Novel Bacteroides Vulgatus strain protects against gluten-induced break of human celiac gut epithelial homeostasis: a pre-clinical proof-of-concept study.

BACKGROUND AND AIMS: We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions. METHODS: We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS). RESULTS: Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS. CONCLUSIONS: We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming. IMPACT: Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.

Microbiome signatures of progression toward celiac disease onset in at-risk children in a longitudinal prospective cohort study.

Other than exposure to gluten and genetic compatibility, the gut microbiome has been suggested to be involved in celiac disease (CD) pathogenesis by mediating interactions between gluten/environmental factors and the host immune system. However, to establish disease progression markers, it is essential to assess alterations in the gut microbiota before disease onset. Here, a prospective metagenomic analysis of the gut microbiota of infants at risk of CD was done to track shifts in the microbiota before CD development. We performed cross-sectional and longitudinal analyses of gut microbiota, functional pathways, and metabolites, starting from 18 mo before CD onset, in 10 infants who developed CD and 10 matched nonaffected infants. Cross-sectional analysis at CD onset identified altered abundance of six microbial strains and several metabolites between cases and controls but no change in microbial species or pathway abundance. Conversely, results of longitudinal analysis revealed several microbial species/strains/pathways/metabolites occurring in increased abundance and detected before CD onset. These had previously been linked to autoimmune and inflammatory conditions (e.g., Dialister invisus, Parabacteroides sp., Lachnospiraceae, tryptophan metabolism, and metabolites serine and threonine). Others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects (e.g., Streptococcus thermophilus, Faecalibacterium prausnitzii, and Clostridium clostridioforme). Additionally, we uncovered previously unreported microbes/pathways/metabolites (e.g., Porphyromonas sp., high mannose-type N-glycan biosynthesis, and serine) that point to CD-specific biomarkers. Our study establishes a road map for prospective longitudinal study designs to better understand the role of gut microbiota in disease pathogenesis and therapeutic targets to reestablish tolerance and/or prevent autoimmunity.

Early Antibody Dynamics in a Prospective Cohort of Children At Risk of Celiac Disease.

INTRODUCTION: The purpose of this study was to identify possible serum biomarkers predicting celiac disease (CD) onset in children at risk. METHODS: A subgroup from an ongoing, international prospective study of children at risk of CD was classified according to an early trajectory of deamidated gliadin peptides (DGPs) immunoglobulin (Ig) G and clinical outcomes (CD, potential CD, and CD autoimmunity). RESULTS: Thirty-eight of 325 children developed anti-tissue transglutaminase IgA antibody (anti-tTG IgA) seroconversion. Twenty-eight of 38 children (73.6%) showed an increase in anti-DGPs IgG before their first anti-tTG IgA seroconversion. DISCUSSION: Anti-DGPs IgG can represent an early preclinical biomarker predicting CD onset in children at risk.

Intra- and Inter-observer Agreement of High Resolution Antroduodenal Manometry in Pediatric Patients Among Single Center Experts.

OBJECTIVES: Studies in adults have suggested that high-resolution technology increases the diagnostic yield of antroduodenal manometry (ADM). However, there is no study comparing high-resolution with low-resolution ADM recordings as well as comparing the 2 types of high-resolution display [conventional line plot (CLP) and pressure topographic plots (PTP)]. We hypothesized that high-resolution ADM is a superior diagnostic modality with higher inter-observer and intra-observer agreement compared with low-resolution recordings. METHODS: Twenty-four anonymized ADM studies were blindly analyzed by 3 experienced pediatric neurogastroenterologists. All studies had been performed using a low-compliance water-perfused system with a 20-channels catheter. Data were displayed as CLP, as both high-resolution and low-resolution, and PTP in different sessions with at least 6-week interval. Accuracy was evaluated using previous established diagnosis and specific pre-prandial and post-prandial manometric patterns. Inter-observer and intra-observer agreements were calculated. RESULTS: Analysis with high-resolution CLP revealed a substantial inter-observer agreement among the 3 observers regarding the diagnosis (Krippendorff's alpha: 0.832; average pairwise percentage agreement: 88.9%). Conversely, PTP and low-resolution CLP showed poor agreement for diagnoses (Krippendorff's alpha: 0.600; average pairwise percentage agreement: 75.3%; Krippendorff's alpha: 0.390; average pairwise percentage agreement: 60.2%, respectively). For the intra-observer agreement, Krippendorff's alpha ranges were 0.891-1 for CLP and 0.19393-0.34621 for PTP. CONCLUSIONS: Our study demonstrated higher diagnostic accuracy for high-resolution ADM compared to the low-resolution recordings. However, although it is well established for other motility investigations, PTP is not yet reliable in assessing foregut motor patterns. Advanced and more sophisticated software are clearly required for analyzing PTP display.

