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

J Gastroenterol Hepatol. 2014 Mar;29(3):502-10. doi: 10.1111/jgh.12435.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Cell Line, Tumor
  • Colitis / chemically induced
  • Colitis / complications
  • Colitis / drug therapy*
  • Colitis / genetics*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / etiology
  • Colonic Neoplasms / genetics*
  • Colonic Neoplasms / metabolism
  • Dextran Sulfate
  • Disease Models, Animal
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use*
  • I-kappa B Kinase / metabolism
  • Inflammation Mediators / metabolism
  • Interleukin-8 / metabolism
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / metabolism
  • Male
  • Metformin / pharmacology*
  • Metformin / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Severity of Illness Index
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / adverse effects


  • Hypoglycemic Agents
  • Inflammation Mediators
  • Interleukin-8
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • Dextran Sulfate
  • Metformin
  • I-kappa B Kinase
  • AMP-Activated Protein Kinases