Foetal gluten immunogenic peptides during pregnancy: a new determinant on the coeliac exposome.

BACKGROUND: The increasing incidence of coeliac disease is leading to a growing interest in active search for associated factors, even the intrauterine and early life. The exposome approach to disease encompasses a life course perspective from conception onwards has recently been highlighted. Knowledge of early exposure to gluten immunogenic peptides (GIP) in utero could challenge the chronology of early prenatal tolerance or inflammation, rather than after the infant's solid diet after birth. METHODS: We developed an accurate and specific immunoassay to detect GIP in amniotic fluid (AF) and studied their accumulates, excretion dynamics and foetal exposure resulting from AF swallowing. One hundred twenty-five pregnant women with different gluten diets and gestational ages were recruited. RESULTS: GIP were detectable in AF from at least the 16th gestational week in gluten-consuming women. Although no significant differences in GIP levels were observed during gestation, amniotic GIP late pregnancy was not altered by maternal fasting, suggesting closed-loop entailing foetal swallowing of GIP-containing AF and subsequent excretion via the foetal kidneys. CONCLUSIONS: The study shows evidence, for the first time, of the foetal exposure to gluten immunogenic peptides and establishes a positive correlation with maternal gluten intake. The results obtained point to a novel physiological concept as they describe a plausible closed-loop circuit entailing foetal swallowing of GIP contained in AF and its subsequent excretion through the foetal kidneys. The study adds important new information to understanding the coeliac exposome.

Early diet and the risk of coeliac disease. An update 2024 position paper by the ESPGHAN special interest group on coeliac disease.

This position paper by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Special Interest Group on Coeliac Disease (SIG-CD) presents an update to the 2016 recommendations concerning early diet and the risk of coeliac disease (CD). This update adheres to the policy that mandates reviewing guidelines every 5 years, particularly when new data emerge. The 2024 statements and recommendations are essentially similar to the 2016 recommendations. Breastfeeding, whether any amount, exclusive, or of any duration, does not reduce the risk of developing CD. Introducing gluten into an infant's diet at any time between completed 4 months (≥17 weeks) and 12 months of age does not affect the cumulative incidence of CD, although earlier introduction may lead to earlier seroconversion and CD. In observational studies involving cohorts with a known risk for CD, consuming a high amount of gluten compared to a low amount during weaning and in the subsequent childhood years-specifically the first 2-3 years, and even up to 5 years in some studies-was associated with an increased risk for CD. However, the specific optimal amounts of gluten consumption remain undetermined due to insufficient evidence on safe thresholds, and the impact of restricting gluten in the diet of healthy children of unknown risk for CD is unknown. Thus, any recommendation on the gluten amount is currently unjustifiable for the general population and infants with known HLA risk types. There is no specific guidance on the type of gluten-containing foods to be introduced at weaning.

Early-life fecal microbiome and metabolome dynamics in response to an intervention with infant formula containing specific prebiotics and postbiotics.

This study examined fecal metabolome dynamics to gain greater functional insights into the interactions between nutrition and the activity of the developing gut microbiota in healthy term-born infants. The fecal samples used here originate from a randomized, controlled, double-blind clinical study that assessed the efficacy of infant formula with prebiotics and postbiotics (experimental arm) compared with a standard infant formula (control arm). A group of exclusively breast-fed term infants was used as a reference arm. First, conventional targeted physiological and microbial measurements were performed, which showed differences in fecal Bifidobacterium levels and corresponding activity (e.g., lactate levels). Next, the overall fecal microbiota composition was determined by 16S rRNA gene amplicon sequencing. The microbiota composition profiles showed several bacterial groups in the experimental arm to be significantly different from the control arm and mostly closer to the levels observed in the reference arm. Finally, we applied an untargeted UPLC-MS/MS approach to examine changes in the fecal metabolome. Fecal metabolome profiles showed the most distinct separation, up to 404 significantly different metabolites, between the study arms. Our data reveal that infant formula with specific prebiotics and postbiotics may trigger responses in the intestinal microbiota composition that brings the ensuing fecal metabolite profile of formula-fed infants closer toward those observed in breast-fed infants. Furthermore, our results demonstrate a clear need for establishing an infant gut metabolome reference database to translate these metabolite profile dynamics into functional and physiologically relevant responses.NEW & NOTEWORTHY Untargeted metabolomics techniques can provide a "snapshot" of an ecosystem in response to environmental stimuli, such as nutritional interventions. Our analyses of fecal samples from infants demonstrate the potential of phenotyping by metabolomics while deciphering the complex interactions of early-life nutrition and gut microbiome development.

