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P047. Metformin inhibits NF-κB signaling in intestinal epithelial cells, and ameliorates experimental colitis and colitis-associated colon cancer in mice

S.-J. Koh1, J.M. Kim2, J.P. Im3, C. Lee3, H.C. Jung3, J.S. Kim3, 1Seoul National University Boramae Hospital, Seoul Korea, Internal Medicine, Seoul, South Korea, 2Hanyang University College of Medicine, Seoul, South Korea, 3Seoul National University College of Medicine, Internal Medicine, Seoul, South Korea

Background

Metformin, a hypoglycemic agent, is known to demonstrate anti-inflammatory and anti-cancer activity. However, little information is available in the effect of metformin on intestinal inflammation and colitis-associated colon cancer.

Methods

COLO 205 intestinal epithelial cells (IECs) were pretreated with metformin and then stimulated with TNF-α. IL-8 transcriptional activity and expression was determined by luciferase reporter assay and real-time RT-PCR/ELISA. IκBα phosphorylation/degradation and DNA binding activity of NF-κB were evaluated by Western blot analysis and electrophretic mobility shift assay (EMSA), respectively. In the acute colitis model, mice were given 4% dextran sulfate sodium (DSS) for 5 days with or without metformin. Immunohistochemical staining for phospho-IκB kinase (IKK) was performed in mouse colon tissue. In the colitis-associated tumor model, mice were given a single intraperitoneal injection of azoxymethane, and then three cycles of 2% DSS for 5 days and 2 weeks of free water consumption.

Results

Metformin significantly inhibited activated NF-κB signals and the upregulated expression of IL-8 in COLO 205 cells stimulated with TNF-α. Pretreatment with metformin attenuated IκBα phosphorylation and NF-κB DNA binding activity induced by TNF-α. In an acute colitis model, administration of metformin significantly reduced the severity of DSS-induced murine colitis, as assessed by the disease activity index, colon length, and histopathology. Immunohistochemical analysis showed that the DSS-induced phospho-IKK activation in IEC was significantly decreased in metformin-treated mice. Finally, metformin significantly reduced the development of colitic cancer in mice.

Conclusion

Metformin inhibits NF-κB activation in IEC and ameliorates DSS-induced acute murine colitis and colitis-associated tumorigenesis, which suggest that metformin is a potential therapeutic agent for the inflammatory bowel disease.