Toxin-Producing Klebsiella oxytoca in Healthy Infants: Commensal or Pathobiont?

OBJECTIVES: Klebsiella oxytoca is a gastrointestinal pathobiont with the potential to produce the toxins tilivalline and tilimycin, which cause antibiotic-associated hemorrhagic colitis. Overgrowth of toxigenic K oxytoca has recently been implicated in necrotizing enterocolitis. K oxytoca colonizes 2-9% of healthy adults, however, there is no systematic data on colonization in healthy children. We investigated K oxytoca colonization and its toxigenic properties in healthy infants. METHODS: We sampled stool of healthy infants and determined K oxytoca colonization using stool culture and PCR (pehX). Toxin in stool was measured with HPLC/high-resolution mass spectrometry. K oxytoca isolates were typed using multi-locus sequence typing (MLST) and K oxytoca toxin PCR (npsA/B). Cytotoxin production of isolates was analyzed by MTT assay. RESULTS: K oxytoca was detected in 30 of 61 infants (49%) using stool culture and in 45 of 61 (73%) using PCR (pehX). Toxin marker PCR (npsA/B) was positive in 66% of stool samples positive for K oxytoca PCR. Stool toxin levels were too low for quantitation but traces of tilivalline were detected. Contrarily, 49% of K oxytoca isolates demonstrated toxicity in the MTT assay. MLST revealed 36 distinct sequence types affiliated with all known K oxytoca sequence type clusters (A, B1 and B2). CONCLUSIONS: More than 70% of healthy infants were colonized with K oxytoca. Toxin quantities in stool of colonized healthy infants were below detection level, yet half of the isolates produced toxin in vitro demonstrating their pathobiont potential. The high occurrence of toxigenic K oxytoca in healthy infants has to be considered for future disease association studies.

ESPGHAN Position Paper on Management and Follow-up of Children and Adolescents With Celiac Disease.

OBJECTIVES: To gather the current evidence and to offer recommendations for follow-up and management. METHODS: The Special Interest Group on Celiac Diseases of the European Society of Paediatric Gastroenterology Hepatology and Nutrition formulated ten questions considered to be essential for follow-up care. A literature search (January 2010-March 2020) was performed in PubMed or Medline. Relevant publications were identified and potentially eligible studies were assessed. Statements and recommendations were developed and discussed by all coauthors. Recommendations were voted upon: joint agreement was set as at least 85%. RESULTS: Publications (n = 2775) were identified and 164 were included. Using evidence or expert opinion, 37 recommendations were formulated on: The need to perform follow-up, its frequency and what should be assessed, how to assess adherence to the gluten-free diet, when to expect catch-up growth, how to treat anemia, how to approach persistent high serum levels of antibodies against tissue-transglutaminase, the indication to perform biopsies, assessment of quality of life, management of children with unclear diagnosis for which a gluten-challenge is indicated, children with associated type 1 diabetes or IgA deficiency, cases of potential celiac disease, which professionals should perform follow-up, how to improve the communication to patients and their parents/caregivers and transition from pediatric to adult health care. CONCLUSIONS: We offer recommendations to improve follow-up of children and adolescents with celiac disease and highlight gaps that should be investigated to further improve management.

Follow-up practices for children and adolescents with celiac disease: results of an international survey.

