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To elucidate the pathophysiological changes leading to postantibiotic diarrhoea caused by Clostridium difficile and its cytotoxin, oral ampicillin was given to rabbits, and jejunal, ileal, and caecal segments of those that developed diarrhoea were investigated in vitro. The rabbits that, in response to treatment, harboured Clostridium difficile in their colonic lumen were studied, and the results expressed according to the presence or absence of Clostridium difficile and/or its cytotoxin. Thus, we refer to either CD+ or CD- segments. The influx of glucose, phenylalanine, glycylphenylalanine, and lysine across the brush border of jejunum and ileum of CD+ segments was severely impaired, while only slightly blunted in CD-. No significant change was detected in the influx of glutamic acid in the jejunum of all treated animals and in the CD- ilea. Morphologic damage in ileum and caecum of CD+ was also more evident than in CD-. Transepithelial ion transport across short circuited ileal mucosa (CD+ and CD-) revealed secretory changes in Cl net transport that were more marked in CD-. We conclude that: (1) Clostridium difficile may also colonise the upper intestinal tract, where it induces morphological and functional damage, severely impairing nutrient absorption; and (2) the ileum contributes to the diarrhoea caused by CD even when the micro-organism is confined to the more distal gut by showing moderate impairment of nutrient absorption and marked electrolyte secretion. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate the efficacy of a multispecies probiotic on clinical and laboratory recovery of children with celiac disease (CeD) at diagnosis., Methods: Children with newly diagnosed CeD entered a randomized double-blind placebo-controlled trial. A gluten-free diet (GFD) plus a multispecies probiotic or placebo were administered for 12 weeks. Growth, laboratory, and clinical parameters were recorded at enrollment, after 3 and 6 months of follow-up., Results: Overall, 96 children completed the study: 49 in group A (placebo) and 47 in group B (probiotic). A significant increase of BMI-Z score was found in both groups after 3 and 6 months of treatment (p < 0.001), however the increase of BMI-Z score was significantly higher and faster in Group B than in Group A. Other clinical and laboratory parameters improved in both groups after 3 and 6 months (p<0.001), but no difference was found between the groups and a comparable time trend was observed in both groups., Conclusions: Treatment with a multispecies probiotic induced a higher and faster increase of BMI in children with newly diagnosed CeD. The mechanism of this positive effect remains to be elucidated., Competing Interests: Funding and Conflict of Interest Carlo Catassi served as consultant for dr Schaer. The other authors have no conflict of interest to declare. This study was funded by Noos s.r.l., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Celiac disease is a common lifelong disorder. Recent studies indicate that the number of clinically detected cases has increased over the last decades, however little is known about changes in the prevalence and the detection rate of celiac disease., Aim: To evaluate the current prevalence and detection rate of celiac disease in Italy by a multicenter, mass screening study on a large sample of school-age children., Methods: children aged 5-11 years were screened at school by HLA-DQ2 and -DQ8 determination on a drop of blood in six Italian cities; total serum IgA and IgA anti-transglutaminase were determined in children showing HLA-DQ2 and/or -DQ8 positivity. Diagnosis of celiac disease was confirmed according to the European guidelines., Results: 5994 children were eligible, 4438 participated and 1873 showed predisposing haplotypes (42.2%, 95% CI=40.7-43.7). The overall prevalence of celiac disease was 1.65% (95% CI, 1.34%-2.01%). Only 40% of celiac children had been diagnosed prior to the school screening. Symptoms evoking celiac disease were as common in celiac children as in controls., Conclusion: In this multicenter study the prevalence of celiac disease in school-age Italian children was one of the highest in the world. Determination of HLA predisposing genotypes is an easy and fast first-level screening test for celiac disease. Without a mass screening strategy, 60% of celiac patients remain currently undiagnosed in Italy., Competing Interests: Conflict of interest Prof Carlo Catassi has served as scientific consultant for Dr. Schaer Food and NOOS s.r.l. The other co-authors have no conflict to declare., (Copyright © 2022. Published by Elsevier Ltd.)

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., (Copyright © 2023 by The American College of Gastroenterology.)

