Ana Luiza dos Santos Lopes 1, Isadora de Araújo Oliveira1, Livia Carvalho Barbosa1, Amanda Carlos Paulino2, Philippe Caloba1,2, Letícia Sant’Ana Fernandes1, Frederico Alisson-Silva1, Adriane Regina Todeschini1
Colorectal cancer (CRC) remains a major public health concern and has been strongly associated with Western dietary patterns, particularly high consumption of red meat. Proposed mechanisms include the high heme iron content, formation of N-nitroso compounds (NOCs), heterocyclic amines (HCAs), and polycyclic aromatic hydrocarbons (PAHs). However, these compounds are also present in poultry and fish, which have not been consistently linked to increased CRC risk. A newer hypothesis suggests that red meat may promote CRC due to its high content of a non-human sialic acid, N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc due to a loss-of-function mutation in the CMAH gene, expressing only N-acetylneuraminic acid (Neu5Ac).
Our group previously demonstrated that a Neu5Gc-enriched diet promotes the development of intestinal polyps with more malignant characteristics in Cmah knockout mice. To further explore the underlying metabolic changes, we conducted metabolomic and lipidomic analyses of colon polyps and adjacent tissue from Cmah KO mice fed either a Neu5Gc-enriched diet or a control diet for two months.
Tissue samples were weighed and extracted using water, methanol, and MTBE. The aqueous phase was analyzed by metabolomics, and the MTBE phase by lipidomics. Metabolomics was performed using a ZHILIC column in both positive and negative ion modes on an ESI-QTOF instrument; lipidomics was conducted with a C18 column under the same conditions. Data were processed using MZmine and analyzed via MetaboAnalyst.
Different metabolic alterations were observed in the polyps versus adjacent (non-polyp) colon tissue between the both diet groups. Polyps from mice on the Neu5Gc-enriched diet exhibited altered pyrimidine, aspartate, and glutathione metabolism than the adjacent tissue. In contrast, tumors from the control diet group, differed from the adjacent tissue primarily on metabolites related to glycosylation pathways. Interestingly, comparison of adjacent colon tissue between diet groups revealed alterations in TCA cycle, alanine, and folate metabolism in the Neu5Gc-fed group, but we found no significant functional enrichment differences in polyp tissue between the two diets.
Altogether, our findings suggest that Neu5Gc consumption induces tumor-like metabolic reprogramming in adjacent colon tissue, potentially contributing to CRC carcinogenesis. These insights may help explain the specific association between red meat and colorectal cancer risk in humans.
Agradecimentos: FAPERJ, CAPES, CNPQ and FINEP.