical trends. RESULTS: A total of 3218 CD-patients were identified (52.2% children), the vast majority detected in clinical care but a few children by screening studies. The age-standardized incidence rate was 18.6 cases/105. The incidence decreased at a rate of -0.75 cases/105 (95% CI -1.14 to -0.35, p 0.002). The incidence among girls under 18 years almost halved throughout the study period, decreasing by -2.94 cases/105 (95% CI -4.59 to -1.29, p 0.002), while there only were small changes among men. The most common age of onset was 3-9 years. CD incidence varied by place of living and was more common in small towns than urban or rural areas. CONCLUSIONS: The incidence of CD in southern Sweden is decreasing, primarily in children and women who traditionally have had the highest risk of CD. CD was diagnosed most frequently in children 3-9 years old. There were regional variations in incidence. CD was most common in small towns, pointing to the importance of environmental factors in CD etiology.

Celiac disease with neurological manifestations mimicking stiff-person syndrome.

Celiac disease (CD), a gluten-related disease, is a multi-system rare disorder mainly involving the gastrointestinal tract. The clinical signs of CD are exceedingly heterogeneous, which increases the difficulty of clinical differential diagnosis. Neurological manifestations are one of the non-classical CD symptoms. As some patients present only neurological symptoms at early stages, the diagnosis of CD is always delayed. Correct diagnosis and management could decrease patient morbidity and deaths. A 32-year-old male was admitted to the hospital due to progressive muscle atrophy of both lower limbs and lumbar stiffness. Based on positive gluten-sensitive enteropathy autoantibody profiles and gastroscopy foundation, the diagnosis of CD was established. The patient was instructed to gluten-free diet. The antibody titer of gluten-sensitive enteropathy autoantibodies decreased, and the patient's symptoms alleviated. We emphasize the importance of CD screening in patients with neurological disorders of unknown aetiology.

Clinical presentation of celiac disease in adult patients: current real-life experience.

BACKGROUND AND AIMS: The clinical presentation of celiac disease (CD) has changed over time with more patients presenting with non-classical symptoms, extra-intestinal manifestations (EIM) or no symptoms. We aimed to investigate the main symptoms/signs leading to the diagnosis of CD in adult patients. As secondary end-point, we evaluated the outcome of gastrointestinal (GI) symptoms following gluten-free diet (GFD). METHODS: All consecutive CD adult patients referring to our University Hospital from September 2022 to February 2024 were included. Clinical data were retrospectively evaluated. RESULTS: 134 patients, 104 females/30 males, median age at diagnosis 35 years, were included. 79 patients reported GI symptoms (i.e., diarrhea, abdominal bloating, dyspepsia) as the main symptom leading to CD diagnosis. In 40 patients, the leading symptom/sign was an EIM (i.e., iron deficiency anemia, infertility/miscarriages, dermatitis, osteoporosis, elevated transaminase levels). Fifteen patients were asymptomatic, being diagnosed because of a positive family history or concomitant autoimmune hypothyroidism. Of the 79 patients reporting GI symptoms, 20 did not experience complete resolution with the GFD. Among the 17 patients who reported a strict adherence to GFD (vs 1 patient with low-adherence, 2 non-compliant), lactose intolerance and irritable bowel syndrome overlap were diagnosed in 2 and 15 patients, respectively. CONCLUSION: GI manifestations remain the main symptoms at presentation of CD, however clinicians should be aware of the EIM of CD and the association with other autoimmune disorders. In non-responsive CD patients, an overlap with functional disorders might be considered.

The Frequently Used Industrial Food Process Additive, Microbial Transglutaminase: Boon or Bane.

