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The worldwide prevalence of asymptomatic coeliac disease (CD) is increasing, which is in part due to the routine screening of children with risk factors. Both symptomatic and asymptomatic patients with CD are at risk of long-term complications. The objective of this study was to compare the clinical characteristics of asymptomatic and symptomatic children at the time of CD diagnosis. A case–control study was conducted using data from a cohort of 4838 CD patients recruited from 73 centers across Spain between 2011 and 2017. A total of 468 asymptomatic patients (cases) were selected and matched by age and sex with 468 symptomatic patients (controls). Clinical data, including any reported symptoms, as well as serologic, genetic, and histopathologic data were collected. No significant differences were found between the two groups in most clinical variables, nor in the degree of intestinal lesion. However, the asymptomatic patients were taller (height z-score −0.12 (1.06) vs. −0.45 (1.19), p < 0.001) and were less likely to have anti transglutaminase IgA antibodies ≥ 10 times the upper normal limit (66.2% vs. 758.4%, p = 0.002). Among the 37.1% of asymptomatic patients who were not screened for CD due to the absence of risk factors, only 34% were truly asymptomatic, while the remaining 66% reported non-specific CD-related symptoms. Therefore, expanding CD screening to any child who undergoes a blood test could reduce the burden of care for some children, as many of those considered asymptomatic reported non-specific CD-related symptoms.

Atherosclerosis is a chronic inflammatory disease that is caused by the accumulation of LDL particles in the intima, causing the activation of immune cells and triggering an inflammatory response. LPS is a potent activator of the innate immune response and it can be transported by lipoproteins. Since humans are much more sensitive to LPS than other mammals, and very low amounts of LPS can elicit an immune response, the aim of this study is to characterize the distribution of LPS and its immunogenic portion (3OHFAs) among lipoprotein types of healthy men. We separated lipoprotein fractions by ultracentrifugation and the amount of each 3OHFA was measured by MS in each lipoprotein fraction to calculate LPS concentration. Lipoprotein particle concentration was measured by NMR. LDL and HDL fractions transported the highest concentration of LPS (35.7% and 31.5%, respectively), but VLDL particles carried more LPS molecules per particle (0.55 molecules/particle) than LDL or HDL (p < 0.01). The distribution of LPS and all 3OHFAs among lipoprotein fractions showed high interindividual variability, suggesting that they may be studied as a potential biomarker. This may help understand the role of LPS in atherosclerosis in those cases where the disease cannot be explained by traditional risk factors.

The objective of this study was to assess the association between serological markers and changes of the intestinal mucosa in children with celiac disease (CD).Clinical data from CD patients under 15 years old were collected from the participating centers in an on-line multicenter nationwide observational Spanish registry called REPAC-2 (2011-2017). Correlation between anti-tissue transglutaminase antibodies (t-TGA) levels and other variables, including mucosal damage and clinical findings (symptoms, age, and gender), was assessed.A total of 2955 of 4838 patients had t-TGA and a small bowel biopsy (SBB) performed for CD diagnosis. A total of 1931 (66.2%) patients with normal IgA values had a Marsh 3b-c lesion and 1892 (64.9%) had t-TGA Immunoglobulin A (IgA) ≥ 10 times upper limit of normal (ULN). There is a statistically significant association between t-TGA IgA levels and the degree of mucosal damage ( P0.001), the higher the t-TGA IgA levels the more severe the mucosal damage. Those patients who reported symptoms had more severe mucosal damage ( P = 0.001). On the contrary, there was a negative association between age and changes of the intestinal mucosa ( P0.001). No association was found with gender. Regarding the IgA-deficient patients, 47.4% (18 cases) had t-TGA Immunoglobulin A (IgA) ≥ 10 times ULN and a Marsh 3b-c lesion was observed in 68.4% (26 patients). No statistical relation was found between t-TGA IgG levels and the changes of the intestinal mucosa, neither a relation with age, gender, or symptoms.There is a positive correlation between t-TGA IgA levels and the severity of changes of the intestinal mucosa. Such correlation was not found in IgA-deficient patients who had positive t-TGA IgG serology. The results in this group of patients support the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition recommendations about the need of performing a SBB in IgA-deficient individuals despite high t-TGA IgG levels.

Over the last several decades, there has been a tendency towards a predominance of less symptomatic forms of coeliac disease (CD) and an increase in the patient age at diagnosis. This study aimed to assess the clinical presentation and diagnostic process of paediatric CD in Spain.A nationwide prospective, observational, multicentre registry of new paediatric CD cases was conducted from January 2011 to June 2017. The data regarding demographic variables, type of birth, breast-feeding history, family history of CD, symptoms, height and weight, associated conditions, serological markers, human leukocyte antigen (HLA) phenotype, and histopathological findings were collected.In total, 4838 cases (61% girls) from 73 centres were registered. The median age at diagnosis was 4 years. Gastrointestinal symptoms were detected in 71.4% of the patients, and diarrhoea was the most frequent symptom (45.9%). The most common clinical presentation was the classical form (65.1%) whereas 9.8% ofthe patients were asymptomatic. There was a trend towards an increase in the age at diagnosis, proportion of asymptomatic CD cases, and usage of anti-deamidated gliadin peptide antibodies and HLA typing for CD diagnosis. There was, however, a decreasing trend in the proportion of patients undergoing biopsies. Some of these significant trend changes may reflect the effects of the 2012 ESPGHAN diagnosis guidelines.Paediatric CD in Spain is evolving in the same direction as in the rest of Europe, although classical CD remains the most common presentation form, and the age at diagnosis remains relatively low.

