Saturated fat-induced food allergy: A paradigm for unfolded protein response (UPR)-mediated allergic inflammation

Abstract Murine food allergy induction and maintenance is promoted by increased epithelial permeability and requires the pro-Th2 cytokines: IL-25, IL-33, and TSLP, but how allergens increase permeability and induce pro-Th2 cytokines is unknown. Saturated fats increase intestinal permeability, promote intestinal epithelial pro-Th2 cytokine expression and induce the UPR in several cell types. Two common food allergens, milk and eggs, contain considerable saturated fat. These observations suggested that saturated fats in food might promote allergy by inducing the UPR, which in turn, induces the pro-Th2 cytokines. To test this, quantitative PCR was used to evaluate the ability of heavy cream and egg yolk plasma (EYP, the fat-containing fraction of egg) to induce UPR-associated and pro-Th2 cytokine gene expression in transformed human intestinal epithelial CACO2 cells. Metformin, 4-PBA and TUDCA were used to block the UPR. EYP and cream, but not protein-rich, lipid-poor egg white, increased CACO2 cell UPR-associated gene expression, followed by increased pro-Th2 cytokine expression. This was blocked by the UPR antagonists and by a lipase antagonist that prevents fat absorption. EYP and cream, but not egg white, also increased epithelial permeability; this was blocked by metformin. In BALB/c mice, food allergy (detected as hypothermia and diarrhea) was induced by skin sensitization with egg white + EYP, followed by oral gavage with egg white + EYP. Metformin and TUDCA each prevented food allergy development and strongly suppressed established food allergy. These observations support our hypothesis and suggest that the saturated fat content of egg and milk contributes to their allergenicity.