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.

Maternal gluten, cereal, and dietary fiber intake during pregnancy and lactation and the risk of islet autoimmunity and type 1 diabetes in the child.

BACKGROUND & AIMS: Maternal gluten intake in relation to child's risk of type 1 diabetes has been studied in few prospective studies considering the diet during pregnancy but none during lactation. Our aim was to study whether gluten, cereals, or dietary fiber in maternal diet during pregnancy and lactation is associated with the risk of islet autoimmunity or type 1 diabetes in the offspring. METHODS: We included 4943 children with genetic susceptibility to type 1 diabetes from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study, born between 1996 and 2004. Maternal intake of gluten, different types of cereals, and dietary fiber were derived from a semi-quantitative validated food frequency questionnaire covering the eighth month of pregnancy and the third month of lactation. Children were monitored for islet autoantibodies up to age of 15 years and type 1 diabetes until year 2017. Risk of islet autoimmunity and clinical type 1 diabetes were estimated using Cox regression model, adjusted for energy intake, child's sex, HLA genotype, and familial diabetes. RESULTS: Altogether 312 children (6.4%) developed islet autoimmunity at median age of 3.5 (IQR 1.7, 6.6) years and 178 children (3.6%) developed type 1 diabetes at median age of 7.1 (IQR 4.3, 10.6) years. Gluten intake during pregnancy was not associated with islet autoimmunity (HR 0.96; 95% CI 0.68, 1.35), per 1 g/MJ increase in intake nor type 1 diabetes (HR 0.96; 95% CI 0.62, 1.50) in the offspring. Higher barley consumption during lactation was associated with increased risk of type 1 diabetes (HR 3.25; 95% CI 1.21, 8.70) per 1 g/MJ increase in intake. Maternal intake of other cereals or dietary fiber was not associated with the offspring outcomes. CONCLUSIONS: We observed no association between maternal intake of gluten, most consumed cereals, or dietary fiber during pregnancy or lactation and the risk of islet autoimmunity or type 1 diabetes in children from a high-risk population.

Potential Celiac Disease in Children: Health Status on A Long-Term Gluten-Containing Diet.

Potential celiac disease (PCD) is a clinical condition characterised by the presence of a positive CD-specific serology and a normal intestinal architecture. Asymptomatic PCD patients are generally advised to continue on a gluten-containing diet (GCD), but long-term risks of this approach have never been explored. In the present study, we aimed to investigate nutritional and autoimmune complications possibly developing overtime in a cohort of asymptomatic PCD children on a GCD. We compared children's parameters of growth, nutritional status, and autoimmunity between the time of diagnosis and on the occasion of their last medical check, after a long-term gluten-containing diet. Altogether, we collected data from 171 PCD children with a mean follow-up time of 3 years (range 0.35-15.3 years). During follow-up, although patients did not reduce their amount of daily gluten intake, their anti-tissue transglutaminase (anti-TG2) antibodies spontaneously and significantly decreased. Most parameters analysed had not changed during follow-up (height centile, ferritin, albumin, cholesterol, calcium, alkaline phosphatase, parathormone, and vitamin D) or even improved significantly (weight and BMI centile, haemoglobin, blood iron, HDL, glycaemia, and HbA1C, p < 0.05), always remaining within the limit of normality. Equally, autoantibodies for other concomitant autoimmune disorders did not increase overtime. Similar results were obtained excluding from analysis patients who had stopped producing anti-TG2 and those with a follow-up time < 3 years. Our pilot study has provided reassuring results regarding the maintenance of a gluten-containing diet in asymptomatic PCD children, even when long-term follow-up was considered.

Efficacy of a Low-FODMAP Diet for Coeliac Patients with Persistent IBS-like Symptoms despite a Gluten-Free Diet: A Systematic Review.

