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.

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.

Promotion of breastfeeding in Italian Maternity Hospitals: a pre-intervention study.

BACKGROUND: In Italy, exclusive breastfeeding (EBF) rates at hospital discharge range unsatisfactorily between 20-97%. METHODS: In 2023, the Project for Hospital Policy on Breastfeeding (HPB) has been launched to promote breastfeeding in Italian Maternity Hospitals (MHs) as a joint initiative of the Italian Scientific Societies involved in perinatal care together with the National Midwife (FNOPO) and Nurse (FNOPI) Boards and with Vivere Onlus, a family association. The HBP Project has been designed as an uncontrolled before-after study to increase EBF rate at hospital discharge in the population of healthy, term infant with a normal weight at birth following an intervention bundle comprising: 1) Establishment of a local hospital Working Group; 2) Adoption of a hospital policy; 3) Implementation of breastfeeding monitoring; 4) Training for perinatal care professionals; 5) Enhanced implementation of the practices of skin-to-skin contact (SSC) and mother-baby rooming-in; 6) Development/Improvement of perinatal care protocols. RESULTS: We report the pre-intervention assessment of 89 out of the 111 enrolled MHs (80.2%) at the beginning of the Project (Time 1 or T1). Almost all MHs (96.6%) have a multi-professional Breastfeeding Working Group, while a hospital policy on breastfeeding is available only in 48.2%. Moreover, only 56.2% of the 9,777 perinatal health workers have been trained in breastfeeding. Over a 1-month period, SSC has been practiced in the delivery room by 76.9% of 6,304 term healthy newborn infants and rooming-in by 83.4% of 6,735 healthy term newborns of normal weight at birth. Over a 4-month period, 69.1% of 33,367 healthy term newborns of normal birth weight were exclusively breastfed at hospital discharge. Noticeably, EBF rate of MHs ranges from 4% up to 100%, the second quartile being 73%. CONCLUSION: At T1 of the HPB Project, breastfeeding rates at hospital discharge for healthy, term infants with a normal weight at birth appear to be suboptimal among Italians MHs. Particularly, the range of EBF rates among participating centers is wide, with 50% of the MHs having EBF rate lower than 73%. Therefore, the ongoing HPB Project might represent not only an opportunity to increase the initiation of breastfeeding and to improve quality of health care in the whole study group of MHs, but possibly also to level differences between centers.

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.

Current hospital policies on breastfeeding: a survey from Italy.

BACKGROUND: The availability of an appropriate newborn feeding policy is an essential component of the promotion of breastfeeding in health facilities. The Italian Society of Neonatology (SIN) and the Italian Society of Paediatrics (SIP) have run an online survey among Maternity Hospitals to explore the existing breastfeeding policies and their characteristics. METHODS: Between February and April 2023, an online survey was carried out among 110 Italian maternity hospitals with a Neonatal Intensive Care Unit (NICU). RESULTS: Forty-nine Maternity Hospitals completed the online questionnaire. Twenty out of 49 (40.8%) reported to have a breastfeeding policy. When a policy is available, its quality appears to be suboptimal because of lack of inclusion of a family representative in the policy working group, limited options for translating breastfeeding policy into minority languages, lack of periodic assessment of their implementation. CONCLUSION: Currently, only a limited number of Italian Maternity Hospitals have developed a breastfeeding policy. Additional efforts are needed for their improvement as well as implementation.

Cohort profile: Celiac disease genomic, environmental, microbiome and metabolome study; a prospective longitudinal birth cohort study of children at-risk for celiac disease.