Microbial transglutaminase (mTG) is a frequently consumed processed food additive, and use of its cross-linked complexes is expanding rapidly. It was designated as a processing aid and was granted the generally recognized as safe (GRAS) classification decades ago, thus avoiding thorough assessment according to current criteria of toxicity and public health safety. In contrast to the manufacturer's declarations and claims, mTG and/or its transamidated complexes are proinflammatory, immunogenic, allergenic, pathogenic, and potentially toxic, hence raising concerns for public health. Being a member of the transglutaminase family and functionally imitating the tissue transglutaminase, mTG was recently identified as a potential inducer of celiac disease. Microbial transglutaminase and its docked complexes have numerous detrimental effects. Those harmful aspects are denied by the manufacturers, who claim the enzyme is deactivated when heated or by gastric acidity, and that its covalently linked isopeptide bonds are safe. The present narrative review describes the potential side effects of mTG, highlighting its thermostability and activity over a broad pH range, thus, challenging the manufacturers' and distributers' safety claims. The national food regulatory authorities and the scientific community are urged to reevaluate mTG's GRAS status, prioritizing public health protection against the possible risks associated with this enzyme and its health-damaging consequences.

[Beyond hypercoagulability in celiac disease]. / Más allá de la hipercoagulabilidad en la enfermedad celíaca.

In celiac disease (CD) there is a state of hypercoagulability and multiple factors have been found that may be involved. Cases of association of CD and antiphospholipid síndrome (APS) have been described and several observational studies have found an increase in antiphospolipid antibodies (AAF) in patients with CD, so both entities may be interrelated, increasing the risk of thrombotic events. A descriptive case of a patient who is simultaneusly diagnosed with CD and APS is presented.

Celiac Disease and Autoimmune Diseases in a Pediatric Population in Morocco: A Cross-Sectional Study.

INTRODUCTION: Celiac disease (CD) is defined as an autoimmune disease (AD) caused by gluten ingestion in genetically sensitive individuals. Several publications have demonstrated the increased risk of AD in patients with CD, both adults and children, which requires systematic research. Our study aimed to determine the prevalence of AD in 60 patients diagnosed with CD and to highlight risk factors that may contribute to the emergence of AD. MATERIALS AND METHODS: We collected medical data from all CD patients under 16 years of age who also had AD. Our study was conducted in the Gastroenterology-Hepatology and Pediatric Nutrition Unit of the Pediatrics Department of the Mohamed VI Hospital and University Center in Oujda, Morocco, during a seven-year period between January 2017 and January 2024. RESULTS: We studied 60 patients with CD in our study. Eight patients (13%) had an associated AD. Their average age was eight years, with extremes varying between two and 15 years. AD was diagnosed before CD in six cases (75%), in parallel with CD in one patient (12.5%), while in only one case, it was diagnosed after CD (12.5%). All our patients had a single AD associated with CD. These ADs were mainly type 1 diabetes in seven cases and autoimmune thyroiditis in only one case. All our patients followed a gluten-free diet in addition to specific treatment for associated AD. Nevertheless, despite regular medical follow-up and targeted dietary advice for the management of CD and associated AD, three patients encountered difficulties in following the recommended diet. CONCLUSION: Younger patients with CD have an increased risk of hypothyroidism and insulin-dependent diabetes. These data necessitate improved surveillance to discover these illnesses as early as possible in order to optimize management and reduce related consequences.

Rapid diagnosis of celiac disease based on plasma Raman spectroscopy combined with deep learning.

Celiac Disease (CD) is a primary malabsorption syndrome resulting from the interplay of genetic, immune, and dietary factors. CD negatively impacts daily activities and may lead to conditions such as osteoporosis, malignancies in the small intestine, ulcerative jejunitis, and enteritis, ultimately causing severe malnutrition. Therefore, an effective and rapid differentiation between healthy individuals and those with celiac disease is crucial for early diagnosis and treatment. This study utilizes Raman spectroscopy combined with deep learning models to achieve a non-invasive, rapid, and accurate diagnostic method for celiac disease and healthy controls. A total of 59 plasma samples, comprising 29 celiac disease cases and 30 healthy controls, were collected for experimental purposes. Convolutional Neural Network (CNN), Multi-Scale Convolutional Neural Network (MCNN), Residual Network (ResNet), and Deep Residual Shrinkage Network (DRSN) classification models were employed. The accuracy rates for these models were found to be 86.67%, 90.76%, 86.67% and 95.00%, respectively. Comparative validation results revealed that the DRSN model exhibited the best performance, with an AUC value and accuracy of 97.60% and 95%, respectively. This confirms the superiority of Raman spectroscopy combined with deep learning in the diagnosis of celiac disease.