Adequate follow-up in celiac disease is important to improve dietary compliance and treat disease-related symptoms and possible complications. However, data on the follow-up of celiac children is scarce. We aimed to assess current pediatric celiac follow-up practices across Europe. Pediatricians and pediatric gastroenterologists from 35 countries in Europe, Israel, Turkey, and Russia completed an anonymous survey which comprised a 52-item questionnaire developed by the ESPGHAN Special Interest Group on Celiac Disease. A total of 911 physicians, the majority of whom exclusively worked in pediatric care (83%) and academic institutions (60%), completed the questionnaire. Mean age and mean experience with celiac care were 48.7 years (± 10.6) and 15.7 years (± 9.9), respectively. The vast majority (≥ 92%) always assessed anthropometry, dietary adherence, and tissue-transglutaminase IgA-antibodies at every visit, with the first visit being between 3 and 6 months after diagnosis. Other parameters (% always tested) were as follows: complete blood count (60%), iron status (48%), liver enzymes (42%), thyroid function (38%), and vitamin D (26%). Quality of life was never assessed by 35% of the responding physicians. Transition to adult care was mostly completed via a written transition report (37%) or no formal transition at all (27%).Conclusions: Follow-up of celiac children and adolescents in Europe may be improved, especially regarding a more rational use of (laboratory) tests, dietary and QoL assessment, and transition to adult care. Evidence-based advice from international scientific societies is needed. What is Known: • Follow-up in celiac disease is important to treat disease-related symptoms, improve dietary compliance, and prevent possible complications. • There is a lack of consensus about the appropriate follow-up. What is New: • Almost all European physicians assess anthropometry, tissue-transglutaminase IgA-antibodies, and dietary adherence at every visit, but there are large variations in other follow-up aspects. • Follow-up could be improved by a more rational use of (laboratory) tests, increased intention to dietary compliance, and quality of life together with transition programs to adult care.

Gluten-free diet impact on dynamics of pancreatic islet-specific autoimmunity detected at celiac disease diagnosis.

OBJECTIVE: Almost 6% of celiac disease (CD) patients at diagnosis are positive for at least one of the main pancreatic islet autoantibodies that characterize type 1 diabetes (T1D). Few information, dated back to almost two decades ago, exist as to whether a gluten-free diet (GFD) could reduce the islet-specific autoimmunity detected in patients at CD diagnosis. Aim of the study was to evaluate the impact of GFD on 31 patients who presented islet-specific autoimmunity at CD diagnosis. METHODS: CD patient sera collected at diagnosis and throughout the GFD were analyzed for the main humoral autoantibodies so far identified in T1D, directed against one or more among insulin, glutamic-acid decarboxylase, tyrosine-phosphatase 2, and zinc cation-efflux transporter autoantigens. RESULTS: GFD (median duration 39 months) was associated to a decrease or disappearance of the islet-specific autoantibodies in 71% of CD patients. Almost 80% of the patients who became autoantibody-negative during the GFD were positive for only one of the islet-specific autoimmune markers at CD diagnosis, with none of them developing diabetes. Conversely, 80% of the CD patients positive at diagnosis for ≥2 islet-specific autoantibodies were still positive after more than two years of GFD, with 25% of them developing T1D. CONCLUSIONS: Various factors appear to influence, individually or in combination, the effects of the GFD on pancreatic islet-specific autoimmune response detected at CD diagnosis. These factors include the number of diabetes autoantibodies found at CD diagnosis, the adherence to the GFD, its duration and an asymptomatic clinical presentation of CD.

Neuropsychiatric manifestations in celiac disease.

Celiac disease (CD) is a systemic, chronic immune-mediated disorder elicited by gluten and related prolamines in genetically susceptible subjects. Main manifestations of CD involve the digestive tract; however, a growing body of evidence supports the theory that symptoms may occur in every part of the body. It is known that some patients with CD can be asymptomatic, and additionally, the incidence of "nonclassical" CD with extraintestinal presentation is apparently increasing. We aimed to perform a thorough review of existing evidence for neurological manifestations of CD, providing an up-to-date description of prevalence and examining the pathogenetic mechanisms possibly involved. Neurological presentations are rare in children but as many as 36% of adult patients present with neurological findings. With severe malnutrition after progression of CD, different vitamin deficiencies may develop. Such problems can in turn overlap with previous neurological abnormalities including ataxia, epilepsy, neuropathy, dementia, and cognitive disorders. Here, the most prevalent clinical manifestations in adults and children have been discussed in further detail. Further research is needed to achieve a complete understanding of the nervous system involvement in CD, but clinicians should always remember that neurological and psychiatric symptoms might be part of the CD spectrum of manifestations.