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.

This guideline presents recommendations for the management of coeliac disease (CD) and other gluten-related disorders both in adults and children. There has been a substantial increase in the prevalence of CD over the last 50 years and many patients remain undiagnosed. Diagnostic testing, including serology and biopsy, should be performed on a gluten-containing diet. The diagnosis of CD is based on a combination of clinical, serological and histopathological data. In a group of children the diagnosis may be made without biopsy if strict criteria are available. The treatment for CD is primarily a gluten-free diet (GFD), which requires significant patient education, motivation and follow-up. Slow-responsiveness occurs frequently, particularly in those diagnosed in adulthood. Persistent or recurring symptoms necessitate a review of the original diagnosis, exclude alternative diagnoses, confirm dietary adherence (dietary review and serology) and follow-up biopsy. In addition, evaluation to exclude complications of CD, such as refractory CD or lymphoma, should be performed. The guideline also deals with other gluten-related disorders, such as dermatitis herpetiformis, which is a cutaneous manifestation of CD characterized by granular IgA deposits in the dermal papillae. The skin lesions clear with gluten withdrawal. Also, less well-defined conditions such as non-coeliac gluten sensitivity (NCGS) and gluten-sensitive neurological manifestations, such as ataxia, have been addressed. Newer therapeutic modalities for CD are being studied in clinical trials but are not yet approved for use in practice.

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. España, Ministerio de Ciencia e Innovación and FEDER funds DELIAC, IPT‐2011‐0952‐900000 España, Corporación Tecnológica de Andalucía SINGLUCHECK, 1737/0118

Celiac disease (CeD) is an immune-mediated disorder triggered by exposure to dietary gluten proteins in genetically predisposed individuals. In addition to the host genome, the microbiome has recently been linked to CeD risk and pathogenesis. To progress in our understanding of the role of breast milk microbiota profiles in CeD, we have analyzed samples from a sub-set of mothers (n = 49) included in the PreventCD project, whose children did or did not develop CeD. The results of the microbiota data analysis indicated that neither the BMI, HLA-DQ genotype, the CeD condition nor the gluten-free diet of the mothers could explain the human milk microbiota profiles. Nevertheless, we found that origin country, the offspring’s birth date and, consequently, the milk sampling date influenced the abundance and prevalence of microbes in human milk, undergoing a transition from an anaerobic to a more aerobic microbiota, including potential pathogenic species. Furthermore, certain microbial species were more abundant in milk samples from mothers whose children went on to develop CeD compared to those that remained healthy. These included increases in facultative methylotrophs such as Methylobacterium komagatae and Methylocapsa palsarum as well as in species such as Bacteroides vulgatus, that consumes fucosylated-oligosaccharides present in human milk, and other breast-abscess associated species. Theoretically, these microbiota components could be vertically transmitted from mothers-to-infants during breastfeeding, thereby influencing CeD risk., This work was supported by grant AGL2017-88801-P from Ministerio de Ciencia, Innovación y Universidades (MCIU, Spain). The postdoctoral contract of Marta Olivares from “Juan de la Cierva” program (MCIU, Spain) is fully acknowledged. PreventCD consortium is supported by grants from the European Commission (FP6-2005-FOOD-4B-36383–PREVENTCD), the Azrieli Foundation, Deutsche Zöliakie Gesellschaft, Eurospital, Fondazione Celiachia, Fria Bröd, Instituto de Salud Carlos III, Spanish Society for Pediatric Gastroenterology, Hepatology, and Nutrition, Komitet Badañ Naukowych (1715/B/P01/2008/34), Fundacja Nutricia (1W44/FNUT3/2013), Hungarian Scientific Research Funds (OTKA101788 and TAMOP 2.2.11/1/KONV-20 12-0023), Stichting Coeliakie Onderzoek Nederland (STICOON), Thermo Fisher Scientific, and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN).

Several cases of eating disorders (EDs) have been reported in patients with celiac disease (CD), suggesting that ED could be a comorbidity associated with CD. Few epidemiological studies have, however, assessed this potential association. We aimed to evaluate the risk of EDs in individuals diagnosed with CD in comparison to healthy controls.A total of 98 cases and 98 controls matched for sex, age, and body mass index between 10 and 23 years old were studied. A questionnaire was completed on medical history and sociodemographic as well as anthropometric characteristics. Various ED screening self-reported tests were administered.A total of 61.2% of the study population were girls with a mean age of 15.3 ± 3.7 years old. Patients with CD scored nonsignificantly higher on all the ED screening tests than control participants. No differences were observed between study groups in terms of the frequency of individuals who exceeded the clinical cutoff identifying those at risk of ED. Patients with CD above 13 years old were associated with a 2.15-point increase in the Eating Attitude Test score compared with controls [β-coefficient = 2.15 SE 1.04; P = 0.04] after adjusting for various confounders.Although being a patient with CD was associated with a significantly higher Eating Attitude Test score in individuals older than 13 years old, no clear differences were observed between individuals with CD and controls in terms of risk of ED when other screening tests were used. More studies with larger samples and prospective designs are warranted to confirm these findings.

