Metabolomic Profiling in Children with Celiac Disease: Beyond the Gluten-Free Diet

FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades Projects FEDER No B-AGR-658 and Excelencia P21_00101Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid” and the Government of Catalonia: Agency for the Management of University and Resarch Grants (2021SGR00990)Nutrición y Ciencias de los Alimentos” from the University of Granad

The Importance of an Early Evaluation after Establishing a Gluten-Free Diet in Children with Celiac Disease

The following are available online at https://www.mdpi.com/article/ 10.3390/nu15071761/s1This research was funded by the FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades/ Project No B-AGR-658. It was also partially funded with the grant “Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid”. It also was partially funded by BIOMEDAL S.L.A gluten-free diet (GFD) is the only treatment available for celiac disease (CD); hence, it is important to ensure correct adherence to the diet and adequate monitoring of the diet. The present study aims to assess the importance of an early follow-up of celiac patients after diagnosis of the disease, identify the role of stool gluten immunogenic peptides (GIPs) in the assessment of GFD adherence, and analyze possible nutritional imbalances or deficiencies in the GFD. This is a cross-sectional study carried out in pediatric patients with newly diagnosed CD in a tertiary hospital in Spain. Of the 61 patients included, 14% had positive stool GIPS at 4 months after CD diagnosis, Among them, 88% had negative stool GIPS at 9 months after diagnosis, following dietary advice. We found nutritional deficiencies in the GFD, such as vitamin D (with only 27% of patients with adequate intakes), folate, calcium, magnesium, and fiber. Similarly, we found imbalances: excess protein and fat intakes and a high percentage of total daily energy intake came from ultra-processed foods (UPF). These findings emphasize the importance of early follow-up of children after diagnosis of CD. It is also crucial to identify patients with poor GFD compliance based on stool GIPS and analyze GFD nutritional imbalances and deficits. Our findings may contribute to the development of specific strategies for the early follow-up of patients with CD, including appropriate nutritional counselling.FEDER/Junta de Andalucía-Consejería de Transformación Económica, Industria, Conocimiento y Universidades/ B-AGR-658"Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid"BIOMEDAL S.L

Celiac Disease Is a Risk Factor for Mature T and NK Cell Lymphoma: A Mendelian Randomization Study

Celiac disease (CeD) is an immune-mediated disorder triggered by gluten ingestion that damages the small intestine. Although CeD has been associated with a higher risk for cancer, the role of CeD as a risk factor for specific malignancies, such as enteropathy-associated T-cell lymphoma (EATL), remains controversial. Using two-sample Mendelian randomization (2SMR) methods and the summarized results of large genome-wide association studies from public repositories, we addressed the causal relationship between CeD and eight different malignancies. Eleven non- HLA SNPs were selected as instrumental variables (IVs), and causality estimates were obtained using four 2SMR methods: random-effects inverse variance-weighted, weighted median estimation, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO).We identified a significant causal relationship between CeD and mature T/NK cell lymphomas. Under a multivariate Mendelian randomization model, we observed that the causal effect of CeD was not dependent on other known lymphoma risk factors. We found that the most instrumental IV was located in the TAGAP locus, suggesting that aberrant T cell activation might be relevant in the T/NK cell malignization process. Our findings provide new insights into the connection between immune imbalance and the development of severe comorbidities, such as EATL, in patients with CeD.Ministry of Science and Innovation, Spain (MICINN) IJC2018-038026-IEuropean CommissionSpanish Ministry of Science and Innovation through the Spanish National Plan for Scientific and Technical Research and Innovation PY20_00212Andalusian Government B-CTS-584-UGR20 B-AGR-658FEDER/Junta de Andalucia-Consejeria de Transformacion Economica, Industria, Conocimiento y UniversidadesGrant "Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madrid" PID2020-120157RB-I0

EEN Yesterday and Today … CDED Today and Tomorrow.

