Bacterial Translocation and Risk of Liver Cancer in a Finnish Cohort

Background: Elevated systemic exposure to gut-derived bacterial products has been associated with hepatic inflammation and chronic liver diseases, potentially increasing the risk of liver cancer. However, only one prior study prospectively examined exposure to bacterial products in the circulation and risk of liver cancer, with a relatively limited coverage of biomarkers. Methods: We conducted a nested case-control study (224 liver cancer cases and 224 matched controls) in a large cohort of Finnish male smokers followed from baseline (1985-1988) to 2014. The associations between a panel of biomarkers for bacterial translocation and the risk of liver cancer were assessed using multivariable-adjusted conditional logistic regression. The biomarkers included immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide (LPS) and flagellin, soluble CD14 (an LPS coreceptor), and the LPS-binding protein. Results: Anti-flagellin IgA [odds ratios (OR), 2.79; 95% confidence intervals (CI), 1.34-5.78; P-trend < 0.01] and anti-LPS IgA (2.44; 95% CI, 1.33-4.48; P-trend < 0.01) were significantly associated with risk of liver cancer. When restricting the analysis to histologically classified hepatocellular carcinoma, the ORs were 4.18 (95% CI, 1.60-10.92; P-trend < 0.01) and 2.48 (95% CI, 1.16-5.29; P-trend < 0.01), respectively. The results were not substantially changed after excluding cases diagnosed within the first 5 years of follow-up and those with hepatitis C virus infection. Conclusions: Antibodies to flagellin and LPS were associated with increased risk of liver cancer. Impact: Gut-derived bacterial translocation into the circulation may play a role in the development of primary liver cancer. Our findings could contribute to the understanding of primary liver cancer etiology and further prevention efforts.