Celiac disease: New therapies on the horizon.

Celiac Disease (CeD) is a chronic intestinal disease which occurs in 0.7-1.4% of the global population. Since the discovery of gluten as its disease-inducing antigen, CeD patients are treated with a gluten-free diet which is effective but has limitations for certain groups of patients. Accordingly, over the past few years, there is a growing interest in alternative treatment options. This review summarizes emerging pharmacological approaches, including tolerance induction strategies, tissue transglutaminase inhibition, gluten degradation, and inhibition of interleukin (IL)-15.

Comparative evaluation of the antioxidant, antimicrobial and nutritive properties of gluten-free flours.

Gluten-free flours are interesting alternative to wheat flours. They could be by-products of oilseed processing, characterized by high content of bioactive compounds. Therefore the aim of the study was to determine the antioxidant, antimicrobial properties, amino acid and fatty acid profile of flours obtained as by-products from the oil industry. The highest total polyphenol content and antioxidant activity was found to have evening primrose flour. The widest spectrum of microbial growth inhibition was indicated for corn germ extract which showed no antimicrobial activity only against Bacillus subtilis. The highest protein content was found in pumpkin, peanut and almond flours (more than 50 g/100 g). The major abundant amino acids in all the analysed oilseed cake flours were aspartic acid, glutamic acid and arginine. The analysed gluten-free flours were found to be a good source of polyunsaturated fatty acids (PUFAs), which comprised mainly linoleic acid and α-linolenic acid, whereas the best source of PUFAs was evening primrose flour. The results suggest that the cold-pressed seed flours possess valuable chemical composition and may be considered for improvement of the nutritional properties of food products.

The Diverse Potential of Gluten from Different Durum Wheat Varieties in Triggering Celiac Disease: A Multilevel In Vitro, Ex Vivo and In Vivo Approach.

The reasons behind the increasing prevalence of celiac disease (CD) worldwide are still not fully understood. This study adopted a multilevel approach (in vitro, ex vivo, in vivo) to assess the potential of gluten from different wheat varieties in triggering CD. Peptides triggering CD were identified and quantified in mixtures generated from simulated gastrointestinal digestion of wheat varieties (n = 82). Multivariate statistics enabled the discrimination of varieties generating low impact on CD (e.g., Saragolla) and high impact (e.g., Cappelli). Enrolled subjects (n = 46) were: 19 healthy subjects included in the control group; 27 celiac patients enrolled for the in vivo phase. Celiacs were divided into a gluten-free diet group (CD-GFD), and a GFD with Saragolla-based pasta group (CD-Sar). The diet was followed for 3 months. Data were compared between CD-Sar and CD-GFD before and after the experimental diet, demonstrating a limited ability of Saragolla to trigger immunity, although not comparable to a GFD. Ex vivo studies showed that Saragolla and Cappelli activated immune responses, although with great variability among patients. The diverse potential of durum wheat varieties in triggering CD immune response was demonstrated. Saragolla is not indicated for celiacs, yet it has a limited potential to trigger adverse immune response.

Hydrolyzed wheat gluten alleviates deoxynivalenol-induced intestinal injury by promoting intestinal stem cell proliferation and differentiation via upregulation of Wnt/ß-catenin signaling in mice.

Disintegration of the intestine caused by deoxynivalenol (DON), which is a fungal metabolite found in cereal grain-based human and animal diets, triggers severe intestinal inflammatory disease. Hydrolyzed wheat gluten (HWG) can promote the development of intestine. Therefore, HWG was administered orally to male mice on 1-14 days, and DON was administered to them on 4-11 days. Feed, water intake and body weight were recorded all over the experimental period. Blood samples were collected then the mice were sacrificed to collect the jejunum for crypt isolation and culture. The intestinal morphology was observed by electron microscopy, and Western blotting was used to investigate intestinal stem cell (ISC) proliferation and differentiation, as well as the primary regulatory mechanism of the Wnt/ß-catenin signaling. The results showed that HWG increased the average daily gain and average daily water intake of mice under DON-induced injury conditions, and increased the jejunum weight, villous height in the jejunum, and promoted jejunal crypt cell expansion. The DON-induced decrease in Wnt/ß-catenin activity, the expression of Ki67, PCNA and KRT20 were rescued by HWG in the jejunum, crypt and enteroid, as well as the number of goblet cells and Paneth cells. Furthermore, HWG increased jejunum diamine oxidase (DAO) activity. In conclusion, HWG alleviates DON-induced intestinal injury by enhancing ISC proliferation and differentiation in a Wnt/ß-catenin-dependent manner.

