Relationship between the microbiome and obesity-associated cancer risk using Mendelian randomisation

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Abstract
Background: The mechanisms underlying obesity-related cancer risk are incompletely understood. We investigated whether the gut microbiome causally mediates this relationship. Methods: We performed two-sample Mendelian randomisation, with mediation analysis, to assess causal links between genetically predicted body mass index (BMI)/waist-to-hip ratio adjusted for BMI (WHRadjBMI), 211 gut microbial taxa, and eight cancers (384,738 cases) of European ancestry. Significant associations were replicated in the FinnGen cohort. Results: Genetically predicted BMI was associated with risk of colorectal (CRC; odds ratio per standard deviation (OR SD ): 1.12; 95% confidence interval (CI): [1.06–1.17]; P = 4.95 × 10 −6 ), kidney (RCC) (OR SD : 1.48; 95% CI: [1.34–1.63]; P = 1.61 × 10 −15 ), endometrial (OR SD : 1.70; 95% CI: [1.55–1.87]; P = 2.09 × 10 −27 ), lung (OR SD : 1.20; 95% CI: [1.12–1.29]; P = 1.40 × 10 −7 ), and oesophageal cancer (OR SD : 1.25; 95% CI: [1.13–1.39]; P = 3.09 × 10 −5 ). Seven microbial taxa were associated with CRC risk. Phylum and class Actinobacteria showed the strongest effects (OR SD : 1.48; 95% CI: [1.29–1.70]; P = 1.78 × 10 −8 ) and (OR SD : 1.36; 95% CI: [1.22–1.51]; P = 2.57 × 10 −8 ), respectively, and replicated in FinnGen, mediating 29% (95% CI: [8-50]) and 21% (95% CI: [4–37]) of the BMI to CRC risk—collectively accounting for 50% of the relationship. No consistent microbiome mediation was observed for other cancers. Conclusions: Gut Actinobacteria may contribute to obesity-driven CRC risk, supporting the rationale of microbiome-targeted interventions to reduce CRC risk.

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