Butyrate upregulates pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase 1 (IDH1), which thereafter increases the contents of their metabolites, acetyl-CoA, and α-ketoglutarate (α-KG), respectively. α-KG promotes DNA demethylation in the promoter of DNA mismatch repair (MMR) genes, as indicated by the conversion of 5mC to 5hmC. Acetyl-CoA enhances the histone acetylation in colorectal cancer cells. Histone acetylation and DNA demethylation jointly promote MMR protein expression, thereby suppressing colorectal carcinogenesis.