Background: Western-style diet (WD) and dysbiosis play an important role in colon inflammation and colorectal cancer (CRC). Metformin (Met) shows anti-inflammatory effects to activate AMP-activated protein kinase (AMPK), resulting in reduced cancer cell proliferation. We investigated the chemopreventive mechanisms of Met in WD induced colitic cancer.
Methods: Male BALB/c mice were randomly divided into three groups: a control diet (CD) group, WD group, and WD+ Met (250 mg/kg/day) group. All mice exposed to azoxymethane (10 mg/kg) followed by 2% dextran sodium sulfate (DSS) for 7 days. Mice were observed daily for water and dietary intake, and they were killed at 13 weeks of age. And we isolated stool extracellular vesicles (EV) of each group during DSS ingestion and analyzed metagenomic sequencing of microbiota in phylum level. Using HCT-116 human colon cancer cell line, expression of AMPK, extracellular signal-regulated kinase (ERK), cyclin D1, and Bcl-2 was investigated. Cell cycle arrest was assessed by flowcytometry.
Results: WD enhanced the severity of colitis and tumor growth compared with CD. The Met treatment group showed lower severity of colitis and reduced tumor growth. Metagenomic analysis of stool EV in WD showed a higher proportion of gram-negative bacterial EV and Met treatment reduced the proportion. In vitro assays showed that the Met treatment promoted late apoptosis by inhibiting cyclin D1 and Bcl-2 and activating AMPK and ERK.
Conclusions: A Met treatment attenuates colon inflammation and tumor growth in WD-induced colitic cancer by promoting late apoptosis and modulating dysbiosis. This strategy could be useful for the chemoprevention of WD induced colitic cancer.