Structural and mechanistic analysis of Ca2+-dependent regulation of transglutaminase 2 activity using a Ca2+-bound intermediate state.

Mammalian transglutaminases, a family of Ca2+-dependent proteins, are implicated in a variety of diseases. For example, celiac disease (CeD) is an autoimmune disorder whose pathogenesis requires transglutaminase 2 (TG2) to deamidate select glutamine residues in diet-derived gluten peptides. Deamidation involves the formation of transient γ-glutamyl thioester intermediates. Recent studies have revealed that in addition to the deamidated gluten peptides themselves, their corresponding thioester intermediates are also pathogenically relevant. A mechanistic understanding of this relevance is hindered by the absence of any structure of Ca2+-bound TG2. We report the X-ray crystallographic structure of human TG2 bound to an inhibitory gluten peptidomimetic and two Ca2+ ions in sites previously designated as S1 and S3. Together with additional structure-guided experiments, this structure provides a mechanistic explanation for how S1 regulates formation of an inhibitory disulfide bond in TG2, while also establishing that S3 is essential for γ-glutamyl thioester formation. Furthermore, our crystallographic findings and associated analyses have revealed that i) two interacting residues, H305 and E363, play a critical role in resolving the thioester intermediate into an isopeptide bond (transamidation) but not in thioester hydrolysis (deamidation); and ii) residues N333 and K176 stabilize preferred TG2 substrates and inhibitors via hydrogen bonding to nonreactive backbone atoms. Overall, the intermediate-state conformer of TG2 reported here represents a superior model to previously characterized conformers for both transition states of the TG2-catalyzed reaction.

Determination of the Frequency of Celiac Disease in Patients Presenting With Chronic Diarrhea.

INTRODUCTION: Celiac disease (CD) is a chronic inflammatory disorder affecting mainly the digestive system and accounts for more than 50% of adult cases presenting to the gastrointestinal clinic with chronic diarrhea. Therefore, in our study, we aimed to determine the prevalence of CD in patients presenting with chronic diarrhea at the gastroenterology outpatient department of Jinnah Hospital, Lahore. METHODS: This cross-sectional study was conducted from December 9, 2021, to June 8, 2022, and included 140 patients aged 18 to 50 years with chronic diarrhea. Exclusion criteria were lack of informed consent and history of abdominal trauma or surgery. Data collected included age, gender, family history of CD, and clinical symptoms. Diagnostic measures involved serum tissue transglutaminase antibody IgA and IgG levels, endoscopy, and duodenal biopsy. Statistical analysis was performed using SPSS version 23 (IBM Corp, Armonk, NY), with a p-value of ≤0.05 considered significant. RESULTS: Among the 140 patients, 80 (57.14%) were males, with a mean age of 21 ± 4.35 years. Common symptoms included weight loss (73.5%), abdominal pain (20.7%), and stunted growth (5.7%). A family history of CD was reported in 14.29% of patients. Endoscopy findings included fissuring of the duodenal mucosa (77.9%), decreased height of duodenal folds (15.7%), and nodularity (6.4%). Histopathological examination revealed Marsh III b (65%), Marsh III c (21.4%), and Marsh III a (9.3%). CD was diagnosed in 23.57% of patients. Significant associations were found between CD and female gender, family history of CD, weight loss, stunted growth, and Marsh III c histopathology. CONCLUSION: CD was diagnosed in 23.57% of patients with chronic diarrhea. It was more prevalent in females and those with a family history of CD. These findings emphasize the need for considering CD in the differential diagnosis of chronic diarrhea to ensure early detection and management.

Aspergillus niger prolyl endopeptidase in celiac disease.