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.

Celiac Disease and Possible Dietary Interventions: From Enzymes and Probiotics to Postbiotics and Viruses.

Celiac Disease (CeD) is a chronic small intestinal immune-mediated enteropathy caused by the ingestion of dietary gluten proteins in genetically susceptible individuals. CeD is one of the most common autoimmune diseases, affecting around 1.4% of the population globally. To date, the only acceptable treatment for CeD is strict, lifelong adherence to a gluten-free diet (GFD). However, in some cases, GFD does not alter gluten-induced symptoms. In addition, strict adherence to a GFD reduces patients' quality of life and is often a socio-economic burden. This narrative review offers an interdisciplinary overview of CeD pathomechanism and the limitations of GFD, focusing on current research on possible dietary interventions. It concentrates on the recent research on the degradation of gluten through enzymes, the modulation of the microbiome, and the different types of "biotics" strategies, from probiotics to the less explored "viromebiotics" as possible beneficial complementary interventions for CeD management. The final aim is to set the context for future research that may consider the role of gluten proteins and the microbiome in nutritional and non-pharmacological interventions for CeD beyond the sole use of the GFD.

[Ibero-latinamerican clinical practical guidelines on pediatric caustic esophagitis: Physiopathology and clinical-endoscopic diagnosis (1st Part)]. / Guía de práctica clínica Ibero-Latinoamericana sobre la esofagitis cáustica en Pediatría: Fisiopatología y diagnóstico clínico-endoscópico (1a Parte).

Caustic ingestion represents a serious social-medical problem due to the devastating and irreversible consequences it can produce in the upper digestive tract. In Ibero-America, there are no published reliable data on the incidence or prevalence of caustic-induced injuries, and most of the available information on clinical presentation, diagnosis, treatment, and prognosis is based on retrospective clinical series and, indeed, its clinical management is often based primarily on expert opinion. Re cently as an initiative of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN) and with the cooperation of the Spanish Society for Pediatric Gastroente rology, Hepatology and Nutrition (SEGHNP), we have designed a Clinical Practice Guideline that include a series of statements and recommendations aimed at optimizing patient medical care which is based on the systematic review of evidence. Two (2) successive papers focused on the evaluation of physiopathological and clinical-endoscopic diagnostic features of caustic esophagitis in children (1st. Paper) and, on the other hand, the most relevant therapeutic considerations (2nd. Paper). We expect this guideline to become a useful tool for the physician in the difficult decision-making process when assessing patients after caustic ingestion.

[Ibero-Latinamerican Clinical Practical Guidelines on pediatric caustic esophagitis: Therapeutical aspects (Part 2)]. / Guía de práctica clínica Ibero-Latinoamericana sobre la esofagitis cáustica en Pediatría: Aspectos terapéuticos (2a. Parte).

Caustic ingestion represents a serious social-medical problem due to the devastating and irreversible consequences it can produce in the upper digestive tract. In Ibero-America, there are no published reliable data on the incidence or prevalence of caustic-induced injuries, and most of the available information on clinical presentation, diagnosis, treatment, and prognosis is based on retrospective clinical series and, indeed, its clinical management is often based primarily on expert opinion. Re cently as an initiative of the Latin American Society for Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN) and with the cooperation of the Spanish Society for Pediatric Gastroente rology, Hepatology and Nutrition (SEGHNP), we have designed a Clinical Practice Guideline that include a series of statements and recommendations aimed at optimizing patient medical care which is based on the systematic review of evidence. Two (2) separate papers focused on the evaluation of physiopathological and clinical-endoscopic diagnostic features of caustic esophagitis in children (1st. Paper) and, on the other hand, the most relevant therapeutic considerations (2nd. Paper). We expect this guideline to become a useful tool for the physician in the difficult decision-making process when assessing patients after caustic ingestion.

Outcome measures in coeliac disease trials: the Tampere recommendations.

