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Our understanding of the role of folate one-carbon metabolism in colon carcinogenesis remains incomplete. Previous studies indicate that a methyl donor-deficient (MDD) diet lacking folic acid, choline, methionine, and vitamin B12 is associated with long-lasting changes to the intestinal epithelium and sustained tumor protection in Apc -mutant mice. However, the metabolic pathways by which the MDD diet affects these changes are unknown. Colon samples harvested from Apc Δ14/+  mice fed the MDD diet for 18 weeks were profiled using a GC-MS and LC-MS/MS metabolomics platform. Random forest and pathway analyses were used to identify altered metabolic pathways, and associated gene expression changes were analyzed by RT-PCR. Approximately 100 metabolites affected by the MDD diet were identified. As expected, metabolites within the methionine cycle, including methionine (-2.9-fold, P &lt; 0.001) and betaine (-3.3-fold, P &lt; 0.001), were reduced. Elevated homocysteine (110-fold, P &lt; 0.001) was associated with increased flux through the transsulfuration pathway. Unexpectedly, levels of deoxycholic acid (-4.5-fold, P &lt; 0.05) and several other secondary bile acids were reduced. There were also unexpected reductions in the levels of carnitine (-2.0-fold, P &lt; 0.01) and a panel of acylcarnitines involved in fatty acid β-oxidation. Finally, metabolites involved in redox balance, including ascorbate and hypotaurine, were found to be persistently elevated. These findings provide clues to the molecular changes underlying MDD-mediated tumor protection and identify regulatable metabolic pathways that may provide new targets for colon cancer prevention and treatment. IMPLICATIONS: Metabolomic profiling reveals molecular changes underlying MDD-induced tumor protection and may provide new targets for colorectal cancer prevention and treatment.

Methyl Donor Deficiency Blocks Colorectal Cancer Development by Affecting Key Metabolic Pathways