Protein-bound AGEs derived from methylglyoxal induce pro-inflammatory response and barrier integrity damage in epithelial cells by disrupting the retinol metabolism

Advanced glycation end-products (AGEs) are complex and heterogeneous compounds widely present in processed foods. Previous studies evidenced the adverse effects of AGEs on gut homeostasis, but the precise pathological mechanisms and molecular pathways responsible for the disruption of intestinal barrier integrity by AGEs remain incompletely elucidated. In this study, protein-bound AGEs (BSA-MGO), the most common type of dietary AGE, were prepared by methylglyoxal-mediated glycation, and an in vitro human epithelial colorectal adenocarcinoma (Caco-2) cell model was employed to evaluate the impact of protein-bound AGEs on gut epithelial function. Results showed that exposure to BSA-MGO significantly increased the permeability of Caco-2 cell monolayers as evidenced by the decreased transepithelial electrical resistance value, increased paracellular transport of FITC-dextran, and down-regulated tight-junction proteins. In parallel, BSA-MGO induced pro-inflammatory responses and oxidative stress in the monolayers. Transcriptomic profiling further revealed that BSA-MGO disrupted the retinol metabolism, thereby contributing to the barrier integrity damage in epithelial cells. Overall, these results provide valuable insights into the disrupting effects of dietary AGEs on intestinal barrier function, and the perturbed pathways present potential targets for further exploration of the molecular mechanisms underlying the detrimental effect of processed foods on gut health.