To analyze the presence of total IgA and anti-gliadin antibodies (AGA) in BM from CD mothers who follow a gluten-free diet (GFD) and from mothers on a normal gluten-containing diet (ND). 218 samples of mature milk were obtained at different months of lactation (1–6) from 83 mothers (2 or more samples per mother) from Italy (Naples), The Netherlands (Leiden) and Spain (Madrid, Valencia and Reus): 42 CD mothers on GFD for more than 2 years and 41 non-CD mothers on a ND. Whey samples were analyzed for AGA-IgA by an indirect homemade ELISA and for total IgA (g/L) by a commercial ELISA kit. AGA-IgA was detected in BM, both in mothers on a GFD and mothers on a ND. AGA-IgA levels in both groups of mothers, CD and non-CD, show the same trend towards decreasing slightly along the months of lactation (p = 0.91). A different trend is observed for total IgA levels, decreasing markedly in CD mothers from the first month of lactation onwards but remaining stable in non-CD mothers (p = 0.048). A statistically significant association was found between the means of total IgA and AGA-IgA (p

Coeliac disease is a systemic immune-mediated disorder triggered by the ingestion of gluten, which is given in genetically predisposed subjects. It manifests with a wide variety of clinical symptoms, specific serological markers, HLA-DQ2/DQ8 haplotype, and enteropathy. The criteria followed for this have usually been those established by the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) since 1969. These criteria have advanced from the need of several intestinal biopsies to, thanks to the development of serological tests of high sensitivity and specificity, considering the enteropathy as one more element in this diagnosis and makes it possible to perform a diagnosis without the need of an intestinal biopsy in certain circumstances. The updated review of the 2012 criteria in 2019 provides new evidence on some aspects, such as the role of HLA, the diagnosis of asymptomatic patients, and the effectiveness of the serological markers. These aspects are reviewed in detail, with the aim of facilitating the rational application of the new 2020 criteria at all care levels. In this sense, Paediatric Primary Care is fundamental in the search for active cases and to perform a first serological study, being recommended that the diagnosis is always establishedby a Paediatric Gastroenterologist, La enfermedad celíaca es un proceso sistémico de carácter inmunológico, desen-cadenado por el consumo de gluten, que se da en sujetos genéticamente predispuestos. Se expresa con una gran variedad de síntomas clínicos, marcadores serológicos específicos, hap-lotipo HLA-DQ2/DQ8 y enteropatía. El tratamiento consiste en eliminar de por vida el gluten de la dieta, por lo que es fundamental un diagnóstico adecuado. Los criterios seguidos para ello han sido habitualmente los establecidos por la European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) desde 1969. Estos criterios han ido evolucionando desde la necesidad de varias biopsias intestinales para el diagnóstico a, gracias al desarrollo de pruebas serológicas de alta sensibilidad y especificidad, considerar la enteropatía como un elemento más en este diagnóstico y posibilitar en determinadas circunstancias realizarlo sin necesidad de biopsia intestinal. La revisión actualizada en 2019 de los criterios 2012 aporta nueva evidencia sobre algunos aspectos, como el papel del HLA, el diagnóstico de los pacientes asintomáticos y la eficacia de los marcadores serológicos. Estos aspectos se revisan en detalle,con el objetivo de facilitar la aplicación de los nuevos criterios 2020 de una forma racional en todos los niveles asistenciales. En este sentido el pediatra de Atención Primaria es fundamental para la búsqueda activa de casos y realizar un primer estudio serológico, recomendándose que el diagnóstico sea siempre establecido por un pediatra gastroenterólogo