Breaking Down Barriers: How Understanding Celiac Disease Pathogenesis Informed the Development of Novel Treatments.

For decades, the pathogenesis of a variety of human diseases has been attributed to increased intestinal paracellular permeability even though scientific evidence supporting this hypothesis has been tenuous. Nevertheless, during the past decade, there have been a growing number of publications focused on human genetics, the gut microbiome, and proteomics, suggesting that loss of mucosal barrier function, particularly in the gastrointestinal tract, may substantially affect antigen trafficking, ultimately causing chronic inflammation, including autoimmunity, in genetically predisposed individuals. The gut mucosa works as a semipermeable barrier in that it permits nutrient absorption and also regulates immune surveillance while retaining potentially harmful microbes and environmental antigens within the intestinal lumen. Celiac disease (CD), a systemic, immune-mediated disorder triggered by gluten in genetically susceptible individuals, is associated with altered gut permeability. Pre-clinical and clinical studies have shown that gliadin, a prolamine component of gluten that is implicated in CD pathogenesis, is capable to disassembling intercellular junctional proteins by upregulating the zonulin pathway, which can be inhibited by the zonulin antagonist larazotide acetate. In this review, we will focus on CD as a paradigm of chronic inflammatory diseases in order to outline the contribution of gut paracellular permeability toward disease pathogenesis; moreover, we will summarize current evidence derived from available clinical trials of larazotide acetate in CD.

Are ESPGHAN "biopsy-sparing" guidelines for celiac disease also suitable for asymptomatic patients?

OBJECTIVES: In 2012, European Society of Pediatric Gastroenterology, Hepatology, and Nutrition published novel guidelines on celiac disease (CD) diagnosis. Symptomatic children with serum anti-transglutaminase (anti-tTG) antibody levels ≥10 times upper limit of normal (ULN) could avoid duodenal biopsies after positive HLA test and serum anti-endomysial antibodies (EMAs). So far, both asymptomatic and symptomatic patients with anti-tTG titer <10 times ULN should undergo upper endoscopy with duodenal biopsies to confirm diagnosis. The aim of this study was to assess the accuracy of serological tests to diagnose CD in asymptomatic patients. METHODS: We retrospectively reviewed data of 286 patients (age range: 10 months to 17 years) with CD diagnosis based on elevated titer of anti-tTG, EMA positivity, and histology. All patients were distinguished between symptomatic and asymptomatic; histological lesions were graded according to the Marsh-Oberhuber (MO) criteria. Fisher exact test was applied to analyze both groups in terms of diagnostic reliability of serological markers. RESULTS: A total of 196 patients (68.53%) had anti-tTG titers ≥10 times ULN. Among them, a group of 156 patients (79.59%) also had symptoms suggestive of CD ("high-titer" symptomatic); of these, 142 patients (91.02%) showed severe lesion degree (3a, 3b, 3c MO). Conversely, 40 out of 196 patients (20.40%) were asymptomatic ("high-titer" asymptomatic) and 37 patients (92.5%) of them showed severe lesion degree (3a, 3b, 3c MO). No difference in histological damage was found between "high-titer" symptomatic and "high-titer" asymptomatic children (Fisher exact test, P=1.000). CONCLUSIONS: If confirmed in large multicenter prospective studies, the "biopsy-sparing" protocol seems to be applicable to both symptomatic and asymptomatic patients with anti-tTG titer ≥10 times ULN, positive EMA, and HLA-DQ2/DQ8.

Mapping histologic patchiness of celiac disease by push enteroscopy.

