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Escudo De La Universidad De Valencia Programa de Doctorado en Ciencias de la Alimentación TESIS DOCTORAL Sensibilidad al trigo y gluten no celiaca. Identificación de la enfermedad y manejo nutricional Presentada por: Dirigida por: Yolanda Reig Otero Dra. Cristina Juan García Dra. Lara Manyes i Font Valencia, Enero 2019 Programa de Doctorado en Ciencias de la Alimentación Departament de Medicina Preventiva i Salut Pública, Ciències de l´Alimentació, Toxicologia i Medicina Legal. Sensibilidad al trigo y gluten no celiaca. Identificación de la enfermedad y manejo nutricional. Tesis Doctoral Valencia, Enero 2019 Presentada por: Dirigida por: Yolanda Reig Otero Dra. Cristina Juan García Dra. Lara Manyes i Font La Dra. Cristina Juan García, Profesora Titular de la Universitat de València y la Dra. Lara Manyes i Font, Profesora Ayudante Doctora de la Universitat de València, CERTIFICAN QUE: La licenciada en Ciencias Químicas Yolanda Reig Otero ha realizado bajo su dirección el trabajo que lleva por título Sensibilidad al trigo y gluten no celiaca. Identificación de la enfermedad y manejo nutricional, y autorizan su presentación para optar al título de Doctor por la Universitat de València. Y para que así conste, expiden y firman el siguiente certificado. Burjassot, Enero 2019 Dra. Cristina Juan García Dra. Lara Manyes i Font Este trabajo ha dado lugar a 3 artículos publicados en las siguientes revistas científicas: 1. Reig-Otero Y, Mañes J, Manyes L. Sensibilidad al gluten no celiaca (SGNC): manejo nutricional de la enfermedad. Nutr. Clin. Diet. Hosp. 2017; 37: 179-190. 2. Reig-Otero Y, Mañes J, Manyes L. Amylase-trypsin Inhibitors in wheat and other cereals as potential activators of the effects of non-celiac gluten sensitivity (NCGS). J. Med. Food. 2017; 21(3), 207-214. 3. Reig-Otero Y, Mañes J, Juan-García C, Manyes L. Análisis de los inhibidores de las α-amilasa y la tripsina contenidos en el trigo y otros cereales: potenciales promotores de la inflamación intestinal. Rev. Toxicol. 2018; 35: 45 – 52. RESUMEN La sensibilidad al gluten no celiaca (SGNC) es un trastorno caracterizado por síntomas tanto intestinales como extraintestinales con la ingestión de alimentos que contienen gluten en individuos con un diagnóstico negativo para la enfermedad celiaca (EC) y alergia al gluten/trigo (AG). Los estudios más recientes señalan que los síntomas podrían ser causa de la ingesta no solo del gluten, sino de otros componentes vinculados al trigo como los inhibidores de la amilasa y la tripsina (ATIs) y los carbohidratos de cadena corta (oligosacáridos, disacáridos y monosacáridos) y polioles (FODMAPS). El tratamiento establecido hasta el momento para evitar estos síntomas es la dieta sin gluten (DSG), aunque se han revisado otras estrategias dietéticas y farmacológicas que podrían aplicarse en esta patología. Hasta el momento, no se ha definido ningún biomarcador que identifique este trastorno y que permita su diagnóstico rápido y sencillo. En la actualidad, el único método reconocido por la comunidad científica para su diagnóstico es a través de un ensayo doble ciego aleatorio con placebo (DCACP) con gluten una vez que se han descartado la EC y la AG. Así mismo, existe una vinculación la SGNC con otras patologías neurológicas, reumáticas e intestinales. El análisis de las publicaciones revisadas indica que en la SGNC existe una activación mayoritaria del sistema inmune innato a diferencia de lo que ocurre con la EC cuyos síntomas están relacionados con una reacción autoinmune donde la predisposición genética del paciente es fundamental e implica tanto a la inmunidad innata como la adaptativa. Diversos estudios han demostrado, en ensayos tanto in vitro como in vivo, que los ATIs son unas proteínas que tienen la capacidad de activar fuertemente el sistema inmunitario innato provocando un aumento de la expresión de los receptores TLR en el intestino. En este sentido, estos trabajos cuestionan el rol de la gliadina del gluten en la activación del sistema inmune innato en la SGNC dado que, al utilizar gliadina digerida con pepsina y tripsina como reactivo, no se observan alteraciones significativas. Se observan incoherencias cuando se comparan los resultados de los distintos estudios DCACP realizados para analizar cómo influye la ingestión de gluten en los síntomas de las personas identificadas con SGNC. Esto es debido a la dificultad de identificar a grupos de individuos con SGNC homogéneos como consecuencia de la inexistencia de biomarcadores y a la posible superposición de los efectos del gluten, los ATIs y los FODMAPS del trigo utilizado. Asimismo, diversos trabajos comprueban que las muestras comerciales de gluten utilizadas para los ensayos contienen cantidades significativas de ATIs, indicando que estas proteínas han sido un contaminante interfiriente en los resultados obtenidos. Los resultados de los estudios que evalúan la concentración de la interleucina IL-8 y otras citoquinas características de la activación del sistema inmune innato, en cultivos celulares de enfermos sensibles al trigo, revelan que la capacidad proinflamatoria de los ATIs es muy superior en cereales que contienen