Background: Persistent symptoms in coeliac disease (CD) can be due to not only poor gluten-free diet (GFD) adherence and complications of CD, but also functional gastrointestinal disorders such as irritable bowel syndrome (IBS). Although the role of a low fermentable oligo-, di-, and monosaccharides and polyols (FODMAP) diet is well-established in IBS, little data are available on its role in coeliac patients with persistent IBS-like symptoms despite a GFD. Methods: We systematically reviewed the literature in accordance with the PRISMA guidelines for studies evaluating the role of FODMAPs and/or a low-FODMAP diet in coeliac patients with persistent symptoms. PubMed and Embase were searched from inception to 16 January 2024 for eligible full-text papers. The study protocol was registered on Open Science Framework. Results: A total of 239 records were identified, and six papers were included. Of these, four were interventional studies comparing a low-FODMAP GFD to a regular GFD for persistent symptoms in 115 total coeliac patients (two randomized controlled trials and two open-label studies). A low-FODMAP GFD for a minimum of 4 weeks was significantly more effective than a regular GFD in reducing symptoms (p < 0.05 in 3/4 studies). Dietary FODMAP content of a conventional GFD was significantly lower than that of non-coeliac patients on a gluten-containing diet (both p < 0.05), especially regarding high-FODMAP grain products. However, coeliac patients consumed more servings of fruits/vegetables high in FODMAP. No relationship between FODMAP intake and persistence of symptoms was reported. Conclusions: A low-FODMAP diet may be beneficial for uncomplicated celiac patients with persistent IBS-like symptoms despite strict adherence to a GFD.

Clinical Presentation and Spectrum of Gluten Symptomatology in Celiac Disease.

Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection. Adverse symptoms greatly impact patient quality of life and can result from chronic gluten exposure in untreated disease or those poorly responsive to the gluten-free diet. They can also present as acute symptoms after episodic gluten exposure. Functional gastrointestinal disease is a common comorbidity. Biomarkers like interleukin-2 that are highly sensitive and specific for celiac disease highlight a role for gluten-specific T cells in acute gluten symptomatology. A mechanistic understanding of symptoms will inform approaches to better measure and treat them effectively.

Past, Present, and Future of Noninvasive Tests to Assess Gluten Exposure, Celiac Disease Activity, and End-Organ Damage.

Although many biomarkers have been proposed, and several are in widespread clinical use, there is no single readout or combination of readouts that correlates tightly with gluten exposure, disease activity, or end-organ damage in treated patients with celiac disease. Challenges to developing and evaluating better biomarkers include significant interindividual variability-related to immune amplification of gluten exposure and how effects of immune activation are manifest. Furthermore, the current "gold standard" for assessment of end-organ damage, small intestinal biopsy, is itself highly imperfect, such that a marker that is a better reflection of the "ground truth" may indeed appear to perform poorly. The goal of this review was to analyze past and present efforts to establish robust noninvasive tools for monitoring treated patients with celiac disease and to highlight emerging tools that may prove to be useful in clinical practice.

New Insights on Genes, Gluten, and Immunopathogenesis of Celiac Disease.

Celiac disease (CeD) is a gluten-induced enteropathy that develops in genetically susceptible individuals upon consumption of cereal gluten proteins. It is a unique and complex immune disorder to study as the driving antigen is known and the tissue targeted by the immune reaction can be interrogated. This review integrates findings gained from genetic, biochemical, and immunologic studies, which together have revealed mechanisms of gluten peptide modification and HLA binding, thereby enabling a maladapted anti-gluten immune response. Observations in human samples combined with experimental mouse models have revealed that the gluten-induced immune response involves CD4+ T cells, cytotoxic CD8+ T cells, and B cells; their cross-talks are critical for the tissue-damaging response. The emergence of high-throughput technologies is increasing our understanding of the phenotype, location, and presumably function of the gluten-specific cells, which are all required to identify novel therapeutic targets and strategies for CeD.

Sensory Symptoms without Structural Pathology in Patients with Gluten Sensitivity.

We report on a group of patients with gluten sensitivity with and without coeliac disease presenting with unexplained sensory symptoms in the absence of structural pathology. METHODS: The patients were selected from the gluten neurology clinic based at the Royal Hallamshire Hospital, Sheffield, UK, on the basis of sensory symptoms but normal neuroaxis imaging and peripheral nerve evaluation. RESULTS: A total of 30 patients were identified with a mean age at presentation of 47 years. The prevalence of enteropathy was 78%. The sensory disturbance was characterised by tingling at 50%, numbness at 27%, pain at 20%, burning at 13% and "buzzing" feeling at 7%. The distribution of the sensory symptoms included hands and feet in 27% of the patients, torso in 27%, legs only in 23%, face in 17% and arms only in 10%. For five patients, the sensory disturbance was migratory and affected different parts of the body at any given time. After the introduction of a gluten-free diet, 77% of patients noted significant improvement in their sensory symptoms. In one-third of the patients, there was a complete resolution of the sensory symptoms. CONCLUSION: Unexplained sensory symptoms can be seen in patients with gluten sensitivity and respond to strict adherence to a gluten-free diet.

Effects of Gluten on Gut Microbiota in Patients with Gastrointestinal Disorders, Migraine, and Dermatitis.

