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 (GÀ) followed by gluten challenge (G þ ) for 30 days. The G þ 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 þ 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 a-gliadin fraction, and its oral delivery in G þ mice improved enteropathy development in association with decrease of epithelial cell CD71 expression and local cytokine production. In conclusion, the G þ 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.

The role of animal models in unravelling therapeutic targets in coeliac disease

“…Yet the outcome of probiotic intervention is difficult to control in humans, and animal studies might help to assess their modulatory capacity on intestinal responses to gluten. In mice immunised in the footpad with gliadin dissolved in ethanol and HCl and emulsified with CFA, oral delivery of the Saccharomyces boulardii KK1 strain decreased IFN-g levels and increased villus/crypt ratio [77]. In intestinal loops of germ-free rats reared on GFD, the addition of Bifidobacterium bifidum IATA-ES2 prevented the gliadin-induced loss of goblet cells and increased the amount of the tight junction protein zonulin 1.…”

Gluten, Transglutaminase, Celiac Disease and IgA Nephropathy

“…It should be noted that the sensitization of mice to gluten by its depletion from the diet during three generations is an experimental design serving to mimic the intolerance of some patients with CD [50]. Although these experiments allowed us to establish a link between gluten and IgAN onset, this strategy could not be applied to patients over generations.…”

Using Animal Models of Celiac Disease to Understand the Role of MHC II

“…In one rat model, gliadin is administered by gavage immediately after birth to germ-free Wistar AVN rats, resulting in shortened villi, crypt hyperplasia, and increased numbers of intestinal CD8αβ + IELs [ 19 ]. A similar model was developed in 2012 using Balb/c mice [ 20 ]. In this model, Balb/c mice were fed a gluten-free chow for three generations, and then the third-generation mice were fed a gluten-containing chow [ 20 ].…”

“…A similar model was developed in 2012 using Balb/c mice [ 20 ]. In this model, Balb/c mice were fed a gluten-free chow for three generations, and then the third-generation mice were fed a gluten-containing chow [ 20 ]. The gluten-challenged mice (G+) developed increased IELs, villous atrophy, and crypt hyperplasia as compared to untreated mice [G−].…”

“…Previous studies have shown that gliadin-specifi c and/or TTG-specifi c antibodies bound to gliadin or TTG can then be transported to the lamina propria, where the proteins are then phagocytosed and presented to T cells by phagocytic antigen presenting cells. In the Balb/c model of gluten-dependent enteropathy, the CD71/IgA/gluten/tTG transcellular pathway was determined to be active [ 20 ]. In the Balb/c third-generation mice that were fed a gluten-containing chow (G+), CD71 expression was increased on the enterocytes as compared to the enterocytes of the (G−) mice, and IgA+ cells were increased in the lamina propria of the G+ mice as compared to the (G−) mice.…”