Abstract
Colorectal cancer (CRC) is one of the most common and deadly cancers worldwide. Grape pomace (GP) is a rich source of bioactive compounds with anti-inflammatory, and anticancer effects. We recently found that dietary GP had protective effects against CRC development in the azoxymethane (AOM)/dextran sulfate sodium (DSS) CRC mouse model through suppression of cell proliferation and modulation of DNA methylation. However, the underlying molecular mechanisms associated with changes in metabolites remain unexamined. This study profiled fecal metabolomic changes in a mouse CRC model in response to GP supplementation using gas chromatography-mass spectrometry (GC-MS) based metabolomic analysis. A total of 29 compounds showed significant changes due to GP supplementation, including bile acids, amino acids, fatty acids, phenols/flavonoids, glycerolipids, carbohydrates, organic acids, and others. The major changes in metabolites of feces include increased deoxycholic acid (DCA) and decreased amino acid content. Dietary GP upregulated the expression of farnesoid X receptor (FXR) downstream genes while decreasing fecal urease activity. DNA repair enzyme MutS Homolog 2 (MSH2) was upregulated by GP supplementation. Consistently, γ-H2AX, as a DNA damage marker, decreased in GP supplemented mice. Moreover, MDM2, a protein in the ataxia telangiectasia mutated (ATM) signaling, was decreased by GP supplementation. These data provided valuable metabolic clues for unraveling the protective effects of GP supplementation against CRC development.
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