Pre-diagnostic immunological markers of bacterial translocation and liver cancer risk: A nested case–control analysis of 12 prospective cohorts

The gut-liver axis may play an important role in hepatocarcinogenesis. However, limited prospective research has explored associations with liver cancer risk. We conducted a nested case–control study based in 12 prospective cohort studies from across the United States, which included 867 cases of liver cancer and 867 matched controls. We measured bacterial translocation markers, specifically immunoglobulin (Ig) A, IgG, and IgM against lipopolysaccharide and flagellin; soluble CD14 (a co-receptor for lipopolysaccharide); and lipopolysaccharide-binding protein. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) between bacterial translocation marker concentrations per doubling in concentrations and liver cancer risk. Lipopolysaccharide-binding protein concentrations were most strongly associated with higher liver cancer risk (OR per doubling in concentrations: 1.48, 95% CI: 1.23–1.79). Concentrations of anti-flagellin IgA (1.13, 1.01–1.28) and IgG (1.13, 1.01–1.28), anti-lipopolysaccharide IgG (1.20, 1.01–1.42), and soluble CD14 (1.12, 1.01–1.24) were also associated with liver cancer risk. When analyses were separated into hepatocellular carcinoma (HCC, N = 436 cases) and intrahepatic cholangiocarcinoma (ICC, N = 110 cases), no evidence of heterogeneity was observed except for lipopolysaccharide-binding protein concentrations, which were positively associated with HCC (1.77, 1.34–2.33) but not ICC (0.67, 0.37–1.22; p-heterogeneity =.003). Associations did not differ by time to liver cancer diagnosis or other subgroups. These findings support the role of gut barrier dysfunction in hepatocarcinogenesis, necessitating further research to understand the complex interplay among the mechanisms and risk factors disrupting the gut barrier, microbiota, and liver cancer.