espanolIntroduccion: hasta la fecha, una dieta sin gluten (SG) es el unico tratamiento para las personas con enfermedad celiaca. Tanto las evaluaciones de ingesta de alimentos individuales como las colectivas son un desafio debido a la falta de una base de datos de composicion de productos SG (PSG). Objetivos: describir el proceso de desarrollo de una base de datos de composicion de PSG y comparar el perfil nutricional y el precio de algunos PSG y productos con gluten. Metodos: inicialmente, se registraron un total de 216 marcas de PSG comercializadas en Espana. La informacion nutricional se recopilo de las etiquetas nutricionales y hojas informativas de los productos, que habian sido proporcionadas por las companias de alimentos o recopiladas de primera mano por los investigadores. Luego, se compararon el perfil nutricional y el precio de los grupos de cereales y subproductos alimenticios, incluidos 19 tipos de productos. Los analisis estadisticos se realizaron utilizando el programa estadistico SPSS (edicion 22.0; SPSS, Chicago, IL, EUA). Resultados: se incluyeron un total de 2247 PSG de 126 marcas de alimentos diferentes en la base de datos de composicion de PSG (CELIAC-BASE). Clasificamos estos productos en 14 grupos de alimentos. El contenido de proteinas de los PSG estudiados fue significativamente menor, y el precio de los mismos fue mas alto, que el de sus homologos con gluten. Algunos PSG, pero no todos, presentaron un mayor contenido de grasa y azucar, y un menor contenido de fibra dietetica, que sus homologos con gluten. Algunos PSG eran hasta 6 veces mas caros que sus homologos con gluten. Conclusiones: CELIAC-BASE es una herramienta pionera para dietistas-nutricionistas. Muchos PSG tienen perfiles nutricionales no saludables y deben consumirse solo ocasionalmente en una dieta equilibrada libre de gluten. EnglishBackground: to date, gluten-free (GF) diet is the only treatment available for individuals with celiac disease. Both individual and collective food intake assessments are a challenge because a food composition database of GF products (GFPs) is lacking. Objectives: to describe the process of developing a food composition database of GFPs, and to compare the nutritional profile and price of some GFPs and non-GFPs. Methods: initially, a total of 216 brands of GFPs marketed in Spain were recorded. Nutritional information was collected from nutritional labels and product fact sheets that had been provided by food companies or collected first-hand by researchers. Then, the nutritional profile and price of the cereal and cereal byproducts foodstuff groups, including 19 types of products, were compared. Statistical analyses were performed using the SPSS statistical program (22.0 edition; SPSS, Chicago, IL, USA). Results: a total of 2,247 GFPs from 126 different foodstuff brands were included in the food composition database of GFPs (CELIAC-BASE). We classified these products into 14 foodstuff groups. The protein content of the GFPs studied was significantly lower, and the price was higher, than that of their non-GFP counterparts. Some, but not all, GFPs had a higher content of fat and sugar, and a lower content of dietary fiber as compared to their non-GFP counterparts. Some GFPs were up to 6 times more expensive than the corresponding non-GFPs. Conclusions: CELIAC-BASE is a pioneering tool for dietitians. Many GFPs have poor nutritional profiles and should be consumed only occasionally in a balanced GF diet.

Objectives: A large retrospective multicentre study was conducted in Spain to evaluate the efficiency of the new European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) criteria for the diagnosis of coeliac disease (CD). Methods: The study protocol was approved by the ethics committee of Hospital Universitari i Politecnic La Fe (Valencia, Spain). The present study included 2177 children (ages 0.6-15.9 years) with small bowel biopsy (SBB) performed for diagnostic purposes (from 2000 to 2009) and with a minimum 2-year follow-up after biopsy. Results: CD was diagnosed in 2126 patients (97.5%) and excluded in 51 (2.5%). Tissue transglutaminase antibodies (TG2A), anti-endomysial antibodies (EMA), and human leukocyte antigen (HLA) were reported in 751 patients, 640 symptomatic and 111 asymptomatic. TG2A levels >10 times the upper limit of normal, plus positive EMA and HLA DQ2 and/or DQ8 haplotypes, were found in 336 symptomatic patients, all of them with final diagnosis of CD. In 65 of 69 asymptomatic patients, 65 had confirmed CD and 4 did not have CD. According to the 2012 ESPGHAN guidelines, SBB may have been omitted in 52% of the symptomatic patients with CD with serologic and HLA available data. Gluten challenge was performed in 158 children, 75 of them

Human milk composition is variable. The identification of influencing factors and interdependencies of components may help to understand the physiology of lactation. In this study, we analyzed linear trends in human milk composition over time, the variation across different European countries and the influence of maternal celiac disease. Within a multicenter European study exploring potential prevention of celiac disease in a high-risk population (PreventCD), 569 human milk samples were donated by women from five European countries between 16 and 163 days postpartum. Some 202 mothers provided two samples at different time points. Protein, carbohydrates, fat and fatty acids, insulin, adiponectin, and insulin-like growth factor II (IGF-II) were analyzed. Milk protein and n-6 long chain polyunsaturated fatty acids decreased during the first three months of lactation. Fatty acid composition was significantly influenced by the country of residence. IGF-II and adiponectin concentrations correlated with protein content (r = 0.24 and r = 0.35), and IGF-II also correlated with fat content (r = 0.36), suggesting a possible regulatory role of IGF in milk macronutrient synthesis. Regarding the impact of celiac disease, only the level in palmitic acid was influenced by this disease, suggesting that breastfeeding by celiac disease mothers should not be discouraged.