BACKGROUND: Despite great improvements in serologic testing, duodenal biopsies are still required to diagnose the majority of celiac disease (CD) cases. Nevertheless, the histologic pattern of CD is often patchy, leading to the risk of missing the diagnosis. OBJECTIVE: To evaluate the patchiness of the CD histologic lesions along the small bowel (SB), push enteroscopy has been performed instead of conventional upper GI endoscopy. DESIGN: Prospective, single-center study. SETTING: Tertiary-care referral center. PATIENTS: A total of 41 pediatric patients with suspected CD. INTERVENTION: Prospective evaluation of bulb, duodenal, and jejunal biopsy specimens in the diagnosis of CD. MAIN OUTCOME MEASUREMENTS: Pattern of lesion distribution along the SB (from bulb up to 60 cm beyond the ligament of Treitz) and yield as well accuracy of pediatric CD diagnosis by using push enteroscopy. RESULTS: There was a homogeneous pattern of histologic damage in 17 patients (41.5%), whereas 24 patients (58.5%) had a lesion pattern of patchiness. The second and fourth duodenal regions were involved in 38 children (92.7%) and 37 children (90.2%), respectively; the bulb was involved in 37 patients (90.2%); both distal and proximal jejunal samples showed histologic lesions in 38 children (92.7%). In 1 patient, without lesions in the bulb and duodenum, CD was diagnosed according to proximal and distal jejunal biopsies only (3B and C, respectively). A significant correlation was found between the degree of villous atrophy and the serum anti-transglutaminase titer. LIMITATIONS: Small sample size; academic tertiary-care setting. CONCLUSION: CD histologic lesions often have a discontinuous distribution along the SB, occasionally with an exclusive jejunal involvement. A high degree of villous atrophy correlates with a high anti-transglutaminase titer. When the new ESPGHAN "biopsy-sparing" criteria are not applicable, in case of potential CD, push enteroscopy might be a valuable second-step tool to re-evaluate and identify false "potential" CD hiding exclusive jejunal lesions.

Autoimmune enteropathy in a 13-year-old celiac girl successfully treated with infliximab.

Autoimmune enteropathy (AIE) is a rare cause of small bowel villous atrophy, characterized by malabsorption, unresponsiveness to dietary restriction, circulating autoantibodies to enterocytes, and an overall predisposition to autoimmunity. Albeit mainly regarded as a disease of early childhood, several adult-onset AIE cases have been identified. This report describes for the first time the life-threatening clinical presentation and the management of overlapping AIE in a compliant-to-diet young celiac girl. A 13-year-old celiac girl was admitted because of vomiting, weight loss, diarrhea, hypoproteinemia, and neurological disturbances such as head tremors, vertical nystagmus, and lower limb hyperesthesia. Before this, she had always been compliant on a strict gluten-free diet and her medical history was unremarkable. The diagnosis of AIE was established on histologic findings and on the presence of antienterocyte antibodies. She was initially treated with high-dose Methylprednisolone and Azathioprine. However, only Infliximab proved itself as a highly effective tool for achieving clinical remission and restoring small bowel villous architecture.

Lack of clinical predictors for low mineral density in children with celiac disease.

OBJECTIVES: Metabolic bone disease remains a significant and common complication of celiac disease (CD). Several studies have demonstrated low bone mineral density (BMD) at the time of CD diagnosis in both children and adults. Low BMD in children and adolescents is defined as an areal BMD <2 SD below the age-adjusted mean value (z score <-2 SD). The aim of the study was to evaluate the BMD in a pediatric population with CD at diagnosis and to correlate z score value, anti-tissue transglutaminase type 2 antibody (anti-tTG2) titer, symptoms, and Marsh-Oberhuber (MO) grading. METHODS: We enrolled 99 patients with celiac disease (male 35, female 64) ages 4 to 15 years at the diagnosis. All of the patients had positive test results for anti-tTG2 antibodies and histological lesions graded according to MO classification, and underwent lumbar dual-energy x-ray absorptiometry. BMD was estimated by z score. RESULTS: Low BMD (z score ≤-2 SD) was found in 13 (13.13%) patients; 22 (22.22%) patients with CD showed -2 < z score ≤ -1; -1 < z score < 0 was found in 41 (41.41%) patients. z score ≥ 0 was detected only in 23 (23.23%) patients with CD. Mean BMD value in patients with CD is z score -0.68. No correlations were found between z score value and anti-tTG2 titer (Spearman ρ 0.13), between z score value and MO degree (Spearman ρ -0.17), and between z score and symptoms (Spearman ρ-0.10). CONCLUSIONS: BMD of patients with CD at diagnosis does not seem to correlate with MO degree, anti-tTG2 titer, and symptoms. At the moment, we do not have clinical predictors for low mineral density in children with CD.

