title: Gluten induces coeliac-like disease in sensitised mice involving IgA, CD71 and transglutaminase 2 interactions that are prevented by probiotics.
abstract: Coeliac disease (CD) is a malabsorptive enteropathy resulting from intolerance to gluten. Environmental factors and the microbiota are suggested to have critical roles in the onset of CD. The CD71 IgA receptor on epithelial cells is responsible for abnormal retrotranscytosis of IgA-gluten peptide complexes from the intestinal lumen into the lamina propria, inducing intestinal inflammation. However, understanding the role of gluten in the CD physiopathology has been hindered by the absence of relevant animal models. Here, we generated a mouse model for CD to study the factors controlling its pathogenesis as well as to investigate the influence of oral delivery of probiotics on disease development. Gluten sensitivity was established by feeding three generations of BALB/c mice a gluten-free diet (G-) followed by gluten challenge (G+) for 30 days. The G+ mice developed villous atrophy, crypt hyperplasia and infiltration of T cells and macrophages in the small intestine. Inflammation was associated with an overexpression of CD71 on the apical side of enterocytes and an increase of plasma cells producing IgA, which colocalised with the CD71. Moreover, IgA colocalised with the transglutaminase 2 (TG2), the production of which was increased in the lamina propria of G+ mice. These mice displayed increased production of cyclooxygenase-2 (COX-2), pro-inflammatory cytokines and IL-15, as well as anti-gliadin and anti-TG2 autoantibodies. The commensal flora-isolated presumptive probiotic Saccharomyces boulardii KK1 strain hydrolysed the 28-kDa α-gliadin fraction, and its oral delivery in G+ mice improved enteropathy development in association with decrease of epithelial cell CD71 expression and local cytokine production. In conclusion, the G+ BALB/c mouse represents a new mouse model for human CD based on histopathological features and expression of common biomarkers. The selected probiotic treatment reversing disease development will allow the study of the role of probiotics as a new therapeutic approach of CD.
authors.affiliation: Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Christina
authors.initials: C
authors.lastname: Papista
authors.forename: Vassilis
authors.initials: V
authors.lastname: Gerakopoulos
authors.forename: Andreas
authors.initials: A
authors.lastname: Kourelis
authors.forename: Maria
authors.initials: M
authors.lastname: Sounidaki
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kontana
authors.forename: Laureline
authors.initials: L
authors.lastname: Berthelot
authors.forename: Ivan C
authors.initials: IC
authors.lastname: Moura
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
authors.forename: Minas
authors.initials: M
authors.lastname: Yiangou
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002446:Celiac Disease / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control; D004195:Disease Models, Animal; D020895:Enterocytes / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005983:Glutens / Q000009:adverse effects* / Q000276:immunology; D007113:Immunity, Innate; D007070:Immunoglobulin A / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology; D007421:Intestine, Small / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019936:Probiotics / Q000627:therapeutic use; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011990:Receptors, Transferrin / Q000378:metabolism*; D012440:Saccharomyces; D011503:Transglutaminases / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; D007070:Immunoglobulin A; D011990:Receptors, Transferrin; D005983:Glutens; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D019204:GTP-Binding Proteins