RESUMEN Objetivo: evaluar la influencia del consumo de gluten en el desarrollo de enfermedad celiaca y describir la historia natural de la misma, en una cohorte española de riesgo genético participante en el estudio Europeo PreventCD. Métodos: estudio prospectivo multicéntrico doble ciego, incluyendo 225 niños, controlados desde el nacimiento, en tres centros de Madrid, Reus y Valencia, todos HLA-DQ2/HLA-DQ8 positivos y con un familiar de primer grado con enfermedad celiaca. Entre cuatro y diez meses, la ingesta de gluten estaba pautada por protocolo. Entre los 11-36 meses, la ingesta fue libre, siendo cuantificada prospectivamente mediante registros dietéticos. Se realizaron visitas clínicas y análisis de anticuerpos específicos de enfermedad celiaca periódicamente. Resultados: se diagnosticaron 26 casos, todos con biopsia y serología positiva, 21 con síntomas gastrointestinales y cinco asintomáticos. Se analizaron 2.565 registros que mostraron diferencias estadísticamente significativas (p < 0,001) en el consumo de gluten entre los tres centros, pero no entre niños celiacos y no celiacos (p = 0,025). El genotipo HLA-DQ2.5/DQ2.5 y DQ2.5/DQ2.2 presentó un riesgo relativo de 4,7 (IC 95%: 0,80-27,55; p = 0,08), superior al resto de genotipos, y el género femenino presentó un riesgo relativo cinco veces superior al masculino. Conclusiones: ni la cantidad de gluten consumida entre los 11 y los 36 meses ni la duración de la lactancia son factores de riesgo de desarrollo de EC en la población española, siendo el genotipo HLA y el sexo los factores más relevantes asociados a la misma. En este grupo de riesgo, la mayoría de casos debutaron antes de los dos años, encontrándose a esta temprana edad pacientes con escasa expresividad clínica. ABSTRACT Aim: to evaluate the influence of gluten consumption on celiac disease development and to describe its natural history in the Spanish cohort of the European PreventCD study. Methods: prospective multi-center double blind study of 225 children that were followed up from birth. All cases were HLA-DQ2/HLA-DQ8 positive with a 1st degree relative with celiac disease and were followed up in three centers from Madrid, Reus and Valencia. Gluten intake was determined between four and ten months according to the protocol. Gluten intake was ad libitum between eleven and 36 months and was prospectively quantified by means of dietary records. Clinical visits and specific antibody analysis for celiac disease were performed periodically. Results: twenty-six cases were diagnosed, all had a positive biopsy and serology; 21 had gastrointestinal symptoms and five were asymptomatic. In addition, 2,565 food records were analyzed and statistically significant differences (p < 0.001) were found with regard to gluten consumption among the three centers, although not between celiac and non-celiac children (p = 0.025). The HLA-DQ2.5/DQ2.5 and DQ2.5/DQ2.2 genotypes had a relative risk of 4.7 (95% CI: 0.80-27.55; p = 0.08), which was higher than for the rest of genotypes. Female gender also had a relative risk that was five times higher than that for males. Conclusions: the amount of gluten intake between 11 and 36 months or the duration of breast feeding were not risk factors for the development of CD in the Spanish population. The HLA genotype and gender were the most relevant associated factors. In this at-risk group, the disease presented before two years of age in the majority of the cases with a weak clinical expression.

Background & aims Breastfeeding is beneficial for mothers and infants. Underlying mechanisms and biochemical mediators thus need to be investigated to develop and support improved infant nutrition practices promoting the child health. We analysed the relation between maternal breast milk composition and infant metabolism. Methods 196 pairs of mothers and infants from a European research project (PreventCD) were studied. Maternal milk samples collected at month 1 and month 4 after birth were analysed for macronutrient classes, hormone, and fatty acid (FA) content. Phospholipids, acylcarnitines, and amino acids were measured in serum samples of 4-month old infants. Associations between milk components and infant metabolites were analysed with spearman correlation and linear mixed effect models (LME). P-values were corrected for multiple testing (P-LME). Results Month 1 milk protein content was strongly associated with infant serum lyso-phosphatidylcholine (LPC) 14: 0 (P-LME = 0.009). Month 1 milk insulin was associated to infant acetylcarnitine (P-LME = 0.01). There were no associations between milk protein content and serum amino acids and milk total fat content and serum polar lipids. Middle- and odd-chain FA% in breast milk at both ages were significantly related to serum LPC and sphingomyelins (SM) species in infant serum (all P-LME < 0.05), while FA% 20: 5n(-3) and 22: 6n(-3) percentages were significantly associated to serum LPC 22:6 (P-LME = 1.91x10(-4)/7.93x10(-5)) in milk only at month 4. Other polyunsaturated fatty acids and hormones in milk showed only weak associations with infant serum metabolites. Conclusions Infant serum LPC are influenced by breast milk FA composition and, intriguingly, milk protein content in early but not late lactation. LPC 14:0, previously found positively associated with obesity risk, was the serum metabolite which was the most strongly associated to milk protein content. Thus, LPC 14:0 might be a key metabolite not only reflecting milk protein intake in infants, but also relating high protein content in milk or infant formula to childhood obesity risk.

Background To investigate whether alterations in the developing intestinal microbiota and immune markers precede celiac disease (CD) onset in infants at familial risk of developing the disease. Methods A nested case-control study was carried out as part of a larger prospective cohort study, which included healthy full-term newborns (> 200) with at least one first relative with biopsy-verified CD. The present study includes cases of CD (n = 10) and the best-matched controls (n = 10) who did not develop the disease after 5-year follow-up. Fecal microbiota, assessed by high-throughput 16S rRNA gene amplicon sequencing, and immune parameters were profiled at 4 and 6 months of age and related to CD onset. Results The microbiota of infants who remained healthy showed an increase in bacterial diversity over time, characterized by increases in Firmicutes families, but not those who developed CD. Infants who subsequently developed CD showed a significant reduction in sIgA levels over time, while those who remained healthy showed increases in TNF-α correlated to Bifidobacterium spp. An increased relative abundance of Bifidobacterium longum was associated with control children while increased proportions of Bifidobacterium breve and Enterococcus spp. were associated with CD development. Conclusion The findings suggest that alterations in the early trajectory of gut microbiota in infants at CD risk could influence the immune maturation process and predispose to CD, although larger population studies are warranted to confirm this hypothesis., This work was supported by grants AGL2011-25169, AGL2014-52101-P, and AGL2007-66126-C03-03/ALI (YS and FP) from the Spanish Ministry of Economy and Competitiveness (MINECO). Funding for AWW and JP and 16S rRNA gene Olivares et al. Microbiome (2018) 6:36 Page 9 of 11 sequencing was provided by Wellcome Trust (Grant 098051); AWW and The Rowett Institute, University of Aberdeen, receive core funding support from the Scottish Government Rural and Environmental Science and Analysis Service (RESAS). The scholarship to MO from CSIC (JAEpre) and the contract to ABP from the European Union’s Seventh Framework Program under the grant agreement no 613979 (MyNewGut) are also fully acknowledged.