The treatment of Pediatric Crohn's Disease (CD) requires attention both to achieve mucosal healing and to optimize growth, while also maintaining proper bone health. Exclusive Enteral Nutrition (EEN) is recommended as first-line treatment in luminal CD. The therapeutic mechanisms of EEN are being discovered by advances in the study of the gut microbiota. Although the total exclusion of a normal diet during the time of EEN continues to be of high importance, new modalities of dietary treatment suggest a successful future for the nutritional management of CD. In this sense, Crohn's Disease Exclusion Diet (CDED) is a long-term strategy, it apparently acts on the mechanisms that influence the appearance of inflammation (reducing dietary exposure to products negatively affecting the microbiota), but does so using specific available whole foods to achieve this goal, increases the time of clinical remission and promotes healthy lifestyle habits. The development of CDED, which partly minimizes the problems of EEN, has enabled a turnaround in the treatment of pediatric CD. This review highlights the role of enteral nutrition in the treatment of Crohn's disease with special emphasis on newer dietary modalities such as CDED

Benefits of Paediatric to Adult Transition Programme in Inflammatory Bowel Disease: The BUTTERFLY Study of GETECCU and SEGHNP

Inflammatory bowel diseases; Transition to adult care; Transitional careEnfermedad inflamatoria intestinal; Tránsito a la atención adulta; Cuidados de transiciónMalaltia inflamatòria intestinal; Trànsit a l'atenció adulta; Cures de transicióBackground: Transition is a planned movement of paediatric patients to adult healthcare systems, and its implementation is not yet established in all inflammatory bowel disease (IBD) units. The aim of the study was to evaluate the impact of transition on IBD outcomes. (2) Methods: Multicentre, retrospective and observational study of IBD paediatric patients transferred to an adult IBD unit between 2017-2020. Two groups were compared: transition (≥1 joint visit involving the gastroenterologist, the paediatrician, a programme coordinator, the parents and the patient) and no-transition. Outcomes within one year after transfer were analysed. The main variable was poor clinical outcome (IBD flare, hospitalisation, surgery or any change in the treatment because of a flare). Predictive factors of poor clinical outcome were identified with multivariable analysis. (3) Results: A total of 278 patients from 34 Spanish hospitals were included. One hundred eighty-five patients (67%) from twenty-two hospitals (65%) performed a structured transition. Eighty-nine patients had poor clinical outcome at one year after transfer: 27% in the transition and 43% in the no-transition group (p = 0.005). One year after transfer, no-transition patients were more likely to have a flare (36% vs. 22%; p = 0.018) and reported more hospitalisations (10% vs. 3%; p = 0.025). The lack of transition, as well as parameters at transfer, including IBD activity, body mass index < 18.5 and corticosteroid treatment, were associated with poor clinical outcome. One patient in the transition group (0.4%) was lost to follow-up. (4) Conclusion: Transition care programmes improve patients' outcomes after the transfer from paediatric to adult IBD units. Active IBD at transfer impairs outcomes.This work was supported by a grant from the Young Group of the Spanish Gastroenterology Association (AEG)

Up-Regulation of Specific Bioactive Lipids in Celiac Disease

Celiac disease (CD) is an autoimmune enteropathy linked to alterations of metabolism. Currently, limited untargeted metabolomic studies evaluating differences in the plasma metabolome of CD subjects have been documented. We engage in a metabolomic study that analyzes plasma metabolome in 17 children with CD treated with a gluten-free diet and 17 healthy control siblings in order to recognize potential changes in metabolic networks. Our data demonstrates the persistence of metabolic defects in CD subjects in spite of the dietary treatment, affecting a minor but significant fraction (around 4%, 209 out of 4893 molecular features) of the analyzed plasma metabolome. The affected molecular species are mainly, but not exclusively, lipid species with a particular affectation of steroids and derivatives (indicating an adrenal gland affectation), glycerophospholipids (to highlight phosphatidic acid), glycerolipids (with a special affectation of diacylglycerols), and fatty acyls (eicosanoids). Our findings are suggestive of an activation of the diacylglycerol-phosphatidic acid signaling pathway in CD that may potentially have detrimental effects via activation of several targets including protein kinases such as mTOR, which could be the basis of the morbidity and mortality connected with untreated CD. However, more studies are necessary to validate this idea regarding CD.Regional Government of Andalusia, Excellence Research (Project No P12-AGR-2581)Spanish Ministry of Science, Innovation, and Universities (Ministerio de Ciencia, Innovación y Universidades, RTI2018-099200-BI00)Generalitat of Catalonia: Agency for Management of University and Research Grants (2017SGR696)Department of Health (SLT002/16/00250)FEDER - European Union (“A way to build Europe”).IRBLleida - CERCA Programme/Generalitat of Catalonia“Investigation grant program by the Association of Celiacs and Sensitive to Gluten of the Community of Madri