Gluten Vehicle and Placebo for Non-Celiac Gluten Sensitivity Assessment.

Non-celiac gluten sensitivity (NCGS) is a syndrome characterized by gastrointestinal and extraintestinal manifestations triggered after gluten ingestion in the absence of celiac disease and wheat allergy. Because of the lack of biomarkers for NCGS diagnosis, the cornerstone for its assessment is a single- or double-blind placebo-controlled (DBPC) gluten challenge. However, there are some non-standardized points in the diagnostic approach proposed by the experts. This complicate comparisons among the results published by different research groups. The gluten vehicle and placebo must be indistinguishable from each other, which entails sensory and technological evaluations of the designed gluten vehicle and placebo products. At the moment, there is no standardized method for the preparation of the gluten vehicle and placebo for carrying out DBPC gluten challenges for NCGS assessment. This review focuses on the challenges that researchers have to face, either for the development of an accepted gluten vehicle and placebo or for identifying NCGS cases on the basis of DBPC gluten challenges.

Nuevas terapias en la enfermedad celiaca y sus complicaciones / New coeliac disease treatments and their complications

El único tratamiento aceptado para la enfermedad celiaca es el seguimiento de forma estricta de la dieta sin gluten. Este tipo de dieta puede ocasionar una disminución de la calidad de vida de los pacientes, dificultades sociales y económicas. Por lo tanto, son frecuentes las transgresiones dietéticas que pueden perpetuar el daño intestinal. En los últimos años se han desarrollado numerosos tratamientos, dirigidos hacia diferentes dianas en la patogenia de la enfermedad celiaca: modificación del gluten para conseguir un gluten no inmunogénico, terapias endoluminales que degraden el gluten en la luz intestinal, favorecer la tolerancia al gluten, modulación de la permeabilidad intestinal o regulación de la respuesta inmune adaptativa. En esta revisión se evalúan estas líneas terapéuticas que se están investigando para la enfermedad celiaca y los tratamientos enfocados al control de las complicaciones de la enfermedad, como la enfermedad celiaca refractaria (AU)

The only accepted treatment for coeliac disease is strict adherence to a gluten-free diet. This type of diet may give rise to reduced patient quality of life with economic and social repercussions. For this reason, dietary transgressions are common and may elicit intestinal damage. Several treatments aimed at different pathogenic targets of coeliac disease have been developed in recent years: modification of gluten to produce non-immunogenic gluten, endoluminal therapies to degrade gluten in the intestinal lumen, increased gluten tolerance, modulation of intestinal permeability and regulation of the adaptive immune response. This review evaluates these coeliac disease treatment lines that are being researched and the treatments that aim to control disease complications like refractory coeliac disease (AU)

Is the evidence of breast feeding protection against coeliac disease real?

Many recent studies discredit breastfeeding protection against coeliac disease. We will try to answer the question: "Is the evidence of breast feeding protection against coeliac disease real?"

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A concise review of Hashimoto thyroiditis (HT) and the importance of iodine, selenium, vitamin D and gluten on the autoimmunity and dietary management of HT patients.Points that need more investigation.

Hashimoto's thyroiditis (HT) is a chronic autoimmune thyroid disease caused by an interaction between genetic factors and environmental conditions, both of which are yet to be fully understood. The management of HT depends on its clinical manifestations, commonly including diffuse or nodular goiter with euthyroidism, subclinical hypothyroidism and permanent hypothyroidism. However, in most cases of patients with HT, lifelong levothyroxine substitution is required. The additional role of diet for the management of HT is usually overlooked. A literature search regarding the importance and the influence of iodine, selenium, vitamin D and gluten on HT was conducted. In HT careful supplementation of possible deficiencies is recommended for the dietary management of these patients. The use of a diet low in gluten among HT patients with or without celiac disease (CD) is discussed.