Effects of Nasal Solution Incorporating Resveratrol and Carboxymethyl-Β-Glucan in Preschool Non-Atopic Children with Wheezing.

Upper respiratory tract infections (URTI) account for more than 80% of wheezing episodes in children with a high incidence of hospitalization in preschool age. Most children with symptoms of wheezing during an URTI are usually non-atopic. As the majority of wheezing episodes resulting from URTI are attributed to viral triggers, several studies have suggested the potential anti-inflammatory and antiviral properties of resveratrol. This study aims to identify the effect of resveratrol for pediatric non-atopic patients with recurrent wheezing triggered by URTIs. We conducted a prospective single-blind study to assess the effectiveness of a short course of nasal solutions incorporating resveratrol and carboxymethyl-ß-glucan, administered for 7 days at the onset of URTIs, compared to standard nasal lavage with 0.9% saline solution. A total of 19 patients entered the active group, 20 patients were assigned to the placebo group. The comparison of overall wheezing days (p < 0.001), mean wheezing days per month (p < 0.01), and wheezing episodes per patient (p < 0.001) in the two groups showed a significant reduction in the group receiving resveratrol compared with the placebo group, with less hospital access (p < 0.001) and oral corticosteroid administration (p < 0.01). Our findings seem to suggest that, in non-atopic children with recurrent wheezing secondary to URTIs, nasal resveratrol could be effective to prevent or reduce the occurrence of wheezing, when started from the onset of upper airway symptoms.

Probiotics and other adjuvants in allergen-specific immunotherapy for food allergy: a comprehensive review.

This review delves into the potential of manipulating the microbiome to enhance oral tolerance in food allergy, focusing on food allergen-specific immunotherapy (FA-AIT) and the use of adjuvants, with a significant emphasis on probiotics. FA-AIT, including oral (OIT), sublingual (SLIT), and epicutaneous (EPIT) immunotherapy, has shown efficacy in desensitizing patients and achieving sustained unresponsiveness (SU). However, the long-term effectiveness and safety of FA-AIT are still under investigation. Probiotics, particularly strains of Lactobacillus, play a crucial role in enhancing immune tolerance by promoting regulatory T cells (Tregs) and modulating cytokine profiles. These probiotics can induce semi-mature dendritic cells, enhance CD40 expression, inhibit IL-4 and IL-5, and promote IL-10 and TGF-ß, thus contributing to mucosal defense and immunological tolerance. Clinical trials combining probiotics with FA-AIT have demonstrated improved desensitization rates and immune tolerance in food-allergic patients. For example, the combination of Lactobacillus rhamnosus with peanut OIT resulted in a significantly higher rate of SU compared to the placebo group, along with notable immune changes such as reduced peanut-specific IgE and increased IgG4 levels. The review also explores other adjuvants in FA-AIT, such as biologic drugs, which target specific immune pathways to improve treatment outcomes. Additionally, nanoparticles and herbal therapies like food allergy herbal formula 2 (FAHF-2) are discussed for their potential to enhance allergen delivery and immunogenicity, reduce adverse events, and improve desensitization. In conclusion, integrating probiotics and other adjuvants into FA-AIT protocols could significantly enhance the safety and efficacy of FA-AIT, leading to better patient outcomes and quality of life.

Zonulin as a Biomarker for the Development of Celiac Disease.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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 = ß = 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). CONCLUSIONS: 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.