8 páginas, 1 figura, 2 tablas, Celiac disease (CD) is an immune-mediated enteropathy involving genetic and environmental factors, whose interaction influences disease risk. The intestinal microbiota, including viruses and bacteria, could play a role in the pathological process leading to gluten intolerance. In this study, we investigated the prevalence of pathogens in the intestinal microbiota of infants at familial risk of developing CD. We included 127 full-term newborns with at least one first-degree relative with CD. Infants were classified according to milk-feeding practice (breastfeeding or formula feeding) and HLA-DQ genotype (low, intermediate or high genetic risk). The prevalence of pathogenic bacteria and viruses was assessed in the faeces of the infants at 7 days, 1 month and 4 months of age. The prevalence of Clostridium perfringens was higher in formula-fed infants than in breast-fed over the study period, and that of C. difficile at 4 months. Among breastfed infants, a higher prevalence of enterotoxigenic E. coli (ETEC) was found in infants with the highest genetic risk compared either to those with a low or intermediate risk. Among formula-fed infants, a higher prevalence of ETEC was also found in infants with a high genetic risk compared to those of intermediate risk. Our results show that specific factors, such as formula feeding and the HLA-DQ2 genotype, previously linked to a higher risk of developing CD, influence the presence of pathogenic bacteria differently in the intestinal microbiota in early life. Further studies are warranted to establish whether these associations are related to CD onset later in life., This work was supported by grants AGL2011-25169, AGL2014-52101-P and AGL2007-66126-C03-03/ALI (YS and FP) from the Spanish Ministry of Economy and Competitiveness (MINECO). The scholarship to MO from CSIC (JAEpre) and the contract to ABP from the European Union's Seventh Framework Program under the grant agreement no 613979 (MyNewGut) are also fully acknowledged.

Gluten-related disorders have recently been reclassified with an emerging scientific literature supporting the concept of non-celiac gluten sensitivity (NCGS). New research has specifically addressed prevalence, immune mechanisms, the recognition of non-immunoglobulin E (non-IgE) wheat allergy and overlap of NCGS with irritable bowel syndrome (IBS)-type symptoms. This review article will provide clinicians with an update that directly impacts on the management of a subgroup of their IBS patients whose symptoms are triggered by wheat ingestion.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555.

Interactions between the immune system and the intestinal microbiota may play a role in coeliac disease (CD). In the present study, the potential effects of Bifidobacterium longum CECT 7347 in children with newly diagnosed CD were evaluated. A double-blind, randomised, placebo-controlled trial was conducted in thirty-three children who received a capsule containing either B. longum CECT 7347 (109 colony-forming units) or placebo (excipients) daily for 3 months together with a gluten-free diet (GFD). Outcome measures (baseline and post-intervention) included immune phenotype of peripheral blood cells, serum cytokine concentration, faecal secretory IgA (sIgA) content, anthropometric parameters and intestinal microbiota composition. Comparisons between the groups revealed greater height percentile increases (P= 0·048) in the B. longum CECT 7347 group than in the placebo group, as well as decreased peripheral CD3+ T lymphocytes (P= 0·004) and slightly reduced TNF-α concentration (P= 0·067). Within-group comparisons of baseline and final values did not reveal any differences in T lymphocytes and cytokines in the placebo group, while decreased CD3+ (P =0·013) and human leucocyte antigen (HLA)-DR+ T lymphocytes (P =0·029) and slightly reduced TNF-α concentration (P= 0·085) were detected in the B. longum CECT 7347 group. Comparison between the groups showed that the administration of B. longum CECT 7347 reduced the numbers of the Bacteroides fragilis group (P= 0·020) and the content of sIgA in stools (P= 0·011) compared with the administration of placebo. Although this is a first exploratory intervention with limitations, the findings suggest that B. longum CECT 7347 could help improve the health status of CD patients who tend to show alterations in gut microbiota composition and a biased immune response even on a GFD.