The Celiac Disease Genomic, Environmental, Microbiome and Metabolomic (CDGEMM) study is an international prospective birth cohort in children at-risk of developing celiac disease (CD). The CDGEMM study has been designed to take a multi-omic approach to predicting CD onset in at-risk individuals. Participants are required to have a first-degree family member with biopsy diagnosed CD and must be enrolled prior to the introduction of solid food. Participation involves providing blood and stool samples longitudinally over a period of five years as well as answering questionnaires related to the participant, their family, and environment. Recruitment and data collection have been ongoing since 2014. As of 2022 we have a total of 554 participants and the average age of the cohort is 56.4 months. A total of 54 participants have developed positive antibodies for CD and 31 have confirmed CD. Approximately 80% of the 54 participants with CD have developed it by 3 years of age. To date we have identified several microbial strains, pathways, and metabolites occurring in increased abundance and detected before CD onset, which have previously been linked to autoimmune and inflammatory conditions while others occurred in decreased abundance before CD onset and are known to have anti-inflammatory effects. Our ongoing analysis includes expanding our metagenomic and metabolomic analyses, evaluating environmental risk factors linked to CD onset, and mechanistic studies investigating how alterations in the microbiome and metabolites may protect against or contribute to CD development.

Role of inflammation in pediatric irritable bowel syndrome.

BACKGROUND: IBS affects a large number of children throughout the world and is thought to be the result of disturbed neuroimmune function along with the brain-gut axis. Although the underlying pathophysiologic mechanisms are not clear, the role of low-grade inflammation and mucosal immune activation in IBS symptom generation has become evident also in subsets of pediatric patients. Animal models provided meaningful insight in the causal relationship between abnormal mucosal immune activation and changes in gastrointestinal (GI) sensory-motor function. Likewise, the development of long-standing GI symptoms fulfilling the current criteria for functional GI disorders after infection gastroenteritis and in patients with IBD or celiac disease in remission further supports this hypothesis. Immune activation, its impact on gut sensory-motor function, and potential implications for symptom generation emerged in both children and adults with IBS. PURPOSE: The aim of this review is to summarize the main evidence on the presence of low-grade inflammation and immune activation in children with IBS, its possible role in symptom generation, and its potential implication for new therapeutic strategies.

Probiotics and Functional Gastrointestinal Disorders in Pediatric Age: A Narrative Review.

Assessment and management of pain are essential components of pediatric care. Pain in pediatric age is characterized by relevant health and socio-economic consequences due to parental concern, medicalization, and long-term physical and psychological impact in children. Pathophysiological mechanisms of nociception include several pathways in which also individual perception and gut-brain axis seem to be involved. In this narrative review, we analyze the rational and the current clinical findings of probiotic use in the management of functional gastrointestinal disorders (FGID) in pediatric age, with special focus on infantile colic, irritable bowel syndrome, constipation, and gastroesophageal reflux. Some specific probiotics showed a significant reduction in crying and fussing compared to placebo in breastfed infants with colic, although their exact mechanism of action in this disorder remains poorly understood. In irritable bowel syndrome, a limited number of studies showed that specific strains of probiotics can improve abdominal pain/discomfort and bloating/gassiness, although data are still scarce. As for constipation, whilst some strains appear to reduce the number of hard stools in constipated children, the evidence is not adequate to support the use of probiotics in the management of functional constipation. Similarly, although some probiotic strains could promote gastric emptying with a potential improvement of functional symptoms related to gastroesophageal reflux, current evidence is insufficient to provide any specific recommendation for the prevention or treatment of gastroesophageal reflux. In conclusion, probiotics have been proposed as part of management of pain in functional gastrointestinal disorders in pediatric age, but mechanisms are still poorly understood and evidence to guide clinical practice is currently inadequate.

Apnea in preterm neonates: what's the role of gastroesophageal reflux? A systematic review.

