Background: Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede
the development of liver cancer. However, human studies, particularly from prospective settings, are lacking.
Methods: We used a case-control study design nested within a large prospective cohort to assess the association
between circulating levels of anti-lipopolysaccharide (LPS) and anti-flagellin immunoglobulin A (IgA) and G (IgG)
(reflecting long-term exposures to LPS and flagellin, respectively) and risk of hepatocellular carcinoma. A total of 139
men and women diagnosed with hepatocellular carcinoma between 1992 and 2010 were matched to 139 control
subjects. Multivariable rate ratios (RRs), including adjustment for potential confounders, hepatitis B/C positivity, and
degree of liver dysfunction, were calculated with conditional logistic regression.
Results: Antibody response to LPS and flagellin was associated with a statistically significant increase in the risk of
hepatocellular carcinoma (highest vs. lowest quartile: RR = 11.76, 95% confidence interval = 1.70–81.40; Ptrend = 0.021).
This finding did not vary substantially by time from enrollment to diagnosis, and did not change after adjustment for
chronic infection with hepatitis B and C viruses.
Conclusions: These novel findings, based on exposures up to several years prior to diagnosis, support a role
for gut-derived bacterial products in hepatocellular carcinoma development. Further study into the role of gut
barrier failure and exposure to bacterial products in liver diseases is warranted.