OBJECTIVE: A gluten-free diet is the only treatment option of coeliac disease, but recently an increasing number of trials have begun to explore alternative treatment strategies. We aimed to review the literature on coeliac disease therapeutic trials and issue recommendations for outcome measures. DESIGN: Based on a literature review of 10 062 references, we (17 researchers and 2 patient representatives from 10 countries) reviewed the use and suitability of both clinical and non-clinical outcome measures. We then made expert-based recommendations for use of these outcomes in coeliac disease trials and identified areas where research is needed. RESULTS: We comment on the use of histology, serology, clinical outcome assessment (including patient-reported outcomes), quality of life and immunological tools including gluten immunogenic peptides for trials in coeliac disease. CONCLUSION: Careful evaluation and reporting of outcome measures will increase transparency and comparability of coeliac disease therapeutic trials, and will benefit patients, healthcare and the pharmaceutical industry.

Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing.

OBJECTIVE: Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage. DESIGN: Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines. RESULTS: GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4-6 h after single gluten intake, and remained detectable for 1-2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery. CONCLUSION: GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development. TRIAL REGISTRATION NUMBER: NCT02344758.

Corrigendum: Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients.

This corrects the article DOI: 10.1038/ajg.2016.439.

Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients.

OBJECTIVES: Treatment for celiac disease (CD) is a lifelong strict gluten-free diet (GFD). Patients should be followed-up with dietary interviews and serology as CD markers to ensure adherence to the diet. However, none of these methods offer an accurate measure of dietary compliance. Our aim was to evaluate the measurement of gluten immunogenic peptides (GIP) in stools as a marker of GFD adherence in CD patients and compare it with traditional methods of GFD monitoring. METHODS: We performed a prospective, nonrandomized, multicenter study including 188 CD patients on GFD and 84 healthy controls. Subjects were given a dietary questionnaire and fecal GIP quantified by enzyme-linked immunosorbent assay (ELISA). Serological anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptide (anti-DGP) IgA antibodies were measured simultaneously. RESULTS: Of the 188 celiac patients, 56 (29.8%) had detectable GIP levels in stools. There was significant association between age and GIP in stools that revealed increasing dietary transgressions with advancing age (39.2% in subjects ≥13 years old) and with gender in certain age groups (60% in men ≥13 years old). No association was found between fecal GIP and dietary questionnaire or anti-tTG antibodies. However, association was detected between GIP and anti-DGP antibodies, although 46 of the 53 GIP stool-positive patients were negative for anti-DGP. CONCLUSIONS: Detection of gluten peptides in stools reveals limitations of traditional methods for monitoring GFD in celiac patients. The GIP ELISA enables direct and quantitative assessment of gluten exposure early after ingestion and could aid in the diagnosis and clinical management of nonresponsive CD and refractory CD. Trial registration number NCT02711397.

Clinical utility of urinary gluten immunogenic peptides in the follow-up of patients with coeliac disease.

BACKGROUND: Gluten-free diet (GFD) is the only treatment for patients with coeliac disease (CD) and its compliance should be monitored to avoid cumulative damage. AIMS: To analyse gluten exposures of coeliac patients on GFD for at least 24 months using different monitoring tools and its impact on duodenal histology at 12-month follow-up and evaluate the interval of determination of urinary gluten immunogenic peptides (u-GIP) for the monitoring of GFD adherence. METHODS: Ninety-four patients with CD on a GFD for at least 24 months were prospectively included. Symptoms, serology, CDAT questionnaire, and u-GIP (three samples/visit) were analysed at inclusion, 3, 6, and 12 months. Duodenal biopsy was performed at inclusion and 12 months. RESULTS: At inclusion, 25.8% presented duodenal mucosal damage; at 12 months, this percentage reduced by half. This histological improvement was indicated by a reduction in u-GIP but did not correlate with the remaining tools. The determination of u-GIP detected a higher number of transgressions than serology, regardless of histological evolution type. The presence of >4 u-GIP-positive samples out of 12 collected during 12 months predicted histological lesion with a specificity of 93%. Most patients (94%) with negative u-GIP in ≥2 follow-up visits showed the absence of histological lesions (p < 0.05). CONCLUSION: This study suggests that the frequency of recurrent gluten exposures, according to serial determination of u-GIP, could be related to the persistence of villous atrophy and that a more regular follow-up every 6 months, instead of annually, provides more useful data about the adequate adherence to GFD and mucosal healing.

