RESUMO
Exposure to gluten, a protein present in wheat rye and barley, is the major inducer for human Celiac Disease (CD), a chronic autoimmune enteropathy. CD occurs in about 1% worldwide population, in genetically predisposed individuals bearing human leukocyte antigen (HLA) DQ2/DQ8. Gut epithelial cell stress and the innate immune activation are responsible for the breaking oral tolerance to gliadin, a gluten component. To date, the only treatment available for CD is a long-term gluten-free diet. Several studies have shown that an altered composition of the intestinal microbiota (dysbiosis) could play a key role in the pathogenesis of CD through the modulation of intestinal permeability and the regulation of the immune system. Here, we show that gliadin induces a chronic endoplasmic reticulum (ER) stress condition in the small intestine of a gluten-sensitive mouse model and that the coadministration of probiotics efficiently attenuates both the unfolded protein response (UPR) and gut inflammation. Moreover, the composition of probiotics formulations might differ in their activity at molecular level, especially toward the three axes of the UPR. Therefore, probiotics administration might potentially represent a new valuable strategy to treat gluten-sensitive patients, such as those affected by CD.
Assuntos
Suplementos Nutricionais , Estresse do Retículo Endoplasmático , Intolerância Alimentar/terapia , Trato Gastrointestinal/patologia , Gliadina/efeitos adversos , Glutens/efeitos adversos , Inflamação/patologia , Probióticos/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Células CACO-2 , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Ligação ao GTP/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Camundongos Endogâmicos BALB C , Permeabilidade , Probióticos/administração & dosagem , Proteína 2 Glutamina gama-Glutamiltransferase , Transglutaminases/metabolismo , Regulação para CimaRESUMO
PURPOSE: The beneficial effects of conjugated linoleic acid (CLA) mixture (cis9, trans11, c9; trans10, cis12, t10) against gliadin-induced toxicity in HLA-DQ8-transgenic mice (DQ8) have been associated with improved duodenal cytoprotective mechanisms [nuclear factor-E2-related factor-2, Nrf2; acylpeptide hydrolase (APEH)/proteasome]. The present study was aimed at investigating the ability of individual CLA isomers to improve the efficacy of these defensive mechanisms and to protect against duodenal injury caused by the combined administration of gliadin and indomethacin (GI). METHODS: Gluten-mediated enteropathy was induced in DQ8 mice by three intra-gastric administration of gliadin (20 mg kg(-1)/bw) and indomethacin (15 mg L(-1)) in drinking water for 10 days (GI). C9 or t10 CLA (520 mg kg(-1)/bw/day) were orally administered for 2 weeks. Pro-oxidant and toxic effects associated with GI treatment, anti-oxidant/detoxifying ability of c9 or t10-CLA and the protective effect induced by c9 pre-treatment (c9 + GI) were evaluated in DQ8 mice duodenum by combining enzymatic, immunoblotting, histological evaluation and quantitative real-time PCR assays. RESULTS: GI treatment produces the time-dependent decline of the considered detoxifying mechanisms thus leading to pro-apoptotic and pro-oxidant effects. APEH/proteasome pathway was not markedly affected by individual CLA isomers, but duodenal redox status and activity/mRNA levels of Nrf2-activated enzymes were significantly improved by c9 administration. c9 pre-treatment protects against GI-mediated accumulation of oxidative stress markers, and histological examination reveals the increase of goblet cells number in mouse duodenum but induces only a partial recovery of APEH/proteasome activity. CONCLUSIONS: The activation of and adaptive response by low doses of c9 supplementation prevents distinct signs of gliadin-induced enteropathy in DQ8 mice.
Assuntos
Doença Celíaca/tratamento farmacológico , Gliadina/efeitos adversos , Ácidos Linoleicos Conjugados/administração & dosagem , Animais , Doença Celíaca/induzido quimicamente , Relação Dose-Resposta a Droga , Indometacina/efeitos adversos , Camundongos , Camundongos Transgênicos , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
SCOPE: The involvement of oxidative stress in gluten-induced toxicity has been evidenced in vitro and in clinical studies but has never been examined in vivo. We recently demonstrated the protective activity of conjugated linoleic acid (CLA), which functions by the activation of nuclear factor erythroid 2-related factor2 (Nrf2), a key transcription factor for the synthesis of antioxidant and detoxifying enzymes (phase 2). Here, we evaluate the involvement of nuclear factor erythroid 2-related factor2 in gliadin-mediated toxicity in human Caco-2 intestinal cells and in gliadin-sensitive human leukocyte antigen-DQ8 transgenic mice (DQ8) and the protective activity of CLA. METHODS AND RESULTS: Gliadin effects in differentiated Caco-2 cells and in DQ8 mice, fed with a gliadin-containing diet with or without CLA supplementation, were evaluated by combining enzymatic, immunochemical, immunohistochemical, and quantitative real-time PCR (qRT-PCR) assays. Gliadin toxicity was accompanied by downregulation of phase 2 and elevates proteasome-acylpeptide hydrolase activities in vitro and in vivo. Notably, gliadin was unable to generate severe oxidative stress extent or pathological consequences in DQ8 mice intestine comparable to those found in celiac patients and the alterations produced were hampered by CLA. CONCLUSION: The beneficial effects of CLA against the depletion of crucial intestinal cytoprotective defenses indicates a novel nutritional approach for the treatment of intestinal disease associated with altered redox homeostasis.