We comment here on the article by Stefanolo et al entitled "Effect of Aspergillus niger prolyl endopeptidase in patients with celiac disease on a long-term gluten-free diet", published in the World Journal of Gastroenterology. Celiac disease is a well-recognized systemic autoimmune disorder. In genetically susceptible people, the most evident damage is located in the small intestine, and is caused and worsened by the ingestion of gluten. For that reason, celiac patients adopt a gluten-free diet (GFD), but it has some limitations, and it does not prevent re-exposure to gluten. Research aims to develop adjuvant therapies, and one of the most studied alternatives is supplementation with Aspergillus niger prolyl endopeptidase protease (AN-PEP), which is able to degrade gluten in the stomach, reducing its concentration in the small intestine. The study found a high adherence to the GFD, but did not address AN-PEP as a gluten immunogenic peptide reducer, as it was only tested in patients following a GFD and not in gluten-exposing conditions. This study opens up new research perspectives in this area and shows that further study is needed to clarify the points that are still in doubt.

The link between gluten intake and the risk of cancers.

Gluten is a complex mixture of hundreds of related proteins, with the two major groups being gliadin and glutenin. Gliadin primarily affects the viscosity of dough, while glutenin contributes to its strength. Nowadays, there is evidence suggesting an increase in gluten exposure due to advancements in cereal technology. Consumption of gluten can lead to development of gluten-related disorders (GRDs) in susceptible individuals. Some GRDs have been strongly associated with an increased risk of developing certain types of cancer. Colorectal cancer and lymphoma are among the most commonly reported malignancies associated with GRDs. Dietary factors, including gluten intake, have been recognized as significant modifiable risk factors for the development of digestive system cancers. The present study aimed to collect current information on the effect of gluten on the incidence of cancer in the general population and among GRDs patients. Protein-Protein Interaction (PPI) Network analysis of common genes between celiac disease (CD) and cancer was also conducted.

In Vitro Protective Effect of Pea-Derived Peptides (PPs) via the Keap1/Nrf2 Signaling Pathway on Alpha-Gliadin-Sensitizing Peptide Induced Cacao-2 Cells.

SCOPE: Celiac disease (CD) is an allergic intestinal disease caused mainly by gliadin in wheat, which is widespread in the population and currently lacks effective treatment. α-Gliadin peptides cause cellular damage by substantially increasing cellular reactive oxygen species (ROS) levels. METHODS AND RESULTS: This study investigates the protective effect of 11 pea-derived peptides (PPs) on ɑ-gliadin peptide (P31-43) treated Caco-2 cells. Results show that cells treated with PP2, PP5, and PP6 peptides significantly reduce the cell mortality caused by P31-43. Three PPs significantly reduce the P31-43-induced decrease in ROS levels to control levels, and there is no difference between them and the vitamin C (Vc) group. The results in terms of antioxidant-related enzymes show that PPs significantly decrease superoxide dismutase activity (SOD), glutathione reductases (GR), and glutathione (GSH)/oxidized glutathione (GSSG) levels, thus significantly enhancing the antioxidant level of cells. By studying the key proteins of the Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) pathway, it is found that PPs activate the Keap1/Nrf2 signaling pathway. CONCLUSION: The study finds that peptides from peas can effectively alleviate ɑ-gliadin peptide-induced cell damage. The discovery of these food-derived peptides provides novel potential solutions for the prevention and treatment of CD.

Duodenal Leishmaniasis Mimicking Celiac Disease in HIV Patient: A Case Report and Literature Review.

It is known that there are several clinical forms that diseases can take when presented in patients living with HIV, especially those in the AIDS phase. Here, we present a case that demonstrates the peculiar capacity of diseases to assume the most varied forms, highlighting the limited research on neglected infectious parasitic diseases. This study aimed to underscore the ability of these diseases to mimic other pathologies, emphasizing the importance of infectious diseases as differential diagnoses in the most diverse clinical entities, as is the case of visceral leishmaniasis.

Celiac Disease, Gluten Sensitivity, and Diet Management.