Background & Aims Celiac disease is a chronic small intestinal inflammatory disorder mediated by an immune response to gluten peptides in genetically susceptible individuals. Celiac disease is often diagnosed in early childhood, but some patients receive a diagnosis late in life. It is uncertain whether pediatric celiac disease is distinct from adult celiac disease. It has been proposed that gluten-reactive T cells in children recognize deamidated and native gluten epitopes, whereas T cells from adults only recognize deamidated gluten peptides. We studied the repertoire of gluten epitopes recognized by T cells from children and adults. Methods We examined T-cell responses against gluten by generating T-cell lines and T-cell clones from intestinal biopsies of adults and children and tested proliferative response to various gluten peptides. We analyzed T cells from 14 children (2−5 years old) at high risk for celiac disease who were followed for celiac disease development. We also analyzed T cells from 6 adults (26−55 years old) with untreated celiac disease. All children and adults were positive for HLA-DQ2.5. Biopsies were incubated with gluten digested with chymotrypsin (modified or unmodified by the enzyme transglutaminase 2) or the peptic-tryptic digest of gliadin (in native and deamidated forms) before T-cell collection. Results Levels of T-cell responses were higher to deamidated gluten than to native gluten in children and adults. T cells from children and adults each reacted to multiple gluten epitopes. Several T-cell clones were cross-reactive, especially clones that recognized epitopes from γ-and ω-gliadin. About half of the generated T-cell clones from children and adults reacted to unknown epitopes. Conclusions T-cell responses to different gluten peptides appear to be similar between adults and children at the time of diagnosis of celiac disease.

Background: Constipation is a common disorder in children. Objective: The objective of this study is to assess the beneficial effects of a daily supplementation with Orafti® inulin‐type fructans in 2–5 year old constipated children. Methods: Double‐blind, randomised, placebo‐controlled parallel group trial where constipated children received two doses of 2 g Orafti® inulin‐type fructans (OF:IN) or placebo (maltodextrin) for 6 weeks. Primary outcome was stool consistency. Secondary outcomes were stool frequency and gastrointestinal symptoms. Results: Twenty-two children were included, 17 completed the study protocol (nine and eight for the control and the OF:IN group, respectively). Results showed that Orafti® inulin‐type fructans supplemented children had softer stools (p = .003). The longitudinal analysis showed no significant changes in controls, whereas supplemented children increased their stool consistency from 2.2 to 2.6 on the modified Bristol scale for children (five items instead of seven) (p = .040). Conclusions: Prebiotic inulin‐type fructans supplementation improves stool consistency in constipated 2–5-year old children. Clinicaltrials.gov, with number NCT02863848.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.-- et al., [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., This work was supported by grants from Ministerio de Ciencia e Innovación and FEDER funds (DELIAC, IPT-2011-0952-900000), and Corporación Tecnológica de Andalucía (SINGLUCHECK, 1737/0118).

OBJECTIVES: The aim of the study was to compare the dietary pattern between subjects with celiac disease (CD) (cases) and subjects without (healthy controls) CD. METHODS: A case-control design study was conducted. A total of 98 subjects with CD (age 10-23 years) were matched by age, sex, and body mass index with 98 nonceliac participants. A nonconsecutive 3-day food record was completed to assess energy, nutrient, and food intake and evaluate the participant's adherence to recommendations. Differences in energy, nutrients, food consumption, and compliance with general recommendations between cases and control groups were assessed by Student t test. Pearson chi-squared test was used to compare categorical variables. Sociodemographic, personal, and family history data were collected. RESULTS: Compared with the control group, the cases with CD reported a significantly higher consumption of added sugar (P

Objectives and study: In the development of Celiac Disease (CD) both genetic and environmental factors play a crucial role. The Human Leukocyte Antigen (HLA)-DQ2 and HLA-DQ8 loci are strongly related to the disease and are necessary but not sufficient for the development of CD. Therefore, increasing interest lies in examining the mechanisms of CD onset from the early beginning. Differences in serum and urine metabolic profiles between healthy individuals and CD patients have been reported previously. We aimed to investigate if the metabolic pathways were already altered in young, 4 month old infants, preceding the CD diagnosis. Methods: Serum samples were available for 230 four month old infants of the PreventCD project, a multicenter, randomized, double-blind, dietary intervention study. All children were positive for HLA-DQ2 and/or HLA-DQ8 and had at least one first-degree relative diagnosed with CD. Amino acids were quantified after derivatization with liquid chromatography tandem mass spectrometry (MS/MS) and polar lipid concentrations (acylcarnitines, lysophosphatidylcholines, phosphatidylcholines, and sphingomyelins) were determined with direct infusion MS/MS. We investigated the association of the metabolic profile with (1) the development of CD up to the age of 8 years (yes/no), (2) with HLA-risk groups, (3) with the age at CD diagnosis, using linear mixed models and cox proportional hazards models. Gender, intervention group, and age at blood withdrawal were included as potential confounder. Results: By the end of 2014, thirty-three out of the 230 children (14%) were diagnosed with CD according to the ESPGHAN criteria. Median age at diagnosis was 3.4 years (IQR, 2.4-5.2). Testing each metabolite for a difference in the mean between healthy and CD children, we (1) could not identify a discriminant analyte or a pattern pointing towards an altered metabolism (Bonferroni corrected P > 0.05 for all). Metabolite concentrations (2) did not differ across the HLA-rislc groups. When investigating the age at diagnosis using (3) survival models, we found no evidence for an association between the metabolic profile and the risk of a later CD diagnosis. Conclusion: The metabolic profile at 4 months of age was not predictive for the development of CD up to the age of 8 years. Our results suggest that metabolic pathways reflected in serum are affected only later in life and that the HLA-genotype does not influence the serum metabolic profile in young infants before introduction of solid food. (C) 2016 Elsevier Ltd. All rights reserved.