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., Competing Interests: Competing interest statement: M.M.L. serves as a consultant to 9 Meters Biopharma and Anokion and performs sponsored research with Glutenostics LLC. H.K. is a former employee of, B.F. is a current employee of, P.S. is a consultant for, and N.A.H. and R.C. are stockholders at CosmosID Inc. A.F. is a stockholder at Alba Therapeutics, serves as a consultant for Inova Diagnostics and Innovate Biopharmaceuticals, is an advisory board member for Axial Biotherapeutics, and has a speaker agreement with Mead Johnson Nutrition. All other authors have declared that no competing interests exist., (Copyright © 2021 the Author(s). Published by PNAS.)

Objective: To evaluate the vitamin D status of children with a new diagnosis of celiac disease compared with healthy controls., Study Design: This was a case-control study. Cases were consecutive children with newly diagnosed celiac disease. Controls were healthy children matched for age, sex, ethnicity, and month of blood testing. Plasma 25-hydroxyvitamin D (25-OHD) was measured as the index of vitamin D nutritional status. The Student t test was used for comparisons. Differences in frequencies were evaluated with the χ 2 test. Associations between variables were estimated by calculating Pearson correlation coefficients., Results: There were 131 children with celiac disease enrolled (62% females; mean age 8.1 ± 1.1 years). The control group included 131 healthy children (62% females; mean age 8.2 ± 1.2). All were of European origin. Plasma 25-OHD levels were significantly lower in patients than in controls (25.3 ± 8.0 and 31.6 ± 13.7 ng/mL; P < .0001). The percentage of children with vitamin D deficiency (<20 ng/mL) was significantly higher in children with celiac diseaseas compared with controls (31% vs 12%; P < .0001). The concentration of 25-OHD was significantly lower in patients than in controls during summer (P < .01) and autumn (P < .0001)., Conclusions: In this case-control study, at diagnosis, children with celiac disease showed lower levels of plasma 25-OHD compared with healthy subjects. Vitamin D status should be checked at diagnosis of celiac disease, particularly during summer and fall months., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Celiac disease (CD) is an autoimmune digestive disorder that occurs in genetically susceptible individuals in response to ingesting gluten, a protein found in wheat, rye, and barley. Research shows that genetic predisposition and exposure to gluten are necessary but not sufficient to trigger the development of CD. This suggests that exposure to other environmental stimuli early in life, e.g., cesarean section delivery and exposure to antibiotics or formula feeding, may also play a key role in CD pathogenesis through yet unknown mechanisms. Here, we use multi-omics analysis to investigate how genetic and early environmental risk factors alter the development of the gut microbiota in infants at risk of CD., Results: Toward this end, we selected 31 infants from a large-scale prospective birth cohort study of infants with a first-degree relative with CD. We then performed rigorous multivariate association, cross-sectional, and longitudinal analyses using metagenomic and metabolomic data collected at birth, 3 months and 6 months of age to explore the impact of genetic predisposition and environmental risk factors on the gut microbiota composition, function, and metabolome prior to the introduction of trigger (gluten). These analyses revealed several microbial species, functional pathways, and metabolites that are associated with each genetic and environmental risk factor or that are differentially abundant between environmentally exposed and non-exposed infants or between time points. Among our significant findings, we found that cesarean section delivery is associated with a decreased abundance of Bacteroides vulgatus and Bacteroides dorei and of folate biosynthesis pathway and with an increased abundance of hydroxyphenylacetic acid, alterations that are implicated in immune system dysfunction and inflammatory conditions. Additionally, longitudinal analysis revealed that, in infants not exposed to any environmental risk factor, the abundances of Bacteroides uniformis and of metabolite 3-3-hydroxyphenylproprionic acid increase over time, while those for lipoic acid and methane metabolism pathways decrease, patterns that are linked to beneficial immunomodulatory and anti-inflammatory effects., Conclusions: Overall, our study provides unprecedented insights into major taxonomic and functional shifts in the developing gut microbiota of infants at risk of CD linking genetic and environmental risk factors to detrimental immunomodulatory and inflammatory effects. Video Abstract.