PURPOSE OF REVIEW: Celiac disease is a common chronic inflammatory condition of the small bowel triggered by gluten in wheat, rye and barley in the diet. Non-celiac gluten sensitivity presents with symptoms similar to celiac disease with the ingestion of gluten or other components of wheat. In this article, we review challenges presented by a gluten free diet for the treatment of both disorders. RECENT FINDINGS: Wheat is ubiquitous in the diet and medications/products. A registered dietitian is mandatory for patient education on the gluten free diet. Naturally gluten free foods provide a healthy diet for those with celiac disease. Whole grains labelled gluten free, including oats, are encouraged in the diet as refined grains may be deficient in fiber, protein, and micronutrients, particularly folate. Gluten contamination is the most common cause of persistent symptoms in celiac disease though shared equipment of food preparation may not be as large a problem as suspected. Most with celiac disease on a gluten free diet will fully recover and gain weight that poses a problem for those overweight to start. The gluten free diet may have a negative impact on quality of life for both celiac patients and their families. Those with hypervigilance of the gluten free diet and avoidance of dining out have the lowest quality of life. The gluten free diet is currently the only effective treatment for celiac disease. A registered dietitian is needed to educate patients on the complexity of the gluten free diet with a goal of healthy eating, maintaining a healthy weight, and avoiding disordered eating or diet hypervigilance; key to a good quality of life.

Celiac disease and attention-deficit/hyperactivity disorder: a bidirectional Mendelian randomization analysis.

Background: Recent observational research suggests a potential link between celiac disease (CeD) and an increased incidence of attention-deficit/hyperactivity disorder (ADHD). However, the genetic relationship between CeD and ADHD remains unclear. In order to assess the potential genetic causality between these two conditions, we conducted a Mendelian randomization (MR) analysis. Methods: We performed a bidirectional MR analysis to investigate the relationship between CeD and ADHD. We carefully selected single nucleotide polymorphisms (SNPs) from publicly available large-scale genome-wide association studies (GWAS) databases, employing rigorous quality screening criteria. MR estimates were obtained using four different methods: fixed-effect inverse variance weighted (fe-IVW), random-effect inverse variance weighting (re-IVW), weighted median (WM), and MR-Egger. The robustness and reliability of our findings were confirmed through sensitivity analyses, assessment of instrumental variable (IV) strength (F-statistic), and statistical power calculations. Results: Our MR analyses did not reveal any significant genetic associations between CeD and ADHD (fe-IVW: OR = 1.003, 95% CI = 0.932-1.079, P = 0.934). Similarly, in the reverse direction analysis, we found no evidence supporting a genetic relationship between ADHD and CeD (fe-IVW: OR = 0.850, 95% CI = 0.591-1.221, P = 0.378). Various MR approaches consistently yielded similar results. Sensitivity analysis indicated the absence of significant horizontal pleiotropy or heterogeneity. However, it's important to note that the limited statistical power of our study may have constrained the causal analysis of the exposure's influence on the outcome. Conclusions: Our findings do not provide compelling evidence for a genetic association between CeD and ADHD within the European population. While the statistical power of our study was limited, future MR research could benefit from larger-scale datasets or datasets involving similar traits. To validate our results in real-world scenarios, further mechanistic studies, large-sample investigations, multicenter collaborations, and longitudinal studies are warranted.

Associations between special diet and incidence risk of osteoporosis: a Mendelian randomization study.

