Cancer Epidemiology, Biomarkers & Prevention · Oct 19, 2026

Gut microbiome-related plasma metabolites and risk of colorectal cancer

By Malcomson FC, O'Connell CP, Farhat Z et al.

BACKGROUND: Perturbations in gut microbiome composition and altered levels of related metabolites may be related to colorectal cancer (CRC). This study assessed whether pre-diagnostic, circulating, microbiome-related metabolite concentrations were associated with CRC risk. METHODS: We undertook a nested case-control study of 739 participants in the Colon Cancer Family Registry Cohort (312 cases, 427 controls). Median follow-up time from blood draw to diagnosis was 7 years. Pre-diagnostic plasma concentrations of 70 metabolites were quantified by targeted liquid chromatography-tandem mass spectrometry. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for metabolite concentrations and CRC risk using multivariable conditional logistic regression models. Stratified analyses were conducted by sex, Lynch syndrome diagnosis, and age at tumor onset. RESULTS: The primary bile acids, cholate and chenodeoxycholate, were positively associated with CRC incidence, overall and among females. The odds of CRC were higher in individuals in the highest compared with the lowest quartiles of cholate (ORQ4vQ1=1.61, 95% CI=1.05-2.49) and chenodeoxycholate (ORQ4vQ1=1.60, 95% CI=1.03-2.50). Two short-chain fatty acids (caproate, valerate) and three metabolites involved in phenylalanine and tyrosine metabolism (cinnamoylglycine, phenylpropionate, 4-ethylphenylsulfate) were suggested to be associated, positively and negatively, respectively, with incident CRC but these associations did not withstand correction for multiple comparisons. In stratified analyses, some differences were observed according to sex, Lynch syndrome diagnosis, and age at tumor onset. CONCLUSIONS: Circulating microbiome-related metabolites, including bile acids and short-chain fatty acids, may be associated with CRC risk. IMPACT: These findings provide insight into potential pathways linking the gut microbiome to colorectal carcinogenesis.

doi.org/10.1158/1055-9965.epi-26-0718PubMed 42895480Biomarkers