Metabolic and microbial signatures of ultra-processed food consumption and their association with cancer pathways in the BC Generations Project

Background: Ultra-processed food (UPF) consumption has been linked to adverse health outcomes, including increased cancer risks. The underlying mechanisms may involve diet-induced metabolic alterations and shifts in gut microbial communities. This study aimed to use metabolomic and gut microbiome profiling to elucidate metabolic pathways and microbial signatures associated with UPF intake and determine the relevance of pathways to carcinogenic processes. Methods: Data were obtained from 800 participants of the BC Generations Project (BCGP). Dietary intake was assessed using a past year validated food frequency questionnaire (FFQ). UPF consumption was quantified as a percentage of total energy intake. Non-fasting serum samples were assayed using mass spectrometry-based metabolomic profiling, and stool samples using whole metagenome shotgun sequencing. Metabolite data were analyzed using multivariate regression, principal component analysis, and orthogonal partial least squares discriminant analysis. Microbial diversity and composition were evaluated using alpha and beta diversity metrics, differential abundance testing, and core microbiome analysis. Results: A total of 1,080 metabolites were detected, of which 68 metabolites were significantly associated with UPF consumption after adjusting for covariates (q<0.05). Among these, seven metabolites were positively associated with UPF, while 61 were negatively associated with UPF. Notably, pipecolate levels were inversely associated with UPF intake, while specific phosphatidylethanolamines and 6-deoxodolichosterone were positively associated with UPF intake. Multivariate analyses, including OPLS-DA, revealed distinct metabolic profiles for low versus high UPF consumers. Enrichment analyses indicated that many metabolite changes were concentrated in pathways frequently implicated in cancer biology such as arginine biosynthesis, TCA cycle, and nucleotide metabolism. Microbiome analyses indicated differences in core microbial taxa between these groups, with seven species unique to Quartile 1 and Quartile 4, respectively. MaAsLin2 differential abundance analyses identified 12 species that varied by UPF consumption. Of particular interest, both approaches consistently demonstrated higher abundances of butyrate-producing bacteria—Faecalibacterium prausnitzii, Roseburia hominis, and Butyribacter sp000436755—in Quartile 1 compared with Quartile 4. Conclusion: Our study suggests that high UPF consumption is associated with distinct serum metabolic profiles and differences in gut microbial composition. These findings provide mechanistic insights into the potential pathways by which UPF consumption may contribute to cancer risk.