Introduction: Osteoporosis is a prevalent challenge in clinical orthopedics, affecting a significant percentage of individuals aged 50 and above. The goal of this study was to comprehensively understand the relationships between a specialized dietary regimen and the risk of developing osteoporosis. Methods: This study employed extensive genome-wide association study (GWAS) summary statistics derived from the UK Biobank. It encompassed 8 kinds of special diets and 7 datasets pertaining to osteoporosis and associated symptoms. The principal analytical approach employed was the inverse-variance weighted method. Additionally, sensitivity analysis was employed to elucidate the diverse multiplicity patterns observed in the final model. Results: Our results showed that there is significant evidence that a gluten-free diet is associated with osteoporosis [odds ratio (OR): 1.080, 95% confidence interval (CI): 1.048-1.112, p = 4.23E-07)]. Furthermore, there exists a suggestive link between the three distinct dietary approaches and osteoporosis [(OR: 0.949, 95%CI: 0.929-0.970, p = 3.00E-06) for comprehensive consumption; (OR: 1.053, 95%CI: 1.018-1.089, p = 2.23E-03) for abstaining from wheat consumption; (OR: 1.036, 95%CI: 1.005-1.068, p = 1.97E-02) for abstaining from sugar consumption]. No additional correlation between the special dietary regimens and osteoporosis has been observed. Conclusion: Our research has uncovered a notable correlation between a gluten-free diet and the occurrence of osteoporosis. Furthermore, it exerts a promoting influence on the onset of osteoporosis, which stands in direct contradiction to the therapeutic principles for Celiac Disease's complications. As such, a novel association among these three elements is postulated.

Evaluation of genetic association between celiac disease and type 1 diabetes.

Purpose: Celiac disease (CD) is a chronic autoimmune disorder with a common genetic pathogenesis with type 1 diabetes (T1D). This study aimed to investigate the immune regulation in patients with both CD and T1D. Methods: A total of 29 CD patients, 29 T1D patients, and 16 patients with both CD and T1D, along with 30 healthy controls (HCs) were included. The mRNA expression levels of TNF-α, IL-6, IL-2, and CTLA4 were evaluated in peripheral blood samples. Results: The results showed that in patients with CD, T1D and CD/T1D, TNF-α mRNA levels were significantly increased (P = 0.0009, 0.0001, and 0.008, respectively), while CTLA4 mRNA levels were significantly decreased in them compared to the control group (P = 0.0009, 0.0001, and 0.004, respectively). IL-2 mRNA expression levels were also significantly higher in CD (P = 0.01) and comorbid CD/T1D (P = 0.01) patients than in the control group. There was no significant difference in terms of IL-6 expression between studied groups (P > 0.05). Conclusions: TNF-α mRNA exhibited potential diagnostic value for distinguishing CD, T1D, and comorbid CD/T1D patients from HCs. These findings contribute to our understanding of the shared genetic factors and potential mechanisms underlying CD and T1D, which can aid in improved diagnostic methods and treatment approaches for these conditions.

Association of HLA Haplotypes with Autoimmune Pathogenesis in Newly Diagnosed Type 1 Romanian Diabetic Children: A Pilot, Single-Center Cross-Sectional Study.

BACKGROUND: The increasing incidence of autoimmune diseases in type 1 diabetes mellitus (T1DM) patients highlights the influence of human leukocyte antigen (HLA) haplotypes on their development. This study aims to determine genetic predisposition to autoimmune diseases in T1DM patients, including thyroid disease and celiac diseases, and explore its correlation with vitamin D deficiency. METHODS: A cross-sectional study involving thirty-six T1DM children was conducted. Typing was performed for the HLA A, B, C, DP, DR, and DQ loci. Regression analysis linked DR-DQ haplotypes to T1DM and the associated conditions. RESULTS: The most frequent predisposing alleles and haplotypes were HLA-DR3 (70.27%), DQ2 (70.27%), DR3-DQ2 (70.27%), DQB1*02:01 (70.27%), A02 (54.05%), whereas the most prevalent protecting allele was DPB1*04:01 (52.63%). Positive correlations were observed between positive anti-thyroid peroxidase antibodies and the absence of protective alleles (DPB1*04:02, p = 0.036; DPB1*04:01, p = 0.002). Associations were found between the absence of DPB1*04:01 and anti-thyroglobulin antibodies (p = 0.03). HLA allele DPB1*03:01 was linked with vitamin D deficiency (p = 0.021). Positive anti-transglutaminase antibodies correlated with C03:03 (p = 0.026) and DRB1*04:01-DQA1*03-DQB1*03:01 (p < 0.0001) and the lack of DQA1*01:03-DQB1*06:03-DRB1*13:01 (p < 0.0001). CONCLUSIONS: The predisposing T1DM haplotypes were associated with the presence of anti-transglutaminase and anti-thyroid antibodies, indicating a genetic predisposition to autoimmune diseases.