Celiac disease and fibromyalgia: is there an association?

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¿Cuál es la edad adecuada para la introducción del gluten en la dieta de los lactantes? / What is the appropriate age for the introduction of gluten in the diet of infants?

Un ensayo clínico, publicado en 2014, bien diseñado y con poca probabilidad de sesgo, muestra que en niños de alto riesgo de enfermedad celíaca, la ingesta de gluten en pequeñas cantidades no reduce la incidencia de enfermedad celíaca a los tres años de vida; también, que la lactancia materna tampoco tuvo ningún efecto en la incidencia de la enfermedad a los tres años. Estos resultados están en clara contradicción con las recomendaciones emitidas en 2008 por la European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). La conclusión es que se mantiene la recomendación de la lactancia materna exclusiva en los primeros seis meses de vida y que la introducción progresiva del gluten entre los cuatro y los seis meses de edad no reduce la incidencia de enfermedad celíaca (AU)

A well designed clinical trial, with low risk of bias, published in 2014, shows that, in celiac disease high risk infants, small amounts of gluten in the diet don’t reduce the incidence of celiac disease at three years of age; moreover, breastfeeding didn’t have any effect in the disease incidence at three years of age either. These results are clearly contradictory with the 2008 ESPGHAN recommendations. The conclusion is the adherence to the recommendation of exclusive breastfeeding the first six months of life and that the progressive introduction of gluten between 4 and 6 months of age do not reduce celiac disease incidence (AU)

Randomised clinical study: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non-coeliac gluten sensitivity.

BACKGROUND: It is unknown whether symptoms in non-coeliac patients (non-CD) meeting clinical diagnostic criteria for noncoeliac gluten sensitivity (NCGS) are specifically triggered by gluten. AIM: To assess gluten sensitivity in patients diagnosed with NCGS. METHODS: We studied 35 non-CD subjects (31 females) that were on a gluten-free diet (GFD), in a double-blind challenge study. Participants were randomised to receive either gluten-containing flour or gluten-free flour for 10 days, followed by a 2-week washout period and were then crossed over. The main outcome measure was their ability to identify which flour contained gluten. Secondary outcome measures were based upon Gastrointestinal Symptoms Rating Scale (GSRS) scores. RESULTS: The gluten-containing flour was correctly identified by 12 participants (34%), who were classified as having NCGS. Their mean GSRS dimension scores were significantly higher following gluten challenge compared to baseline. The scores were: pain, 1.7 ± 0.8 vs. 2.6 ± 1.0; reflux, 1.6 ± 0.5 vs. 2.2 ± 0.9; indigestion, 1.9 ± 0.7 vs. 3.2 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 2.9 ± 1.5 and constipation, 1.9 ± 0.9 vs. 2.9 ± 1.3. Seventeen participants (49%) erroneously considered the gluten-free flour to contain gluten. Their mean GSRS dimension scores were significantly higher following gluten-free flour challenge compared to baseline. The scores were: pain, 1.6 ± 0.9 vs. 3.0 ± 0.9; reflux, 1.4 ± 0.5 vs. 2.3 ± 1.1; indigestion, 2.0 ± 1.1 vs. 3.7 ± 1.1; diarrhoea, 1.6 ± 0.7 vs. 3.0 ± 1.2 and constipation, 1.6 ± 0.9 vs. 2.6 ± 1.3. The other six participants (17%) were unable to distinguish between the flours. CONCLUSION: Double-blind gluten challenge induces symptom recurrence in just one-third of patients fulfilling the clinical diagnostic criteria for non-coeliac gluten sensitivity.