Time Following a Gluten-Free Diet, Ultra-Processed Food Consumption and Quality of Life in Children with Celiac Disease

Maintaining a strict gluten-free diet (GFD) may affect the quality of life of children with celiac disease (CD) and promote a less healthy diet by substituting gluten-containing foods with ultra-processed foods. We aimed to assess the influences of the GFD and ultra-processed food consumption on parents' perception of the quality of life of children with CD. Fifty-eight children (mean age 8.6 +/- 4.1 years) were included. The participants were divided into groups based on the time following a GFD: = 12 months (n = 37). Their dietary consumption was assessed through a three-day food record. The 20-item Celiac Disease Quality Of Life survey (CD-QOL), which contains four subscales (limitations, dysphoria, health concerns, and inadequate treatment) was used to assess the quality of life. The children who followed a GFD for >= 12 months presented poorer scores in the limitations subscale than those who followed a GFD for <6 months (p = 0.010). The mean % of the energy intake from ultra-processed foods was 47.3 +/- 13.5. Children with CD consuming more than 50% of their total energy from ultra-processed foods showed poorer scores for the limitation and inadequate treatment (both, p = 0.019) subscales than their counterparts. According to parents' perceptions, those children who consumed more than 50% of their energy through ultra-processed foods had more limitations, and their treatment was perceived as less effective.European Commission B-AGR-658Association of Celiacs and Sensitive to Gluten of the Community of MadridSpanish Government FPU17/0371

Multifactorial Etiology of Anemia in Celiac Disease and Effect of Gluten-Free Diet: A Comprehensive Review

Celiac disease (CD) is a multisystemic disorder with di erent clinical expressions, from malabsorption with diarrhea, anemia, and nutritional compromise to extraintestinal manifestations. Anemia might be the only clinical expression of the disease, and iron deficiency anemia is considered one of the most frequent extraintestinal clinical manifestations of CD. Therefore, CD should be suspected in the presence of anemia without a known etiology. Assessment of tissue anti-transglutaminase and anti-endomysial antibodies are indicated in these cases and, if positive, digestive endoscopy and intestinal biopsy should be performed. Anemia in CD has a multifactorial pathogenesis and, although it is frequently a consequence of iron deficiency, it can be caused by deficiencies of folate or vitamin B12, or by blood loss or by its association with inflammatory bowel disease (IBD) or other associated diseases. The association between CD and IBD should be considered during anemia treatment in patients with IBD, because the similarity of symptoms could delay the diagnosis. Vitamin B12 deficiency is common in CD and may be responsible for anemia and peripheral myeloneuropathy. Folate deficiency is a well-known cause of anemia in adults, but there is little information in children with CD; it is still unknown if anemia is a symptom of the most typical CD in adult patients either by predisposition due to the fact of age or because biochemical and clinical manifestations take longer to appear

Predictors of Response to Exclusive Enteral Nutrition in Newly Diagnosed Crohn´s Disease in Children: PRESENCE Study from SEGHNP

Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014–2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6–8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn’s Disease activity index [wPCDAI] 15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6–8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn’s disease regardless of the location of disease and disease activityS

Estudio del perfil metabolómico en niños celiacos y sus diferencias respecto a la población sana: probabilidad de desarrollo de biomarcadores

