Impairment of intestinal immunity in gluten-sensitive HLA-DQ8 transgenic mice on a high-fat diet

A high-fat diet (HFD) has been associated with dysregulated immunity both at the systemic and mucosal levels in mouse models. The underlying mechanisms are partially known. We analysed the effect of diet on immunity in HLA-DQ8 (DQ8) transgenic mice, a specific model of gluten sensitivity, and investigated a possible interplay between gluten and an HFD. Our aim was to further dissect the impact of a long-term HFD regimen on both systemic and intestinal immunity. Adult DQ8 mice (n = 6/group) were fed a gluten-free diet (GFD), an HFD, or an HFD containing 8% gluten (HFD+G) for 23 weeks. We assessed clinical parameters, the phenotype and function of splenic and lamina propria (LP) T cells by flow cytometry, and multiparametric quantitation of cytokines induced in vitro. An HFD for 23 weeks increased body weight as expected, paralleled by a significant shortening of the caecum (P < 0.001). FACS analysis revealed that an HFD drastically increased the number of potentially cytotoxic (CD8⁺) T cells in the LP but not in the spleen. An HFD+G significantly reduced, but did not abolish, the percentage of these cells (p < 0.01). Induction of cytokine secretion in vitro showed that LP cells from both HFD- and HFD+G-fed mice did not secrete any cytokines, whereas both innate (TNF-α) and adaptive immunity (IL-4, IFN-γ and IL-17) cytokines were induced in the LP of GFD-fed mice. In conclusion, we found that a long-term HFD regimen impaired the phenotype of immune cells and their effector functions distinctly in the small intestine of gluten-sensitive DQ8 mice. The presence of gluten in the diet changed the phenotype but did not abolish the block of effector activity. Our findings could help further elucidate the functional status of the immune system under the HFD regimen.