Celiaquía. Prevención a través de la nutrición del lactante / Celiac Disease: Prevention through infant nutrition

Introducción. La enfermedad celiaca es una intolerancia permanente al gluten en individuos genéticamente predispuestos. Pero no todos los individuos susceptibles y expuestos al gluten desarrollan la enfermedad: parece que también pueden influir factores ambientales como las infecciones gastrointestinales, la microbiota intestinal, la introducción temprana y en grandes cantidades del gluten y la lactancia materna. Objetivo. El objetivo de este trabajo es conocer si la nutrición del lactante puede disminuir el riesgo de desarrollar enfermedad celiaca. Método. Se realizó una búsqueda bibliográfica en Cuiden, Cochrane Library, PubMed, SciELO y Google Académico, combinando los descriptores. Se incluyeron trabajos relacionados con el objetivo del presente trabajo. Diez artículos cumplieron los criterios de inclusión y obtuvieron una puntuación alta en cuanto a la validez metodológica según la Guía CASPe. Resultados. La literatura evidencia que dar lactancia materna el máximo tiempo posible e introducir el gluten en la dieta en pequeñas cantidades y de forma gradual mientras el bebe aún se alimenta con leche materna disminuye el riesgo de desarrollar enfermedad celiaca. Conclusiones. La efectividad de la nutrición del lactante como estrategia de prevención de la enfermedad celiaca ha quedado demostrada. Pero no está claro si previene la enfermedad o solo retrasa el inicio de los síntomas, por lo cual se deben desarrollar nuevos estudios en este sentido (AU)

Introduction. Celiac disease is a permanent intolerance to gluten in genetically predisposed individuals. But not all susceptible individuals exposed to gluten and develop disease: appears that environmental factors may also influence such as gastrointestinal infections, intestinal microbiota, early and in large quantities of gluten introduction and breastfeeding. Objective. The objetive of this study is to determine if the infant nutrition may decrease the risk of developing celiac disease. Method. A literature search was performed Cuiden, Cochrane Library, PubMed, SciELO and Google Scholar, combining descriptors. Related to the objective of this paper work is included. Ten articles met the inclusion criteria and scored high in terms of methodological validity according to CASPe Guide. Results. The literature evidence to breastfeed as long as possible and introducing the gluten in the diet in small amounts and incrementally while the baby is still breastfed decreases the risk of developing celiac disease. Conclusions. The efficacy of the infant nutrition as prevention strategies for celiac disease has been demonstrated. But it is not clear whether this strategy prevents the disease or only delays the onset of symptoms. New studies should be developed to clarify this (AU)

Glutenase and collagenase activities of wheat cysteine protease Triticain-α: feasibility for enzymatic therapy assays.

Insufficient and/or improper protein degradation is associated with the development of various human pathologies. Enzymatic therapy with proteolytic enzymes aimed to improve insufficient proteolytic activity was suggested as a treatment of protease deficiency-induced disorders. Since in many cases human degradome is incapable of degrading the entire target protein(s), other organisms can be used as a source of proteases exhibiting activities distinct from human enzymes, and plants are perspective candidates for this source. In this study recombinant wheat cysteine protease Triticain-α was shown to refold in vitro into an autocatalytically activated proteolytic enzyme possessing glutenase and collagenase activities at acidic (or close to neutral) pH levels at the temperature of human body. Mass-spectrometry analysis of the products of Triticain-α-catalyzed gluten hydrolysis revealed multiple cleavage sites within the sequences of gliadin toxic peptides, in particular, in the major toxic 33-mer α-gliadin-derived peptide initiating inflammatory responses to gluten in celiac disease (CD) patients. Triticain-α was found to be relatively stable in the conditions simulating stomach environment. We conclude that Triticain-α can be exploited as a basic compound for development of (i) pharmaceuticals for oral administration aimed at release of the active enzyme into the gastric lumen for CD treatment, and (ii) topically active pharmaceuticals for wound debridement applications.

Corn gluten hydrolysate and capsaicin have complimentary actions on body weight reduction and lipid-related genes in diet-induced obese rats.

