Western-Style Diet, pks Island-Carrying Escherichia coli, and Colorectal Cancer: Analyses From Two Large Prospective Cohort Studies

Abstract

Background & aims: Evidence supports a carcinogenic role of Escherichia coli carrying the pks island that encodes enzymes for colibactin biosynthesis. We hypothesized that the association of the Western-style diet (rich in red and processed meat) with colorectal cancer incidence might be stronger for tumors containing higher amounts of pks⁺E coli.

Methods: Western diet score was calculated using food frequency questionnaire data obtained every 4 years during follow-up of 134,775 participants in 2 United States-wide prospective cohort studies. Using quantitative polymerase chain reaction, we measured pks⁺E coli DNA in 1175 tumors among 3200 incident colorectal cancer cases that had occurred during the follow-up. We used the 3200 cases and inverse probability weighting (to adjust for selection bias due to tissue availability), integrated in multivariable-adjusted duplication-method Cox proportional hazards regression analyses.

Results: The association of the Western diet score with colorectal cancer incidence was stronger for tumors containing higher levels of pks⁺E coli (P_{heterogeneity} = .014). Multivariable-adjusted hazard ratios (with 95% confidence interval) for the highest (vs lowest) tertile of the Western diet score were 3.45 (1.53-7.78) (P_trend = 0.001) for pks⁺E coli-high tumors, 1.22 (0.57-2.63) for pks⁺E coli-low tumors, and 1.10 (0.85-1.42) for pks⁺E coli-negative tumors. The pks⁺E coli level was associated with lower disease stage but not with tumor location, microsatellite instability, or BRAF, KRAS, or PIK3CA mutations.

Conclusions: The Western-style diet is associated with a higher incidence of colorectal cancer containing abundant pks⁺E coli, supporting a potential link between diet, the intestinal microbiota, and colorectal carcinogenesis.

Keywords: Immunology; Microbiome; Molecular Pathological Epidemiology.

Figure 1.

Flow diagram of the study population in the Nurses’ Health Study and the Health Professionals Follow-up Study. Abbreviation: HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study.

Figure 2.

Assessment of linearity in quantitative real-time PCR assay. (A): Quantitative real-time PCR assay for pks+ E. coli DNA and the human reference gene SLCO2A1 using 2-fold dilution series (10, 20, 40, and 80 ng) from the same DNA specimen from formalin-fixed paraffin-embedded tissue. (B): Quantitative real-time PCR assay for pks+ E. coli DNA using 10-fold dilution series (0.0001, 0.001, 0.01, 0.1, and 1 ng) from DNA from cultured pks+ E. coli. Symbols indicate mean, error bars, standard deviation of cycle threshold values of quadruplicate runs. The coefficient of determination (r²) in the assays for pks+ E. coli DNA and SLCO2A1 is shown. Abbreviation: PCR, polymerase chain reaction.