Prevalence of delivery mode in an Italian nationwide cohort with celiac disease: a SIGENP multicenter retrospective study (the CD-deliver-IT).

BACKGROUND: Studies have indicated an association between cesarean section (CS), especially elective CS, and an increased risk of celiac disease (CD), but the conclusions of other studies are contradictory. The primary aim of this study (CD-deliver-IT) was to evaluate the rate of CS in a large population of CD patients throughout Italy.  METHODS: This national multicenter retrospective study was conducted between December 2020 and November 2021. The coordinating center was the Pediatric Gastroenterology and Liver Unit of Policlinico Umberto I, Sapienza, University of Rome, Lazio, Italy. Eleven other referral centers for CD have participated to the study. Each center has collected data on mode of delivery and perinatal period of all CD patients referring to the center in the last 40 years. RESULTS: Out of 3,259 CD patients recruited in different Italian regions, data on the mode of delivery were obtained from 3,234. One thousand nine hundred forty-one (1,941) patients (60%) were born vaginally and 1,293 (40%) by CS (8.3% emergency CS, 30.1% planned CS, 1.5% undefined CS). A statistically significant difference was found comparing median age at time of CD diagnosis of patients who were born by emergency CS (4 years, CI 95% 3.40-4.59), planned CS (7 years, CI 95% 6.02-7.97) and vaginal delivery (6 years, CI 95% 5.62-6.37) (log rank p < 0.0001). CONCLUSIONS: This is the first Italian multicenter study aiming at evaluating the rate of CS in a large population of CD patients through Italy. The CS rate found in our CD patients is higher than rates reported in the general population over the last 40 years and emergency CS seems to be associated with an earlier onset of CD compared to vaginal delivery or elective CS in our large nationwide retrospective cohort. This suggests a potential role of the mode of delivery on the risk of developing CD and on its age of onset, but it is more likely that it works in concert with other perinatal factors. Further prospective studies on other perinatal factors potentially influencing gut microbiota are awaited in order to address heavy conflicting evidence reaming in this research field.

Celiac Disease on the Bed-Side: Embedding Case Finding and Screening in Hospitalized Children.

BACKGROUND: Strategies for diagnosing celiac disease (CD) include case-finding and population-screening programs. Case finding consists of testing individuals at increased risk for the disease due to symptoms or associated conditions. Screening programs are widespread campaigns, which definitely perform better in terms of unveiling CD diagnoses but nowadays are still debatable. The global prevalence of CD is around 1% but it almost doubles when considering screening programs among school children. Within this framework, we aimed to estimate the prevalence of CD among hospitalized children in the Pediatric Department of a Southern Italy University Hospital in the period from January 2018 through December 2021. In addition, we attempted to explore, at the time of diagnosis, the prevalence of leading clinical alerts due to malabsorption/malnutrition such as anemia or failure to thrive or due to systemic inflammation/immune dysfunction as hypertransaminasemia and thyroid dysfunction. METHODS: Data records of pediatric patients admitted as inpatients and tested by anti-transglutaminase IgA antibodies (TGA-IgA) were retrospectively analyzed. CD was diagnosed according to either 2012 or 2020 ESPGHAN guidelines, depending on the year of diagnosis. CD autoimmunity (CDA) was a wider group defined within our protocol if patients had elevated TGA-IgA on at least one occasion, regardless of anti-endomysial antibodies (EMA-IgA) and without biopsy confirmation. RESULTS: During the observation period, 3608 pediatric patients were admitted and 1320 were screened for CD (median age 5 years, IQR 2-9 years; CD test rate: 36.6% out of all admissions). The available prevalence of newly diagnosed CD was 1.59% (21 patients diagnosed) and the available prevalence of CDA was 3.86% (51 subjects). Among CD patients, underweight/malnourished children accounted for 28.6% (6 out of 21). CONCLUSIONS: The estimated prevalence of CD diagnoses within our setting was comparable to the most recent population-screening programs. The estimated prevalence of CDA was even higher. A hospital-admission CD testing during routine blood draws might be a non-invasive, cost-effective and valuable approach to reduce discrepancy of prevalence between case-finding and population-screening programs.