Abstract
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.
Highlights
G2−G4 were challenged with oral gavage with gliadin (Sigma; 5 mg/daily for 1 week, 5 mg/daily thrice a week for 3 weeks) for 4 weeks [6,21]
We evaluated the intestinal permeability in our gliadin sensitive mice in vivo, exposing animals to gliadin for 6 weeks using The fluorescein isothiocyanateconjugated dextran (FITC-Dextran) administrated as a single dose at 4 h prior animal sacrifice [6,21]
A major rule in the ignition of immune response toward gliadin peptides produced by partial enzymatic digestion in the intestine is played by tissue transglutaminase 2 (TG2)
Summary
1% of worldwide population, in genetically predisposed individuals carrying human leukocyte antigen (HLA) DQ2/DQ8 [1]. Through tissue transglutaminase 2 (TG2) activity, deamidated gliadin binds the HLADQ2/8 molecules on antigen-presenting cells (APCs) [2,3] and presents on CD4+ T cells, resulting in their activation and migration to the small intestinal lamina propria [4]. Once in the lamina propria, activated CD4+ T cells proliferate and start to produce proinflammatory cytokines, such as IFNγ and metalloproteases, and stimulate the production of growth factors by stromal cells, which induces cryptal hyperplasia and villous atrophy due to intestinal epithelial cells death induced by intraepithelial lymphocytes (IELs) [5]. CF is the most common genetic lethal disease in the Caucasian population and is caused by loss-of-function mutations of the cftr gene. CFTR was originally identified as a cAMP-activated transmembrane anion channel mediating the transport of
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