Methyl donor deficiency blocks colorectal cancer development by affecting key metabolic pathways
Menée notamment à partir d'échantillons coliques d'un modèle murin, cette étude met en évidence un mécanisme par lequel une alimentation sans composés donneurs de groupes méthyle (sans acide folique, choline, méthionine et vitamine B12) bloque le développement tumoral en affectant les voies métaboliques principales
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 effects these changes are unknown. Colon samples harvested from Apc∆14/+ 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 impacted by the MDD diet were identified. As expected, metabolites within the methionine cycle, including methionine (-2.9-fold, P<0.001) and betaine (-3.3-fold, P<0.001), were reduced. Elevated homocysteine (110-fold, P<0.001) was associated with increased flux through the transsulfuration pathway. Unexpectedly, levels of deoxycholic acid (-4.5-fold, P<0.05) and several other secondary bile acids were reduced. There were also unexpected reductions in the levels of carnitine (-2.0-fold, P<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.