Dietary advanced glycation end-products promote food allergy by disrupting intestinal barrier and enhancing Th2 immunity

Epidemiological studies have suggested a link between the consumption of foods high in advanced glycation end-products (AGEs) and an increased risk of food allergy (FA). However, the underlying mechanisms remain largely unelucidated. In this study, we present complementary epidemiological and experimental evidence showing the pathogenic role of dietary AGEs (dAGEs) in facilitating the development of FA. We first provide a population-based cross-sectional survey supporting the association between a dietary pattern rich in AGE-laden processed foods and an increased prevalence of self-reported allergic diseases, including FA. Through multiple experimental models of FA, we demonstrate that exposure to dAGEs promotes susceptibility to allergic sensitization and amplifies Th2-biased immune response to concomitant food allergens. dAGEs possess both barrier-disruptive and Th2-adjuvant properties to induce a compromised intestinal barrier function and Th2-skewed immunity at intestinal mucosal sites. This aberrant immune response is mediated by the intricate interplay between the receptor for AGEs (RAGE) and toll-like receptor-4 (TLR4) signaling pathways. Furthermore, the Th2-stimulating effect of dAGEs involving RAGE-TLR4 crosstalk was validated in human peripheral immune cells. This study contributes to our understanding of dAGEs as a risk factor for FA and highlights the potential of dAGEs restriction as a promising preventative strategy for susceptible populations.