As gluten may trigger gastrointestinal disorders (GIDs), its presence or absence in the diet can change the diversity and proportion of gut microbiota. The effects of gluten after six weeks of a double-blind, placebo-controlled intervention with a gluten-free diet (GFD) were studied in participants with GIDs suffering from migraines and atopic dermatitis (n = 46). Clinical biomarkers, digestive symptoms, stool, the Migraine Disability Assessment questionnaire, and zonulin levels were analyzed. Next-generation sequencing was used to amplify the 16S rRNA gene of bacteria and the internal transcribed spacer (ITS) regions of fungi. The GFD increased Chao1 fungal diversity after the intervention, while the fungal composition showed no changes. Bacterial diversity and composition remained stable, but a positive association between bacterial and fungal Chao1 diversity and a negative association between Dothideomycetes and Akkermansia were observed. GIDs decreased in both groups and migraines improved in the placebo group. Our findings may aid the development of GID treatment strategies.

Risk of Gluten Cross-Contamination Due to Food Handling Practices: A Mini-Review.

Celiac disease (CD) is an autoimmune disease triggered by the ingestion of gluten in genetically predisposed individuals, affecting 1.4% of the world population. CD induces an inflammatory reaction that compromises small intestine villi, leading to nutrient malabsorption, and gastro and extraintestinal manifestations. Although other treatment approaches are being studied, adherence to a gluten-free diet (GFD) is the only effective intervention to date. Despite this, about 50% of patients experience persistent inflammation, often associated with unintentional gluten ingestion through contaminated food. There are regulations for labeling gluten-free foods which specify a limit of 20 mg/kg (20 ppm). The risks of gluten cross-contamination above that level are present throughout the whole food production chain, emphasizing the need for caution. This review explores studies that tested different procedures regarding the shared production of gluten-containing and gluten-free food, including the use of shared equipment and utensils. A literature review covering PubMed, Scielo, Web of Science, VHL and Scopus identified five relevant studies. The results indicate that shared environments and equipment may not significantly increase gluten cross-contamination if appropriate protocols are followed. Simultaneous cooking of gluten-containing and gluten-free pizzas in shared ovens has demonstrated a low risk of contamination. In general, shared kitchen utensils and equipment (spoon, ladle, colander, knife, fryer, toaster) in controlled experiments did not lead to significant contamination of samples. On the other hand, cooking gluten-free and gluten-containing pasta in shared water resulted in gluten levels above the established limit of 20 ppm. However, rinsing the pasta under running water for a few seconds was enough to reduce the gluten content of the samples to less than 20 ppm.

Gluten-Free Diet and Other Celiac Disease Therapies: Current Understanding and Emerging Strategies.

A lifelong gluten-free diet (GFD) is the only treatment for celiac disease and other gluten-related disorders. Nevertheless, strict adherence to the GFD is often challenging due to concerns about social isolation, risk of gluten contaminations, high cost, poor quality and the taste of gluten-free products. Moreover, although the GFD is effective in achieving mucosal healing, it may lead to dietary imbalances due to nutrient deficiencies over a long period of time. To overcome these issues, several gluten-free wheat flours have been developed to create products that closely resemble their gluten-containing counterparts. Furthermore, given the critical importance of adhering to the GFD, it becomes essential to promote adherence and monitor possible voluntary or involuntary transgressions. Various methods, including clinical assessment, questionnaires, serology for celiac disease, duodenal biopsies and the detection of Gluten Immunogenic Peptides (GIPs) are employed for this purpose, but none are considered entirely satisfactory. Since adherence to the GFD poses challenges, alternative therapies should be implemented in the coming years to improve treatment efficacy and the quality of life of patients with celiac disease. The aim of this narrative review is to explore current knowledge of the GFD and investigate its future perspectives, focusing on technology advancements, follow-up strategies and insights into a rapidly changing future.

Monitoring coeliac disease in 2024, time to change practice?