Associations between Celiac Disease, Extra-Gastrointestinal Manifestations, and Gluten-Free Diet: A Narrative Overview.

Millions of children and adults worldwide suffer from undiagnosed and untreated celiac disease (CeD). The clinical picture of CeD is highly heterogeneous and comprises manifestations that can affect almost the whole body. This narrative overview is aimed at characterizing diseases and complaints that are associated with unrecognized CeD and that frequently involve sites other than the gastrointestinal (G.I.) tract, i.e., dental, otorhinolaryngological, and ocular complications; skin and hair abnormalities; afflictions of the bones, joints, and muscles; cardiovascular affectations; kidney diseases; neuro-psychiatric disorders; and gynecological-obstetrical manifestations. The association between CeD and extra-GI manifestations is frequently overlooked, which leads to a delay in diagnosis. Most CeD-mediated disorders can be treated with a strict gluten-free diet (GFD), but some of them are irreversible unless CeD is diagnosed in time. Some manifestations can be classified as risk factors for CeD, and CeD screening tests for affected patients should be selectively considered. Apart from gastroenterologists, specialists in other medical disciplines can play an important role in identifying people with unrecognized CeD and may help prevent its progress and long-term complications. Further comprehensive investigations are necessary to clarify the pathogenesis of extra-GI manifestations and the effect of a GFD.

How the Microbiota May Affect Celiac Disease and What We Can Do.

Celiac disease (CeD) is an autoimmune disease with a strong association with human leukocyte antigen (HLA), characterized by the production of specific autoantibodies and immune-mediated enterocyte killing. CeD is a unique autoimmune condition, as it is the only one in which the environmental trigger is known: gluten, a storage protein present in wheat, barley, and rye. How and when the loss of tolerance of the intestinal mucosa to gluten occurs is still unknown. This event, through the activation of adaptive immune responses, enhances epithelial cell death, increases the permeability of the epithelial barrier, and induces secretion of pro-inflammatory cytokines, resulting in the transition from genetic predisposition to the actual onset of the disease. While the role of gastrointestinal infections as a possible trigger has been considered on the basis of a possible mechanism of antigen mimicry, a more likely alternative mechanism appears to involve a complex disruption of the gastrointestinal microbiota ecosystem triggered by infections, rather than the specific effect of a single pathogen on intestinal mucosal homeostasis. Several lines of evidence show the existence of intestinal dysbiosis that precedes the onset of CeD in genetically at-risk subjects, characterized by the loss of protective bacterial elements that both epigenetically and functionally can influence the response of the intestinal epithelium leading to the loss of gluten tolerance. We have conducted a literature review in order to summarize the current knowledge about the complex and in part still unraveled dysbiosis that precedes and accompanies CeD and present some exciting new data on how this dysbiosis might be prevented and/or counteracted. The literature search was conducted on PubMed.gov in the time frame 2010 to March 2024 utilizing the terms "celiac disease and microbiota", "celiac disease and microbiome", and "celiac disease and probiotics" and restricting the search to the following article types: Clinical Trials, Meta-Analysis, Review, and Systematic Review. A total of 364 papers were identified and reviewed. The main conclusions of this review can be outlined as follows: (1) quantitative and qualitative changes in gut microbiota have been clearly documented in CeD patients; (2) intestinal microbiota's extensive and variable interactions with enterocytes, viral and bacterial pathogens and even gluten combine to impact the inflammatory immune response to gluten and the loss of gluten tolerance, ultimately affecting the pathogenesis, progression, and clinical expression of CeD; (3) gluten-free diet fails to restore the eubiosis of the digestive tract in CeD patients, and also negatively affects microbial homeostasis; (4) new tools allowing targeted microbiota therapy, such as the use of probiotics (a good example being precision probiotics like the novel strain of B. vulgatus (20220303-A2) begin to show exciting potential applications.