Background: Despite a well-established diagnostic algorithm for celiac disease, it remains unclear whether prescriptions for celiac serological tests comply with the current pediatric guidelines., Aim: To analyze the appropriateness of test prescription in children investigated for celiac disease in Italy, compared to the current European pediatric guidelines., Methods: All children who had performed a first evaluation for celiac disease were prospectively enrolled. Prescribed tests and related indications for testing were recorded, and compared to the European pediatric guidelines., Results: Overall, 202 children were enrolled (females 59%, mean age 7.1 years ±4.1) in two centers. The reasons for celiac disease testing were typical, atypical symptoms or celiac disease-associated conditions in 46.5%, 49%, and 4.5% of cases, respectively. First-line tests were IgA and IgG anti-transglutaminase antibodies in 88.1% and 29.7% of children, IgA and IgG anti-deamidated gliadin peptide antibodies in 43% and 47%, IgA and IgG anti native gliadin in 15.8%, IgA anti-endomysium antibodies in 44.5%, HLA predisposing genes in 10% of patients. Test redundancy was very common, and the current diagnostic guidelines were correctly followed only in 23/202 patients (11.4%)., Conclusions: Diagnostic European guidelines for celiac disease screening are often disregarded in Italy. Intervention to implement adherence to these guidelines is needed, with the aim of improving resource utilization, and quality of patient care., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background Familial hypercholesterolemia (FH) is a genetic disorder caused by mutations in genes involved in low-density lipoprotein (LDL) uptake (LDLR, APOB and PCSK9). Genetic diagnosis is particularly useful in asymptomatic children allowing for the detection of definite FH patients. Furthermore, defining their genetic status may be of considerable importance as the compound heterozygous status is much more severe than the heterozygous one. Our study aims at depicting the genetic background of an Italian pediatric population with FH focusing on the correlation between lipid profile and genetic status. Methods Out of 196 patients with clinically suspected FH (LDL-cholesterol [LDL-C] levels above 3.37 mmol/L, cholesterol level above 6.46 mmol/L in a first-degree relative or the presence of premature cardiovascular acute disease in a first/second-degree relative), we screened 164 index cases for mutations in the LDLR, APOB and PCSK9 genes. Results Patients with mutations (129/164) showed increased levels of LDL-C, 95th percentile-adjusted LDL-C and LDL/high-density lipoprotein (HDL) ratio and decreased levels of HDL-C, adjusted HDL-C. The association of the LDL/HDL ratio with the presence of mutations was assessed independently of age, (body mass index) BMI, parental hypercholesterolemia, premature coronary artery disease (CAD), triglycerides by multivariate logistic regression (odds ratio [OR]=1.701 [1.103-2.621], p=0.016). The LDL/HDL ratio gradually increased from patients without mutations to patients with missense mutations, null mutations and compound heterozygotes. Conclusions In conclusion, the LDL/HDL ratio proved to be a better parameter than LDL-C for discriminating patients with from patients without mutations across different genetic statuses.

Background: Iodine is an essential micronutrient for intellectual development in children. Information on iodine intakes based on 24-h urinary iodine excretion (UIE) is scant, because iodine status is only assessed by the measurement of urinary iodine concentration (UIC) in spot urine samples., Objectives: The aim of our study was to evaluate the iodine intake of school-age children and adolescents, using UIE measurement in 24-h urine collections., Methods: The study population included 1270 healthy subjects (677 boys, 593 girls) aged 6-18 y (mean age ± SD: 10.3 ± 2.9) from 10 Italian regions. Daily iodine intake was estimated as UIE/0.92, based on the notion that $\sim$92% of the dietary iodine intake is absorbed. The adequacy of intakes was assessed according to the Dietary Reference Values for iodine of the European Food Safety Authority (EFSA). Body mass index (BMI) and UIC were also measured for each subject., Results: Based on the scientific opinion of EFSA, 600 of 1270 subjects (47.2%) had a lower than adequate iodine intake, with a higher prevalence among girls (54.6%) compared with boys (40.2%) (P < 0.001). Although UIE and 24-h urinary volumes increased with age (P < 0.001), a progressive decrease in the percentage of subjects with iodine excretion <100 µg/24 h (P < 0.001) was observed, without any significant difference in the percentage of subjects with UIC <100 µg/L. No significant association was detected between BMI z-score and UIE (P = 0.603) or UIC (P = 0.869)., Conclusions: A sizable proportion of our population, especially girls, appeared to be at risk of iodine inadequacy. The simple measurement of UIC could lead to underestimation of the occurrence of iodine deficiency in younger children, because of the age-related smaller urine volumes producing spuriously higher iodine concentrations., (Copyright © American Society for Nutrition 2019.)