PURPOSE OF REVIEW: Persistent villous atrophy is associated with morbidity in coeliac disease and most commonly due to ongoing gluten ingestion. Current methods for assessing gluten exposure and persisting villous atrophy include dietary questionnaires and repeat duodenal biopsy, which have limited accuracy or are invasive. This review discusses adjunctive and/or novel tests that could be used to overcome these challenges. RECENT FINDINGS: Small bowel capsule endoscopy is well tolerated and helps to evaluate for persisting villous atrophy and importantly, complications associated with coeliac disease. Testing for urinary and/or stool gluten immunogenic peptides may help identify recent gluten exposure, but further studies are still warranted to evaluate the accuracy and applicability of this approach. Measuring spikes in circulating Interleukin-2 following gluten challenge has shown promise for coeliac disease diagnosis, and thus may serve as a useful confirmatory test in those with persisting symptoms but provides no information on mucosal inflammation. No specific gut microbial signature has been identified in coeliac disease; however, studies have shown a reduced microbial diversity in active disease, which with future refinement may prove clinically useful. SUMMARY: There is no evidence to support alternative methods for assessing persisting villous atrophy in coeliac disease over performing an up-to-date duodenal biopsy. Monitoring for adherence to a gluten-free diet remains clinically challenging and should be a priority for future research.

Advances in Nonresponsive and Refractory Celiac Disease.

Nonresponsive celiac disease (CeD) is relatively common. It is generally attributed to persistent gluten exposure and resolves after correction of diet errors. However, other complications of CeD and disorders clinically mimicking CeD need to be excluded. Novel therapies are being evaluated to facilitate mucosal recovery, which might benefit patients with nonresponsive CeD. Refractory CeD (RCeD) is rare and is divided into 2 types. The etiology of type I RCeD is unclear. A switch to gluten-independent autoimmunity is suspected in some patients. In contrast, type II RCeD represents a low-grade intraepithelial lymphoma. Type I RCeD remains a diagnosis of exclusion, requiring ruling out gluten intake and other nonmalignant causes of villous atrophy. Diagnosis of type II RCeD relies on the demonstration of a clonal population of neoplastic intraepithelial lymphocytes with an atypical immunophenotype. Type I RCeD and type II RCeD generally respond to open-capsule budesonide, but the latter has a dismal prognosis due to severe malnutrition and frequent progression to enteropathy-associated T-cell lymphoma; more efficient therapy is needed.

Coeliac disease: the paradox of diagnosing a food hypersensitivity disorder with autoantibodies.

Serum antibodies to the autoantigen transglutaminase 2 (TG2) are increasingly harnessed to diagnose coeliac disease. Diagnostic guidelines for children give recommendation for a no-biopsy-based diagnosis through detection of high amounts of IgA anti-TG2 antibodies in serum with confirmation of positivity in a separate blood sample by characteristic autoantibody-staining of tissue. While measurement of IgA anti-TG2 also is important in the diagnostic workup of adults, the adult guidelines still mandate examination of gut biopsies. This requirement might well change in the future, as might the necessity for confirming autoantibody positivity by tissue staining. The key role of autoantibody serology for diagnosis of coeliac disease is paradoxical. Coeliac disease was considered, and still can be considered, a food intolerance disorder where autoantibodies at face value are out of place. The immunological mechanisms underlying the formation of autoantibodies in response to gluten exposure have been dissected. This review presents the current insights demonstrating that the autoantibodies in coeliac disease are intimately integrated in the maladapted immune response to gluten.

Exploration of differential responses to FODMAPs and gluten in people with irritable bowel syndrome- a double-blind randomized cross-over challenge study.

INTRODUCTION: There is large variation in response to diet in irritable bowel syndrome (IBS) and determinants for differential response are poorly understood. OBJECTIVES: Our aim was to investigate differential clinical and molecular responses to provocation with fermentable oligo-, di-, monosaccharides, and polyols (FODMAPs) and gluten in individuals with IBS. METHODS: Data were used from a crossover study with week-long interventions with either FODMAPs, gluten or placebo. The study also included a rapid provocation test. Molecular data consisted of fecal microbiota, short chain fatty acids, and untargeted plasma metabolomics. IBS symptoms were evaluated with the IBS severity scoring system. IBS symptoms were modelled against molecular and baseline questionnaire data, using Random Forest (RF; regression and clustering), Parallel Factor Analysis (PARAFAC), and univariate methods. RESULTS: Regression and classification RF models were in general of low predictive power (Q2 ≤ 0.22, classification rate < 0.73). Out of 864 clustering models, only 2 had significant associations to clusters (0.69 < CR < 0.73, p < 0.05), but with no associations to baseline clinical measures. Similarly, PARAFAC revealed no clear association between metabolome data and IBS symptoms. CONCLUSION: Differential IBS responses to FODMAPs or gluten exposures could not be explained from clinical and molecular data despite extensive exploration with different data analytical approaches. The trial is registered at www. CLINICALTRIALS: gov as NCT03653689 31/08/2018.