A causal relationship between gastro-esophageal reflux (GER) and apnea in preterm infants has been frequently hypothesized and is currently debated. The present study aims at reviewing the currently available scientific evidence, in order to clarify the role of GER on the occurrence of apnea and to help improving the clinical management of apneic preterm neonates. We performed a systematic literature search to identify all the clinical studies on preterm neonates that properly assessed the relationship between apnea and GER. Two-hundred and fifty-two papers, including 32 reviews and meta-analysis, were screened. Out of them, only 7 were included in the final analysis according to the selected criteria. Among them, 3 studies reported an increased frequency of apnea after reflux compared to reflux-free period and 4 denied a significant temporal relation. In conclusion, a minority of apneic events occurs soon after GER episodes. Whether this happens by chance or because of a causal relationship is still impossible to define. Based on the available data, empirical treatment with acid inhibitors is not recommended in neonates with apnea unless a proven temporal relation is shown by simultaneous esophageal pH-impedance and polysomnography or cardiorespiratory monitoring and in the absence of a clear clinical benefit.

Fecal calprotectin: cutoff values for identifying intestinal distress in preterm infants.

This study aimed to determine cutoff levels for fecal calprotectin as a marker of intestinal distress in preterm neonates. A total of 126 infants born at a median gestational age of 33 weeks (range 25.7-35 weeks) were enrolled. Samples (n = 312) were collected weekly from the end of the first week of life until the end of the first month and if any gastrointestinal event occurred. Receiver operating characteristic curves analysis gave cutoff values of 363 microg/g (sensitivity 0.65, specificity 0.82) and 636 microg/g (sensitivity 0.72, specificity 0.95) for the development of mild or severe enteropathy.

Esophageal pH-impedance monitoring in children: position paper on indications, methodology and interpretation by the SIGENP working group.

Multichannel intraluminal impedance pH (MII-pH) monitoring currently represents the gold standard diagnostic technique for the detection of gastro-esophageal reflux (GER), since it allows to quantify and characterize all reflux events and their possible relation with symptoms. Over the last ten years, thanks to its strengths and along with the publication of several clinical studies, its worldwide use has gradually increased, particularly in infants and children. Nevertheless, factors such as the limited pediatric reference values and limited therapeutic options still weaken its current clinical impact. Through an up-to-date review of the available scientific evidence, our aim was to produce a position paper on behalf of the working group on neurogastroenterology and acid-related disorders of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP) on MII-pH monitoring technique, indications and interpretation in pediatric age, in order to standardise its use and to help clinicians in the diagnostic approach to children with GER symptoms.

Bowel habit in preterm newborns: effect of new formulas.

Preterm infants may pass meconium only after the first 48 hours of life, even in absence of any gastrointestinal disease. The role of various factors in determining the time of meconium elimination has been recently assessed. Gestational age and start of feeding had been demonstrated to influence first meconium timing. The aim of our study was to evaluate time of first meconium passage and the time to achieve regular bowel movements (RBM), correlating these two events to different factors such as gestational age (GA), sex, type of delivery [caesarean section (CS) vs spontaneous delivery (SD)], 1' and 5' Apgar score (1'AS, 5'AS), time and type of feeding, oxygen requirement and any mode of respiratory support.

Celiac disease: pathogenesis and novel therapeutic strategies.

Celiac disease is a digestive disease, considered as an autoimmune disorder, that damages the small intestine and interferes with absorption of nutrients. Individuals affected by celiac disease cannot tolerate a protein called gluten, present in wheat, rye, and barley, but also in other common products such as stamp and envelope adhesive, medicines, and vitamins. Celiac disease is a genetic condition that is triggered--or becomes active for the first time--after surgery, pregnancy, childbirth, viral infection, or severe emotional stress. Symptoms may occur in the digestive system, or in other parts of the body. Diagnosis involves blood tests and a biopsy of the small intestine. Recent findings estimate that about 2 million people in the United States have celiac disease, or about 1 in 133 people, as in Europe. Recent studies have shown that it may be more common in Africa, South America, and Asia than previously believed. The only treatment for celiac disease is to follow a gluten-free diet. Various other approaches are being studied that would reduce the need of dieting. One of those promising new approaches involves treating celiac patients with AT-1001, a paracellular permeability inhibitor, and with R-spondin1, a recombinant, secreted protein that early animal studies have shown to act as a highly specific stimulator of the gastrointestinal (GI) epithelial cells.

