Effects of Methylglyoxal on Intestinal Cells: Insights on Epigenetic Regulatory Enzymes

Methylglyoxal (MGO) is endogenously produced under physiological conditions as a by-product of glycolysis and by autooxidation of glucose and lipid peroxidation. The digestive system can also take up MGO from exogenous sources, especially from ultra-processed foods. MGO is a highly reactive molecule, able to react with macromolecules forming covalent adducts resulting in advanced glycation end-products formation. MGO can also enter the nucleus and react with nucleic acids with the formation of MGO-nucleic acid adducts. The intestinal epithelium is continuously exposed to dietary and endogenous stimuli, including MGO, but the potential harmful role of MGO at the intestinal level has been poorly investigated. Therefore, the aim of the study was to further investigate the effects of MGO in intestinal cells and the molecular mechanisms involved, with particular attention to epigenetic regulatory enzymes such as histone deacetylases (HDAC), ten-eleven translocation (TET) family enzymes, and DNA methyltransferases (DNMT). Our results demonstrate that MGO exposure induces alterations in intestinal barrier function in differentiated Caco-2 cells monolayers. Moreover, MGO treatment induces cell apoptosis associated with an increase in cytosolic and mitochondrial reactive oxygen species. MGO-induced oxidative stress was associated with activation of the NFκB pathway and increased levels of proinflammatory molecules such as TNF-α and antioxidant enzymes (superoxide dismutase 1 [SOD1] and catalase). The increased expression of γH2AX suggests damage to DNA in MGO-treated cells. A decrease in HDAC1/2 expression, consistent with the increase in acetylated histone H4 levels, and an inhibition of the expression of TET (TET1, TET2) proteins was observed in MGO-treated cells. These results suggest that MGO may also disrupt epigenetic homeostasis mechanisms, offering further insight into the pathways through which MGO causes cellular damage in intestinal cells.