Metformin alleviates colitis-associated colorectal cancer via inhibition of the TLR4/MyD88/NFκB/MAPK pathway and macrophage M2 polarization
Abstract
BACKGROUND
Colon inflammation plays an essential role in the development and progression of colorectal cancer. Emerging evidence from clinical and animal studies indicates that metformin may reduce the risk of colorectal cancer through its anti-inflammatory effects.
AIMS
To investigate the efficacy of metformin in reducing the risk of colorectal cancer and the possible pathways and mechanisms.
METHODS
The Enterotoxigenic Bacteroides Fragilis (ETBF)/azoxymethane (AOM)/dextran sulfate sodium (DSS) mouse model was established and low-dose metformin (125 mg/kg) or high-dose metformin (250 mg/kg) was administered daily by gavage. Colon tumors were counted, and colon tissue was stained with hematoxylin and eosin (HE) and Periodic Acid-Schiff's and Alcian Blue (PAS-AB). Colon Ki67, ZO-1 Muc2, Claudin-1, Occludin, MPO, reactive oxygen species (ROS), E-cadherin, CD206 and Arg-1 expression were detected by immunohistochemistry or immunofluorescence staining. NF-κB pathway-related protein expression was assessed by Western blot. Fecal short-chain fatty acid (SCFA) levels were also examined.
RESULTS
Our results showed that low- or high-dose metformin ameliorates colonic mucosal damage, reduces colonic inflammation, and eventually inhibits colorectal tumorigenesis in the ETBF/AOM/DSS mouse model. Our further research found that metformin suppresses the expression of TLR4/MyD88/NFκB/MAPK pathway-related proteins, modulates macrophage M2 polarization and increases SCFA levels in colon…
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