Central venous sinus thrombosis in a young girl with ulcerative colitis.

Paediatric central venous sinus thrombosis (CVST) is an uncommon but important life-threatening complication of inflammatory bowel disease (IBD). As the incidence of IBD has increased in the last four decades, paediatricians need to be aware of this complication. There is currently no consensus on when children with IBD should receive prophylactic anticoagulation. We present the case of a young girl with ulcerative colitis who suffered an acute ischaemic event secondary to a CVST during an acute flare of her disease. We aim to bring awareness to CVST in IBD due to its high risk of morbidity and mortality.

Rationale for Timing of Follow-Up Visits to Assess Gluten-Free Diet in Celiac Disease Patients Based on Data Mining.

The assessment of compliance of gluten-free diet (GFD) is a keystone in the supervision of celiac disease (CD) patients. Few data are available documenting evidence-based follow-up frequency for CD patients. In this work we aim at creating a criterion for timing of clinical follow-up for CD patients using data mining. We have applied data mining to a dataset with 188 CD patients on GFD (75% of them are children below 14 years old), evaluating the presence of gluten immunogenic peptides (GIP) in stools as an adherence to diet marker. The variables considered are gender, age, years following GFD and adherence to the GFD by fecal GIP. The results identify patients on GFD for more than two years (41.5% of the patients) as more prone to poor compliance and so needing more frequent follow-up than patients with less than 2 years on GFD. This is against the usual clinical practice of following less patients on long term GFD, as they are supposed to perform better. Our results support different timing follow-up frequency taking into consideration the number of years on GFD, age and gender. Patients on long term GFD should have a more frequent monitoring as they show a higher level of gluten exposure. A gender perspective should also be considered as non-compliance is partially linked to gender in our results: Males tend to get more gluten exposure, at least in the cultural context where our study was carried out. Children tend to perform better than teenagers or adults.

Verifying Diagnosis of Refractory Celiac Disease With Urine Gluten Immunogenic Peptides as Biomarker.

Refractory celiac disease (RCD) involves T-lymphocyte activation despite supposed absence of gluten exposure. Assessing dietary adherence is the cornerstone of RCD diagnosis, but available diagnostic tools fail to monitor gluten-free diet (GFD). A recently acknowledged GFD biomarker is gluten immunogenic peptides (GIP) in urine. This study assessed urine GIP to verify whether RCD patients could be reclassified as "exposed to gluten." Three out of four RCD patients had at least two positive-GIP urine samples in a follow-up of 3 months, demonstrating gluten exposure. Urine GIP may enable the accurate RCD verification and decrease overuse of immunosuppressants, increasing cost effectiveness.

Negative predictive value of the repeated absence of gluten immunogenic peptides in the urine of treated celiac patients in predicting mucosal healing: new proposals for follow-up in celiac disease.

BACKGROUND: The treatment of celiac disease (CD) is a lifelong gluten-free diet (GFD). The current methods for monitoring GFD conformance, such as a dietary questionnaire or serology tests, may be inaccurate in detecting dietary transgressions, and duodenal biopsies are invasive, expensive, and not a routine monitoring technique. OBJECTIVES: Our aim was to determine the clinical usefulness of urine gluten immunogenic peptides (GIP) as a biomarker monitoring GFD adherence in celiac patients and to evaluate the concordance of the results with the degree of mucosal damage. METHODS: A prospective observational study was conducted involving 22 de novo CD patients, 77 celiac patients consuming a GFD, and 13 nonceliac subjects. On 3 d of the week, urine samples were collected and the GIP concentrations were tested. Simultaneously, anti-tissue transglutaminase antibodies, questionnaire results, clinical manifestations, and histological findings were analyzed. RESULTS: Approximately 24% (18 of 76) of the celiac patients consuming a GFD exhibited Marsh II-III mucosal damage. Among this population, 94% (17 of 18) had detectable urine GIP; however, between 60% and 80% were asymptomatic and exhibited negative serology and appropriate GFD adherence based on the questionnaire. In contrast, 97% (31 of 32) of the celiac patients without duodenal damage had no detectable GIP. These results demonstrated the high sensitivity (94%) and negative predictive value (97%) of GIP measurements in relation to duodenal biopsy findings. In the de novo CD-diagnosed cohort, 82% (18 of 22) of patients had measurable amounts of GIP in the urine. CONCLUSIONS: Determining GIP concentrations in several urine samples may be an especially convenient approach to assess recent gluten exposure in celiac patients and appears to accurately predict the absence of histological lesions. The introduction of GIP testing as an assessment technique for GFD adherence may help in ascertaining dietary compliance and to target the most suitable intervention during follow-up.

