Faecalibacterium Mediates the Effect of Dairy Preference on Colorectal Cancer Susceptibility

Current evidence supports the associations between diet, intestinal microbiome, and colorectal cancer (CRC) risk, but their causal relationships have not been extensively determined. Using large-scale genome-wide association study (GWAS) datasets of gut microbes (18,340 individuals), food preference (161,625 individuals), and CRC (24,476 cases vs. 23,073 controls), we applied a phenome-wide two-step bidirectional Mendelian randomization (MR) study to evaluate the causal effects of 45 food-liking traits on CRC susceptibility, and the mediating role of 131 microbiota. The inverse variance weighted (IVW) method was primarily employed, followed by multiple sensitivity analysis to assess the validity of the results. Among 45 categories, fatty/salty food preference was suggestively associated with a decreased risk of CRC [odds ratio (OR)_IVW 0.65, 95% confidence interval (CI) 0.43-0.98, p = 0.040]. Furthermore, we identified four distinct food-microbiota association pairs, along with nine bacteria-CRC pairs. By integrating the association pairs, a putative causal pathway was found in dairy preference, increased abundance of Faecalibacterium (dairy preference-Faecalibacterium: β_IVW = 0.72, 95% CI 0.30-1.13, p = 6.87 × 10^-4), and decreased CRC risk (Faecalibacterium-CRC: OR_IVW 0.91, 95% CI 0.85-0.97, p = 7.05 × 10^-3), among which Faecalibacterium served as a potential mediator (p _mediation = 0.035). Subsequent stratified analysis showed a consistent mediation in late-onset (age > 50; p = 0.029) and female (p = 0.049) populations. Our findings uncovered a novel causal pathway of dairy preference, gut Faecalibacterium levels, and CRC susceptibility, providing additional insights into CRC etiology and early prevention of CRC through dietary interventions.

The online version contains supplementary material available at https://doi.org/10.1007/s43657-025-00241-w.