Abstract
BackgroundLeakage 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.MethodsWe 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.ResultsAntibody 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.ConclusionsThese 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.
Highlights
Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer
Animal data suggest that exposure to LPS or flagellin can produce liver inflammation, liver injury, or steatohepatitis [14,15,16], while human data indicate higher circulating LPS in patients with chronic liver diseases predisposing to Hepatocellular carcinoma (HCC) [17,18,19,20,21,22,23,24]
In consideration of these points, in a first study of its kind, we investigate whether prediagnostic serum anti-LPS- and anti-flagellin-specific immunoglobulin A and G (IgA and IgG) levels are associated with HCC risk within European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort of geographically diverse Western European populations
Summary
Leakage of bacterial products across the gut barrier may play a role in liver diseases which often precede the development of liver cancer. Overabundance of bacterial LPS from the gut microbiota may trigger chronic inflammation and higher oxidative stress [13] Since these bacterial cell components are transported to the liver through the portal vein, it has been suggested that they drive the development of metabolic and liver diseases. Despite a probable role of gut-derived bacterial products in the pathogenesis and progression of liver disease, no epidemiologic studies to date have investigated the association between biomarkers of LPS and flagellin and risk of HCC. In consideration of these points, in a first study of its kind, we investigate whether prediagnostic serum anti-LPS- and anti-flagellin-specific immunoglobulin A and G (IgA and IgG) levels are associated with HCC risk within EPIC, a large cohort of geographically diverse Western European populations
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