Risk of non-Hodgkin lymphoma in celiac disease.

CONTEXT: Celiac disease is one of the most common lifelong disorders. Non-Hodgkin lymphoma is a possible complication of celiac disease and may lead to a large portion of lymphoma cases. OBJECTIVE: To quantify the risk for developing non-Hodgkin lymphoma of any primary site associated with celiac disease. DESIGN AND SETTING: Multicenter, case-control study conducted between January 1996 and December 1999 throughout Italy. PATIENTS: Cases were older than 20 years (median, 57; range, 20-92 years) with non-Hodgkin lymphoma of any primary site and histological type and were recruited at the time of the diagnosis. Controls were healthy adults (2739 men and 2981 women) from the general population. MAIN OUTCOME MEASURE: Positive test result for class A serum antiendomysial antibody. RESULTS: Celiac disease was diagnosed in 6 (0.92%) of 653 patients with lymphoma. Of the 6 cases, 3 were of B-cell and 3 were of T-cell origin. Four of 6 cases had lymphoma primarily located in the gut. In the control group, 24 (0.42%) had celiac disease. The odds ratio (adjusted for age and sex) for non-Hodgkin lymphoma of any primary site associated with celiac disease was 3.1 (95% confidence interval [CI], 1.3-7.6), 16.9 (95% CI, 7.4-38.7) for gut lymphoma, and 19.2 (95% CI, 7.9-46.6) for T-cell lymphoma, respectively. The risk for non-Hodgkin lymphoma for the overall population, which was adjusted for age and sex, was 0.63% (95% CI, - 0.12% to 1.37%). CONCLUSION: Celiac disease is associated with an increased risk for non-Hodgkin lymphoma, especially of T-cell type and primarily localized in the gut. However, the association does not represent a great enough risk to justify early mass screening for celiac disease.

Autoimmune thyroid disease and celiac disease in children.

BACKGROUND: Celiac disease (CD) may be associated with other immunologic disorders in adults and children. Previous studies linking CD and autoimmune thyroid disease in children have included very few patients with limited biochemical and immunologic screening tests. The aim of this multicenter study was to establish the prevalence of autoimmune thyroid involvement in a large series of pediatric patients with CD. METHODS: Five hundred seventy-three consecutive pediatric patients were enrolled from clinics in Torino, Bologna, Foggia, Rome (two clinics), Naples, and Bari. Three hundred forty-three patients with CD were studied, 230 girls and 113 boys (median age, 8.5 years). Two hundred fifty-six of the patients with CD (median age, 9 years) had been following a gluten-free diet for 3 months to 16 years; 87 patients were untreated (median age, 6.2 years). The diagnosis of CD was made using the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) criteria. A control group of 230 subjects (median age, 8.3 years) was enrolled. Serum free triiodothyronine, free thyroxine, and thyroid-stimulating hormone (TSH), antithyroperoxidase, antithyroglobulin, anti-TSH receptor antibodies, and thyroid echographic pattern were considered. RESULTS: Autoimmune thyroid disease was found in 90 of 343 (26.2%) patients with CD (62 on a gluten-free diet) and in 20 (10%) of the control subjects (P = 0.001). Fifty-four (15.7%) patients with CD and autoimmune markers had normal thyroid function (euthyroidism) as did 12 (6.0%) of the control subjects; hypothyroidism was observed in 28 (8.1%) patients with CD and in 7 (3.5%) of the control subjects. Hyperthyroidism was diagnosed in four patients with CD and in none of the control subjects with autoimmune markers. An abnormal echographic pattern was seen in 37 patients with CD (16.8%) and only in 1 (1.6%) of the control subjects (P = 0.002). CONCLUSIONS: The high frequency of autoimmune thyroid disease found among patients with CD, even those on a gluten-free diet, may justify a thyroid status assessment at diagnosis and at follow-up evaluation of children with CD.