Integrative analyses of dicarbonyls and advanced glycation end-products with multiomic profiles across tissue, plasma and stool samples reveal methylglyoxal accumulation in colon cancer

Advanced Glycation Endproducts (AGEs) arise from the reaction of proteins with highly reactive dicarbonyl compounds such as methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), which have been implicated in inflammation and carcinogenesis. How dicarbonyls and AGEs are distributed across tumor tissue and surrogate specimens, and how they relate to systemic metabolism, AGE-related pathways, and alterations in gut microbiota in colon cancer, remains poorly understood. An integrative multi-specimen analysis of MGO, GO, 3-DG and major AGEs was performed using targeted tandem mass spectrometry in matched tumor tissue, adjacent normal mucosa, plasma, and stool from 26 sporadic colon cancer patients. These measurements were combined with tumor RNA-sequencing, untargeted plasma metabolomics, and stool shotgun metagenomics generated from the same individuals. A marked accumulation of MGO was observed in tumor tissue when compared with adjacent mucosa, accompanied by higher levels of the MGO-derived AGE Nδ-[5-hydro-5-methyl-4-imidazolon-2-yl]-ornithine (MG-H1). Tissue MG-H1 concentrations significantly correlated with corresponding plasma levels. Elevated tumor MGO levels were associated with up-regulation of GLO1 (encoding for the detoxifying enzyme glyoxalase-1), DDOST (coding for the AGE-clearance receptor AGE-R1), and the glycolytic flux marker triose phosphate isomerase (TPI), alongside down-regulation of the AGE-scavenger receptor CD36. These findings suggest a candidate remodeling of dicarbonyl-handling pathways. The MGO/GO ratio in tumors was positively associated with the relative abundances of Fusobacterium nucleatum and Parvimonas micra, two bacterial species related to colorectal carcinogenesis, and with metagenomic signatures of oral-derived taxa colonizing the gut. This pilot integrative analysis highlighted novel coherent associations among tissue, circulating, and stool levels of MGO-derived AGEs, the expression of AGE-related metabolic pathways, and microbial signatures in colon cancer. If confirmed in larger studies, these candidate molecular and microbial interactions may provide novel insights into the dicarbonyl stress involvement in tumor biology.