Gut-Ex-Vivo system as a model to study gluten response in celiac disease

Mara Gagliardi, Nausicaa Clemente, Romina Monzani, Luca Fusaro, Eleonora Ferrari, Valentina Saverio, Giovanna Grieco, Elżbieta Pańczyszyn, Flavia Carton, Claudio Santoro, Sara Del Mare-Roumani, Sivan Amidror, Nissan Yissachar, Francesca Boccafoschi, Silvia Zucchelli, Marco Corazzari

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5 Scopus citations

Abstract

Celiac disease (CD) is a complex immune-mediated chronic disease characterized by a consistent inflammation of the gastrointestinal tract induced by gluten intake in genetically predisposed individuals. Although initiated by the interaction between digestion-derived gliadin, a gluten component, peptides, and the intestinal epithelium, the disorder is highly complex and involving other components of the intestine, such as the immune system. Therefore, conventional model systems, mainly based on two- or three-dimension cell cultures and co-cultures, cannot fully recapitulate such a complex disease. The development of mouse models has facilitated the study of different interacting cell types involved in the disorder, together with the impact of environmental factors. However, such in vivo models are often expensive and time consuming. Here we propose an organ ex vivo culture (gut-ex-vivo system) based on small intestines from gluten-sensitive mice cultivated in a dynamic condition, able to fully recapitulate the biochemical and morphological features of the mouse model exposed to gliadin (4 weeks), in 16 h. Indeed, upon gliadin exposure, we observed: i) a down-regulation of cystic fibrosis transmembrane regulator (CFTR) and an up-regulation of transglutaminase 2 (TG2) at both mRNA and protein levels; ii) increased intestinal permeability associated with deregulated tight junction protein expression; iii) induction and production of pro-inflammatory cytokines such as interleukin (IL)-15, IL-17 and interferon gamma (IFNγ); and iv) consistent alteration of intestinal epithelium/villi morphology. Altogether, these data indicate that the proposed model can be efficiently used to study the pathogenesis of CD, test new or repurposed molecules to accelerate the search for new treatments, and to study the impact of the microbiome and derived metabolites, in a time- and cost- effective manner.

Original languageEnglish
Article number45
JournalCell Death Discovery
Volume7
Issue number1
Early online date12 Mar 2021
DOIs
StatePublished - 12 Mar 2021

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