Plasma metabolites, metabolic risk score and colorectal cancer risk: a prospective cohort study

The associations of colorectal cancer (CRC) risk with metabolites, lifestyle factors and their joint effects have not been fully elucidated. Therefore, we conducted a prospective cohort study to estimate the associations of CRC risk with metabolites, metabolic risk score (MRS) and its joint associations with lifestyle factors. This study included 82,514 participants with plasma metabolites data in the UK Biobank. LASSO-COX and Random Forest was used to select metabolites. Cox regression was utilized to construct MRS and estimate the associations of CRC risk with metabolites, MRS and its joint associations with lifestyle factors. Single-cell RNA sequencing data were analyzed to identify metabolism-related genes and metabolic pathways during CRC progression. During a median follow-up of 13.28 years, 1151 incident CRC cases were identified. MRS, constructed using 6 metabolites, was significantly associated with increased CRC risk (HR = 1.39, 95% CI 1.22-1.56 for high vs. low MRS), with the strongest association for proximal colon cancer (HR = 1.51, 95% CI 1.24-1.84), followed by distal colon cancer and rectal cancer (HR = 1.35, 95% CI 1.05-1.72; HR = 1.37, 95% CI 1.11-1.69). Joint associations were identified between MRS and lifestyle factors with CRC risk. Individuals with healthy sleep, never smoking, healthy diet, and healthy lifestyle but high MRS also exhibited elevated CRC risk. Linoleic acid, histidine and tyrosine metabolism pathways played important roles during normal intestinal mucosa to CRC progression. Pre-diagnostic metabolites and MRS were significantly associated with increased CRC risk, especially proximal colon cancer. Individuals should maintain normal metabolite levels and healthy lifestyles for CRC prevention.