gluten. Asimismo, estos ensayos indican que la actividad proinflamatoria de los ATIs es inferior en alimentos procesados térmicamente respecto a los cereales en crudo. Esta capacidad está relacionada con su estructura secundaria y terciaria y del estado de agregación que se encuentran, pudiéndose clasificar los alimentos según su capacidad de activar el sistema inmune innato. En la SGNC, la existencia de una alteración en la barrera intestinal es la condición inicial para que se inicie toda la cascada de señales en el sistema inmune. Esto puede ser debido principalmente a infecciones previas de parásitos, bacterias o virus, al desequilibrio en la flora intestinal, al consumo continuado de antibióticos y antiinflamatorios o a la existencia de enfermedades autoinmunes. En este sentido, la revisión realizada indica que la restauración y modulación de la microbiota intestinal es una de las vías para el tratamiento de la SGNC. Aunque las técnicas analíticas para identificar los ATIs en alimentos más utilizadas están basadas en la espectrometría de masas (MS), esta revisión pone en evidencia la variedad de métodos utilizados y la no existencia de un consenso científico en un método rápido, fiable, contrastable y económicamente viable para utilizarlo en el análisis rutinario de los alimentos. Asimismo, es necesario disponer de materiales de referencia imprescindibles para validar el método usado por los laboratorios prioritariamente a través de un estudio interlaboratorio. Por último, este trabajo pone en relieve que la alimentación es un elemento preventivo y terapéutico para tratar trastornos como SGNC, y que el diseño de dietas y alimentos con una reducción de los componentes proinflamatorios, como son los ATIs, abre nuevas líneas de investigación prometedoras aplicables no solo para la SGNC sino para otras muchas patologías no celiacas que se han asociado con el consumo del trigo. PALABRAS CLAVE: Trigo, gluten, sensibilidad al trigo, inhibidores de la amilasa y la tripsina, inmunidad innata, técnicas analíticas. ABSTRACT Non-coeliac gluten sensitivity (NCGS) is a disorder characterized by both intestinal and extra-intestinal symptoms with the ingestion of gluten-containing foods in individuals with a negative diagnosis for celiac disease (CD) and gluten/wheat allergy (GA). The most recent studies show that symptoms may be the cause of intake not only of gluten, but of other wheat-related components such as amylase and trypsin inhibitors (ATIs) and low fermentable, oligo-, di-, mono- saccharides and polyol (FODMAPS). The treatment established so far to avoid these symptoms is the gluten-free diet (GFD), although other dietary and pharmacological strategies that could be applied in this pathology have been reviewed. So far, no biomarker has been defined that identifies this disorder and allows its rapid and simple diagnosis. At present, the only method recognized by the scientific community for its diagnosis is through a double-blind randomized placebo trial (DBRP) with gluten once EC and GA have been ruled out. There is also a link between NCGS and other neurological, rheumatic and intestinal pathologies. The analysis of the reviewed publications indicates that in the NCGS pathology there is a majority activation of the innate immune system unlike what happens with CD whose symptoms are related to an autoimmune reaction where is fundamental the genetic predisposition of the patient and involves both innate and adaptive immunity. Several studies have shown, in both in vitro and in vivo assays, that ATIs are proteins that could strongly activate the innate immune system causing an increase in the expression of TLR receptors in the gut. In this sense, these works question the role of gluten gliadin in the activation of the innate immune system in the NCGS since, when using digested gliadin with pepsin and trypsin as a reagent, no significant alterations are observed. Inconsistencies are observed when comparing the results of the different DBRP studies performed to analyze how gluten ingestion influences the symptoms of patients identified with NCGS. This is due to the difficulty of identifying homogeneous groups of individuals with NCGS due to the lack of biomarkers and the possible overlap of the effects of gluten, ATIs and FODMAPS of the wheat used. Also, several studies prove that the commercial gluten samples used for the assays contain significant amounts of ATIs, indicating that these proteins have been an interfering contaminant in the results obtained. Studies evaluating the concentration of IL-8 interleukin and other cytokines characteristic of the activation of the innate immune system in cell cultures of wheat-sensitive patients, reveal that the pro-inflammatory capacity of ATIs is much higher in cereals containing gluten. With these assays it has been possible to determine the pro-inflammatory activity of ATIs observing that it is lower in heat- processed foods than in raw cereals. This capacity is linked to its secondary and tertiary structure and the state of aggregation found, allowing foods to be classified according to their ability to activate the innate immune system.
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