Disruption of Tight Junctions in Intestinal Epithelial Cells by Toxic Advanced Glycation End-Products

Abstract

Intestinal epithelial cells (IECs) play a crucial role in forming a protective barrier and regulating the absorption of substances passing through the small intestine. Disrupting the epithelial barrier function can result in intestinal diseases such as inflammatory bowel disease. Glyceraldehyde (GA)-derived advanced glycation end-products (AGEs) (toxic AGEs, TAGE) are AGEs formed by the nonenzymatic Maillard reaction. Although AGEs have been implicated in intestinal barrier breakdown, the associated mechanism remains underexplored. In this study, the effects of accumulated TAGE in IECs were investigated by focusing on tight junctions using Caco-2 cells—a human colorectal epithelial adenocarcinoma cell line. While GA treatment induced the formation of intracellular TAGE in Caco-2 cells, resulting in cell death, the generated intracellular TAGE triggered increased paracellular permeability. In addition, immunofluorescence staining showed that GA treatment decreased the fluorescence intensities of ZO-1 and claudin-7, which are tight junction proteins attached to the plasma membrane. Furthermore, an evaluation of the mechanism behind intestinal barrier breakdown revealed excessive reactive oxygen species (ROS) production and increased expression of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase subunit genes, a mechanism of ROS production, in the GA-treated group compared with the control group. Furthermore, GA treatment induced necrosis and caused cytotoxicity in this condition. Overall, these results suggest that TAGE induction can disrupt tight junctions in IECs via cell injury as a pathway.