Anti-inflammatory mechanism of metformin and its effects in intestinal inflammation and colitis-associated colon cancer

Abstract

Abstract Background and Aim The aim of this study is to evaluate the effect of metformin on intestinal inflammation. Methods COLO205 cells were pretreated with metformin and stimulated with tumor necrosis factor (TNF)?α. Expression of interleukin (IL)?8 was determined by luciferase assay and real?time PCR. Inhibitor of kappaB (IκB) phosphorylation/degradation and adenosine monohosphate?activated protein kinase (AMPK) activity were evaluated by Western blotting. DNA?binding activity of transcription factor nuclear factor?kappaB (NF?κB) was assessed by electrophoretic mobility shift assay. In an acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days. IL?10?/? mice were used to evaluate the effect of metformin on chronic colitis. In an inflamation?associated tumor model, mice were given a single intraperitoneal injection of azoxymethane followed by three cycles of 2% DSS for 5 days and 2 weeks of free water consumption. Results Metformin significantly inhibited IL?8 induction in COLO 205 cells stimulated with TNF?α. Metformin attenuated IκBα phosphorylation and NF?κB DNA?binding activity. Administration of metformin significantly reduced the severity of DSS?induced colitis. In addition, DSS?induced IκB kinase (IKK) activation was significantly reduced in mice treated with metformin. Metformin significantly attenuated the severity of colitis in IL?10?/? mice, induced AMPK activity in intestinal epithelial cells, and inhibited the development of colitic cancer in mice. Conclusions These results indicate that metformin suppresses NF?κB activation in intestinal epithelial cells and ameliorates murine colitis and colitis?associated tumorigenesis in mice, suggesting that metformin could be a potential therapeutic agent for the treatment of inflammatory bowel disease.