Protective Mechanism of Ethyl Gallate against Intestinal Ischemia‐Reperfusion Injury in Mice by in Vivo and in Vitro Studies Based on Transcriptomics

Abstract Intestinal ischemia‐reperfusion injury (IIRI) is a common clinical disease that can be life‐threatening in severe cases. This study aimed to investigate the effects of ethyl gallate (EG) on IIRI and its underlying mechanisms. A mouse model was established to mimic human IIRI by clamping the superior mesenteric artery. Transcriptomics techniques were used in conjunction with experiments to explore the potential mechanisms of EG action. Intestinal histomorphological damage, including intestinal villi damage and mucosal hemorrhage, was significantly reversed by EG. EG also alleviated the oxidative stress, inflammation, and intestinal epithelial apoptosis caused by IIRI. 2592 up‐regulated genes and 2754 down‐regulated genes were identified after EG treatment, and these differential genes were enriched in signaling pathways, including fat digestion and absorption, and extracellular matrix (ECM) receptor interactions. In IIRI mouse intestinal tissue, expression of the differential protein matrix metalloproteinase 9 (MMP9), as well as its co‐protein NF‐κB‐p65, was significantly increased, while EG inhibited the expression of MMP9 and NF‐κB‐p65. In Caco‐2 cells in an established oxygen‐glucose deprivation/reperfusion model (OGD/R), EG significantly reversed the decrease in intestinal barrier trans‐ epithelial electrical resistance (TEER). However, in the presence of MMP9 inhibitors, EG did not reverse the decreasing trend in TEER. This study illustrates the protective effect and mechanism of action of EG on IIRI and, combined with in vivo and in vitro experiments, it reveals that MMP9 may be the main target of EG action. This study provides new scientific information on the therapeutic effects of EG on IIRI.