BACKGROUND: The European Society for Paediatric Gastroenterology, Hepatology and Nutrition recommended in 2008, based on observational data, to avoid both early (OBJECTIVE: To provide updated recommendations regarding gluten introduction in infants and the risk of developing coeliac disease (CD) during childhood.SUMMARY: The risk of inducing CD through a gluten-containing diet exclusively applies to persons carrying at least one of the CD risk alleles. Because genetic risk alleles are generally not known in an infant at the time of solid food introduction, the following recommendations apply to all infants, although they are derived from studying families with first-degree relatives with CD. Although breast-feeding should be promoted for its other well-established health benefits, neither any breast-feeding nor breast-feeding during gluten introduction has been shown to reduce the risk of CD. Gluten may be introduced into the infant's diet anytime between 4 and 12 completed months of age. In children at high risk for CD, earlier introduction of gluten (4 vs 6 months or 6 vs 12 months) is associated with earlier development of CD autoimmunity (defined as positive serology) and CD, but the cumulative incidence of each in later childhood is similar. Based on observational data pointing to the association between the amount of gluten intake and risk of CD, consumption of large quantities of gluten should be avoided during the first weeks after gluten introduction and during infancy. The optimal amounts of gluten to be introduced at weaning, however, have not been established.

Coeliac disease is a permanent immunological intolerance to gluten proteins in genetically predisposed individuals. The only management is life-long strict adherence to a gluten-free diet. Unfortunately, compliance with gluten-free diet is very difficult in practice due to the widespread presence of gluten in Western diets. For this reason, about 50% of coeliacs following a gluten-free diet continue to suffer from symptoms and present with autoantibodies and/or villous atrophy while on a gluten-free diet. It is therefore important to explore new therapies to improve the management of coeliac disease. To date, five experimental therapies have been tested in randomized and controlled clinical trials. Larazotide acetate reduces the para-cellular passage of gluten to the lamina propria by preventing the opening of intercellular tight junctions. The endopeptidases ALV003 and AN-PEP break down gluten to produce less or non-toxic peptide fragments. A therapeutic vaccine is being tested with the aim of developing gluten tolerance. Finally, infection with the nematode Necator americanus and treatment with the CCR9 antagonist Traficet-EN have also been reported. While substantial progress has been made in the last few years, it is important to remember that all these investigational therapies are in research stage and are generally being considered as "adjunctive" therapies to the gluten-free diet and not as substitutes of the gluten-free diet at this point in time.

Non-Celiac Gluten Sensitivity (NCGS) is a syndrome characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected by either celiac disease or wheat allergy. Given the lack of a NCGS biomarker, there is the need for standardizing the procedure leading to the diagnosis confirmation. In this paper we report experts' recommendations on how the diagnostic protocol should be performed for the confirmation of NCGS. A full diagnostic procedure should assess the clinical response to the gluten-free diet (GFD) and measure the effect of a gluten challenge after a period of treatment with the GFD. The clinical evaluation is performed using a self-administered instrument incorporating a modified version of the Gastrointestinal Symptom Rating Scale. The patient identifies one to three main symptoms that are quantitatively assessed using a Numerical Rating Scale with a score ranging from 1 to 10. The double-blind placebo-controlled gluten challenge (8 g/day) includes a one-week challenge followed by a one-week washout of strict GFD and by the crossover to the second one-week challenge. The vehicle should contain cooked, homogeneously distributed gluten. At least a variation of 30% of one to three main symptoms between the gluten and the placebo challenge should be detected to discriminate a positive from a negative result. The guidelines provided in this paper will help the clinician to reach a firm and positive diagnosis of NCGS and facilitate the comparisons of different studies, if adopted internationally.

Purpose To investigate whether breast-milk composition and microbiota differ in healthy mothers and mothers with celiac disease (CD) to ultimately contribute to identify additional factors determining CD risk. Methods Breast-milk samples from healthy mothers (n = 12) and mothers with CD (n = 12) were collected. Cytokines and secretory immunoglobulin A (sIgA) were analyzed by bead-arrays and flow cytometry and human milk oligosaccharides (HMOs) were assessed by capillary electrophoresis with laser-induced fluorescence (CE-LIF) detection. Breast-milk microbiota composition was analyzed by conventional and quantitative real-time PCR. Result Breast milk from CD mothers showed significantly lower levels of interleukin (IL) 12p70 (P < 0.042), transforming growth factor (TGF)-beta 1 (P < 0.018) and sIgA (P < 0.003) and almost significantly lower levels of interferon (IFN)-gamma (P < 0.058). Six mothers in each group belonged to the secretor Le(a-b+) type, one to the secretor Le(a-b-) type and five to the non-secretor Le(a+b-) type. CD mothers of non-secretor Le(a+b-) type showed increased Lacto-N-tetraose content (P < 0.042) compared with healthy mothers. CD mothers' milk showed reduced gene copy numbers of Bifidobacterium spp. (P < 0.026) and B. fragilis group (P < 0.044). Conclusion CD mothers' breast milk is characterized by a reduced abundance of immunoprotective compounds (TGF-beta 1 and sIgA) and bifidobacteria. The reduction in these components could theoretically diminish the protective effects of breast-feeding on the child's future risk of developing CD.