Assuntos
Gliadina/toxicidade , Intestinos/efeitos dos fármacos , Intestinos/fisiologia , Ácidos Linoleicos Conjugados/farmacologia , Animais , Antioxidantes/metabolismo , Células CACO-2 , Doença Celíaca/metabolismo , Diferenciação Celular/efeitos dos fármacos , Enzimas/genética , Enzimas/metabolismo , Gliadina/efeitos adversos , Antígenos HLA-DQ/genética , Humanos , Inativação Metabólica , Camundongos , Camundongos Transgênicos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Transglutaminases/metabolismoRESUMO
Idiopathic pulmonary hemosiderosis (IPH) is a rare disease characterized by anemia, hemoptysis and recurrent alveolar hemorrhage. The combination of IPH and celiac disease (CD) is extremely rare. We report a 9-year-old boy with Lane-Hamilton syndrome, co-occurrence of pulmonary hemosiderosis with CD. This presentation is unique presentation because he has also retinal pigmentation.
Assuntos
Doença Celíaca/diagnóstico , Hemossiderose/diagnóstico , Pneumopatias/diagnóstico , Retinose Pigmentar/diagnóstico , Doença Celíaca/dietoterapia , Criança , Suplementos Nutricionais , Gliadina/efeitos adversos , Hemossiderose/dietoterapia , Humanos , Ferro/uso terapêutico , Pneumopatias/dietoterapia , Masculino , Retinose Pigmentar/dietoterapia , Hemossiderose PulmonarRESUMO
Wheat proteins are involved in respiratory allergy, contact allergy and food allergy. Wheat allergens involve in these pathologies are well-known. However, establishment of wheat allergy diagnostic can be sometimes difficult on account of the complex allergenic composition of skin prick test (SPT) solutions of wheat flour. Therefore, we have studied specific IgE reactivity from patient sera with wheat food allergy, and characterized allergenic composition of wheat SPT solutions by specific antibodies directed to wheat allergens. The results showed that 20 of the 25 sera analyzed contained specific IgE to at least one wheat protein fraction. Among positive sera, 75% have specific IgE to water/salt soluble fraction, 85% to native gluten fractions and 65% to wheat isolate fraction. The results showed also that SPT solutions of wheat flour contained major food allergens from each allergenic fraction. These results highlighted the importance of using fractions, which constitute the whole wheat allergenic pattern, during specific IgE reactivity analyses. Moreover, we have observed that wheat isolate extract (results of food industrial process) contained not only modified allergens (neo-allergens) involve of specific food allergy to wheat isolate but also some native allergens involve in wheat food allergy. Thus, these results showed the importance to use, for wheat in vivo diagnosis together wheat SPT solutions (gluten extract and wheat isolate) in order to differentiate wheat food allergy to specific wheat isolate allergy.
Assuntos
Alérgenos/efeitos adversos , Antígenos de Plantas/efeitos adversos , Farinha/efeitos adversos , Imunoglobulina E/sangue , Extratos Vegetais , Proteínas de Plantas/efeitos adversos , Triticum/efeitos adversos , Hipersensibilidade a Trigo/diagnóstico , Alérgenos/imunologia , Alérgenos/isolamento & purificação , Especificidade de Anticorpos , Antígenos de Plantas/imunologia , Antígenos de Plantas/isolamento & purificação , Ensaio de Imunoadsorção Enzimática , Farinha/análise , Indústria Alimentícia/métodos , Gliadina/efeitos adversos , Gliadina/imunologia , Glutens/efeitos adversos , Glutens/imunologia , Glutens/isolamento & purificação , Humanos , Imunoglobulina E/imunologia , Peso Molecular , Extratos Vegetais/imunologia , Extratos Vegetais/isolamento & purificação , Proteínas de Plantas/imunologia , Proteínas de Plantas/isolamento & purificação , Cloreto de Sódio , Solubilidade , Triticum/química , Água , Hipersensibilidade a Trigo/sangue , Hipersensibilidade a Trigo/etiologia , Hipersensibilidade a Trigo/imunologiaRESUMO
In an approach to examine the lectin-hypothesis in the pathogenesis of coeliac disease, the presence of lectin-like components in three wheat gluten preparations known to induce coeliac disease, gliadin, Frazer fraction III and an acetic acid/ethanol extract of gluten, was investigated. Lectin-like components in these wheat gluten preparations were traced in binding studies employing a variety of model glycoproteins glycosylated with the different types of N-linked oligosaccharides, i.e., those of the high mannose-, complex- and hybrid-type. Binding affinity of wheat proteins to these glycoproteins was analyzed by affinity dotting and blotting techniques and was compared to that of the well characterized lectins Galanthus nivalis agglutinin, Concanavalin A and wheat germ agglutinin. Though the three wheat gluten preparations exhibited binding reactivity for distinct model glycoproteins, no correlation was found between the type of N-glycosylation of the model glycoproteins and their binding capability to the different wheat gluten preparations. Moreover, binding of the three gluten preparations to the model glycoproteins could not be inhibited by competitive saccharides (methyl-alpha-D-mannopyranoside, N-acetyl-D-glucosamine, mannan). Enzymatic deglycosylation of the ligand glycoproteins with endo-beta-N-acetylglucosaminidase H (Endo H, EC 3.2.1.96) or peptide N-glycosidase F (PNGase F, EC 3.5.1.52) abolished their binding reactivity for the plant lectins, but did not affect binding of the wheat gluten preparations. These results give no evidence for the presence of lectin-like components in wheat gluten preparations and do question the 'lectin hypothesis' of coeliac disease.