Gastro-oesophageal reflux is common in children, especially in the first year of life, and it may be regarded as physiological. Good functioning of the lower oesophageal sphincter depends largely on the anatomical relationships between oesophagus, stomach and diaphragm hiatus. Relative immaturity of these structures in newborn babies and young children is a risk factor in reflux disease, which may result in a wide variety of typical and/or atypical symptoms and, sometimes, serious complications such as oesophagitis and stenosis. Reflux disease may be diagnosed and studied, basing on morphological and functional aspects and, since the advent of pH-metry, it is possible to personalise the therapeutic approach to children with reflux. Surgical treatment of reflux disease in children has recently been improved due to a mini-invasive surgical approach. Absolute indications are recurrent pneumonia, intractable pain due to oesophagitis and retarded growth, often in association with neurological impairment. In the last three years, 18 children with reflux disease underwent videolaparoscopic surgery in our department, 14 by the Nissen and 4 by the Toupet technique. Post-operative pH-metry always showed a reduction in exposure of the distal oesophagus to acid (integral of H+) and an improvement in oesophageal clearance (short refluxes percentage) indicative of good functioning of the gastro-oesophageal junction. PH-metry proved to be an invaluable technique for planning therapeutic strategy. In follow-up evaluations, it enabled us to monitor functioning of the gastro-oesophageal junction and to avoid other more difficult and invasive tests in patients with severe neurological impairment.

According to the 2012 ESPGHAN criteria for diagnosis of celiac disease (CD), duodenal biopsy (DB) can be avoided in children with a clear malabsorption syndrome, anti-tissue transglutaminase IgA (tTG2) ≥ 10x the cut-off, anti-endomysium IgA (EMA) and HLA DQ2/DQ8 genes. The aim of this study is to report our experience and evaluate the accuracy of the actual guidelines., Patients and Methods: This is a retrospective study conducted on all patients diagnosed CD from 2012 to 2018 in our Center. For all patients enrolled were analyzed: data of family history, symptoms, serology, genetics, Marsh grade and follow-up., Results: A total of 481 children [mean age 6,4 yrs; F:M= 1.8:1] were included in the study. The mean age of patients who were not subject to DB was lower (4.51 yrs) comparing with patients that received DB (6.48 yrs). Out of the 256 patients with anti-tTG2 ≥ 10 fold, 121 underwent DB because of mild symptoms (84/121) or no symptoms (37/121). In all cases Marsh type 3 was found and HLA haplotypes was compatible with CD diagnosis., Conclusions: Our study confirms that the serology has a primary importance to diagnose CD, regardless of the symptoms. These data suggest that biopsy and HLA haplotypes search, in presence of anti-tTG2 IgA ≥ 10x the cut-off, are wasteful and unhelpful for the patients.

Background: As of now, no established model for the transition from childhood to adulthood in coeliac disease exists. We aim to describe the dietary compliance and the quality of life of a population of young coeliac disease patients around transition age and to develop a practical tool (TRANSIT-CeD disk) which can be used during the transition process effectively to transmit young adults to the adult healthcare giver., Methods: We consecutively recruited all coeliac disease patients with a paediatric diagnosis (≤16 years) and aged between 9 and 20 years at the time of the study. The patients were asked to answer some questions concerning their adherence to a gluten-free diet, knowledge about coeliac disease, relationship with healthcare givers and quality of life., Results: We included 58 subjects, mean age 14.5 ± 3.6 years, of which 62% were girls/young women. We observed that dietary compliance was independently and positively related to age at diagnosis and coeliac disease knowledge, while quality of life was only independently and positively related to coeliac disease knowledge., Conclusion: A good coeliac disease knowledge is positively related to dietary compliance and quality of life. With the help of the TRANSIT-CeD disk we proposed, paediatricians and adult gastroenterologists can follow the patients during the transition and identify some points to work on.