Para la realización del estudio se solicitaron diversas ayudas, concediéndose las siguientes: o Subvencionado por la Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (Proyectos de Investigación de Excelencia, convocatoria 2012). Título del proyecto: Estudio multidisciplinar del efecto de la dieta sin gluten en niños celíacos, para el desarrollo de productos adaptados a sus requerimientos (Referencia: P12-AGR-2581). o Subvencionado por la Universidad de Granada. Título del proyecto: estudio multidisciplinar del valor nutricional de la dieta sin gluten y su impacto sobre el estado nutricional, la respuesta metabólica y calidad de vida en niños celíacos. (Referencia: PP2017.PIP014). o Subvencionado por la Sociedad Pediatría Andalucía Oriental (SPAO) mediante beca para ayuda a la Investigación 2020. o Premio Especial de Investigación sobre Enfermedad Celíaca, concedido por la Asociación de Celíacos y Sensibles al Gluten de la Comunidad de Madrid, en convocatoria de 2020.La Enfermedad Celiaca es la patología crónica intestinal más frecuente en nuestro medio, cuya incidencia a nivel mundial está aumentando. La gran expresión clínica se debe a la compleja interacción entre factores genéticos, inmunológicos y ambientales, que hace necesaria una visión mucho más holística para tratar de comprender los procesos metabólicos subyacentes. Un mejor conocimiento de dichos procesos podría ofrecer la oportunidad de descubrir nuevos mecanismos fisiopatológicos y biomarcadores potenciales útiles para el diagnóstico de casos dudosos debido a los resultados histológicos, así como para el seguimiento de la enfermedad. En este sentido, la metabolómica es una aproximación complementaria para estudiar enfermedades multifactoriales, que informa de modo global de los procesos celulares en el organismo dinámico, mejorando nuestra comprensión sobre la fisiología de los sistemas biológicos. En los últimos años, escasos aunque recientes estudios sugieren que se deben considerar las alteraciones metabólicas en sujetos con la enfermedad. El objetivo de esta Tesis Doctoral fue estudiar el perfil metabolómico en niños con la enfermedad, y comparar sus diferencias respecto a población sana. Para ello, se tomaron como controles hermanos de los pacientes sin la enfermedad, disminuyendo así la variabilidad interindividual debida a la dieta, genética o factores ambientales. Se realizó mediante espectrometría de masas análisis dirigido y no dirigido del plasma de los pacientes. Los resultados del análisis dirigido mostraron afectación de la vía de la transulfuración, con disminución de cisteína y cistationina, que unido a la normalidad de glutatión y vitamina B6 sugiere un defecto específico a nivel de enzimas implicadas en la defensa antioxidante, la detección de oxígeno, la función mitocondrial, la inflamación y la señalización de segundos mensajeros. Este hallazgo, además, podría ser justificado por una mutación de SAH hidrolasa que cursa con síntomas típicos de la enfermedad, como retraso del crecimiento, anomalías dentales o hipertransaminasemia. El análisis no dirigido mostró alteraciones en todo el metaboloma circulante a pesar de la dieta sin gluten, sobre todo en mediadores lipídicos, sugiriendo una huella metabólica característica. Encontramos diferencias en metabolitos implicados en vías inflamatorias, metabolismo de los esteroides y metabolismo de la bilirrubina, sugiriendo alteraciones a nivel hepático y suprarrenal, siendo esta la primera descripción reportada sobre alteraciones a nivel de esta vía. Por último, observamos diferencias en los niveles de diacilglicerol, que juega un papel central en el control de la comunicación neuronal, la fagocitosis y el control de las respuestas inmunes, y que como segundo mensajero desempeña un papel importante en la regulación de mTOR, descrito recientemente como factor clave para mantener una respuesta inflamatoria sostenida en la enfermedad. Los datos aquí presentados, sugieren por primera vez, alteraciones como resultado de la expresión de nuevos mecanismos fisiopatológicos subyacentes a la enfermedad. El mayor conocimiento de dichas vías podría ayudar a un mejor entendimiento de la enfermedad, así como al desarrollo de huellas propias que han de ser verificadas. Estos resultados contribuyen a dilucidar la compleja interacción que se produce entre genética, transcriptoma y metaboloma en la enfermedad, con un mayor conocimiento de dichas vías. El hecho de que probablemente haya una huella característica de la enfermedad es esperanzador. Estas diferencias metabolómicas deberán de ser exploradas con una perspectiva inmunológica e interrelacionadas con factores epigenéticos. Con más estudios, quizás, podamos establecer biomarcadores que ayuden a mejorar el diagnóstico o seguimiento de la enfermedad.Tesis Univ. Granada.Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía (P12-AGR-2581)Universidad de Granada (PP2017.PIP014)Sociedad Pediatría Andalucía OrientalPremio Especial de Investigación sobre Enfermedad Celíaca, concedido por la Asociación de Celíacos y Sensibles al Gluten de la Comunidad de Madrid (2020