Gastrointestinal Tolerance, Growth and Safety of a Partly Fermented Formula with Specific Prebiotics in Healthy Infants: A Double-Blind, Randomized, Controlled Trial.

This study evaluated the effect of a partly fermented infant formula (using the bacterial strains Bifidobacterium breve C50 and Streptococcus thermophilus 065) with a specific prebiotic mixture (short-chain galacto-oligosaccharides (scGOS) and long-chain fructo-oligosaccharides (lcFOS; 9:1)) on the incidence of gastrointestinal symptoms, stool characteristics, sleeping and crying behaviour, growth adequacy and safety. Two-hundred infants ≤28 days of age were assigned either to experimental infant formula containing 30% fermented formula and 0.8 g/100 mL scGOS/lcFOS or to non-fermented control infant formula without scGOS/lcFOS. A group of breastfed infants served as a reference. No relevant differences in parent-reported gastrointestinal symptoms were observed. Stool consistency was softer in the experimental versus control group with values closer to the breastfed reference group. Daily weight gain was equivalent for both formula groups (0.5 SD margins) with growth outcomes close to breastfed infants. No clinically relevant differences in adverse events were observed, apart from a lower investigator-reported prevalence of infantile colic in the experimental versus control group (1.1% vs. 8.7%; p < 0.02). Both study formulae are well-tolerated, support an adequate infant growth and are safe for use in healthy term infants. Compared to the control formula, the partly fermented formula with prebiotics induces stool consistencies closer to breastfed infants.

Prospective longitudinal study: use of faecal gluten immunogenic peptides to monitor children diagnosed with coeliac disease during transition to a gluten-free diet.

BACKGROUND: Treatment for coeliac disease is a lifelong strict gluten-free diet. Although guidelines recommend regular follow-up with dietary interviews and coeliac serology, these methods may be inaccurate. AIM: To evaluate the usefulness of faecal gluten immunogenic peptides to support the diagnosis and to determine the adherence to the gluten-free diet in coeliac children. METHODS: Multicentre prospective observational study including 64 coeliac children. Faecal gluten peptides, and tissue transglutaminase and deamidated gliadin peptide antibodies were analyzed at diagnosis, and 6, 12 and 24 months thereafter. Gluten consumption was estimated from gluten peptide levels. RESULTS: Most children (97%) had detectable gluten peptides at diagnosis. On a gluten-free diet, the rate of gluten peptides increased from 13% at 6 months to 25% at 24 months. Mean estimated gluten exposure dropped from 5543 mg/d at diagnosis to 144 mg/d at 6 months, then increased to 606 mg/d by 24 months. In contrast, deamidated gliadin peptide antibodies normalised and only 20% had elevated tissue transglutaminase antibody by 24 months. The elevation of tissue transglutaminase antibody was more prolonged in patients with detectable gluten peptides (P < 0.05). Nevertheless, absolute levels of tissue transglutaminase antibody had low sensitivity to identify patients with detectable gluten peptides (P > 0.1). Dietitian assessment was only moderately correlated with gluten peptide detection (κ = 0.5). CONCLUSIONS: Faecal gluten peptides testing may guide treatment of coeliac disease prior to diagnosis and during the assessment diet adherence. Further studies could determine if early identification of gluten exposure reduces the need for expensive/invasive investigations for non-responsive coeliac disease. ClinicalTrials.gov Number: NCT02711397.

Pneumocystis jirovecii transmission from immunocompetent carriers to infant.

We report a case of Pneumocystis jirovecii transmission from colonized grandparents to their infant granddaughter. Genotyping of P. jirovecii showed the same genotypes in samples from the infant and her grandparents. These findings support P. jirovecii transmission from immunocompetent carrier adults to a susceptible child.