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

## TL;DR

This study found that immune markers of gut bacteria leakage are linked to higher liver cancer risk, suggesting gut health may influence cancer development.

## Contribution

The study is the first to show pre-diagnostic bacterial translocation markers are associated with liver cancer risk in a large prospective analysis.

## Key findings

- Lipopolysaccharide-binding protein concentrations were strongly linked to increased liver cancer risk.
- Higher anti-flagellin IgA and IgG, anti-lipopolysaccharide IgG, and soluble CD14 were also associated with liver cancer risk.
- Lipopolysaccharide-binding protein was linked to hepatocellular carcinoma but not intrahepatic cholangiocarcinoma.

## Abstract

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.

What's new?

Disruption of the gut–liver axis has been suggested to play an important role in liver carcinogenesis. However, limited prospective research has explored associations between potentially harmful gut‐derived bacterial products and liver cancer risk. In this nested case–control study, pre‐diagnostic immunological markers of bacterial translocation, measured an average of 12 years before diagnosis, were positively associated with liver cancer risk. Lipopolysaccharide‐binding protein concentrations were associated with hepatocellular carcinoma, but not intrahepatic cholangiocarcinoma. These findings point to modulation of the gut barrier as a potential strategy for reducing liver cancer risk.