The aim of this study was to test the hypothesis that a combination of corn gluten hydrolysate (CGH) and capsaicin may have an additive or synergistic effect on body weight reduction. For 13 weeks, male Sprague-Dawley rats were provided a diet to induce obesity. Afterward, the rats were randomly divided into 5 dietary groups: the normal control (n = 5), the high-fat control (n = 8), the high-fat diet (HFD) containing 35% CGH (n = 7), the HFD containing 0.02% capsaicin (HF-P) (n = 8), and the HFD containing both CGH and capsaicin (HF-CP) (n = 7) for an additional 4 weeks. Administration of CGH plus capsaicin, along with a HFD, led to significant decreases in body weight, fat mass, lipids in the liver, and plasma leptin as well as increases in plasma adiponectin. The pattern of gene expression was different in each target organ. In the liver, up-regulation of peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1α, and acyl-coenzyme A oxidase was found in the HF-CP group. In contrast, down-regulation of peroxisome proliferator-activated receptor γ was found in both the HFD containing 35% CGH and HF-CP groups. In skeletal muscle, up-regulation of insulin receptor and uncoupling protein 3 was found in the HF-P group only, whereas up-regulation of the glucose transporter 4 gene was observed in both the HF-CP and HF-P groups. In adipose tissue, up-regulation of peroxisome proliferator-activated receptor γ and hormone-sensitive lipase was only found in the HF-CP group. In summary, this study suggests that CGH and capsaicin perform complementary actions on food intake, lipid metabolism, and insulin sensitivity by a coordinated control of energy metabolism in the liver, adipose tissue, and skeletal muscle, thus exerting an additive effect on body weight reduction.

MicroRNAs, mecanismo epigenético para estudiar la enfermedad celiaca / MicroRNAs: an epigenetic tool to study celiac disease

Este artículo pone al día los conceptos básicos de la enfermedad celiaca (EC) y resume los hallazgos sobre los microRNAs (miRNAs) en procesos biológicos asociados a la regulación de la inflamación crónica y autoinmunidad. Los miRNAs, una nueva clase de moduladores de la expresión génica a nivel post-traduccional, son moléculas de RNA pequeñas y no codificables que se unen a secuencias complementarias de RNAs mensajeros específicos, que pueden interferir con la síntesis de proteínas. Se revisaron los estudios publicados que evaluaron los patrones de expresión de miRNAs en diferentes Enfermedades Autoinmunes (EAI) y especialmente en la EC. La EC es una enteropatía crónica del intestino delgado provocada por proteínas del gluten, caracterizada por una respuesta inmune alterada en individuos genéticamente susceptibles, que se traduce en daño de la mucosa del intestino delgado. Esta enfermedad tiene una alta prevalencia y un tratamiento efectivo a través de una dieta libre de gluten. En la patogenia de esta enfermedad se ha demostrado que factores genéticos otorgan susceptibilidad, pero no explican el total de los casos. El estudio de la función de los miRNA es de particular interés en la EC, dado que este mecanismo epigenético ha sido recientemente descrito en la patogenia de las EAI e inflamatorias. El estudio de los miRNA en la EC contribuirá a dilucidar cómo alteraciones en la regulación epigenética participarían en el desarrollo y evolución de esta enfermedad (AU)

This article summarizes recent findings on the role of microRNAs in biological processes associated with the regulation of chronic inflammation and autoimmunity. miRNAs are small non-coding RNA molecules that have been recently emerged as a new class of modulators of gene expression at the posttranscriptional level. MiRNAs bind to complementary sequences of specific targets of messengers RNA, which can interfere with protein synthesis. We reviewed studies that evaluated the expression patterns of miRNAs in different autoimmune diseases, especially in celiac disease (CD). CD is a chronic enteropathy triggered by gluten proteins, characterized by altered immune responses in genetically susceptible individuals that results in damage to the bowel mucosa. CD has a high prevalence and an effective treatment by a specific diet ("gluten free diet"). Genetic factors confer susceptibility but do not explain the whole disease, suggesting that environmental factors do play a relevant role in the development of the condition. The evaluation of the potential role of miRNA is of particular interest in CD given that these epigenetic mechanisms in the pathogenesis of autoimmune and inflammatory diseases have been recently described. Improving our understanding of miRNAs in CD will contribute to clarify the role of altered epigenetic regulation in the development and course of this disease (AU)