Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study

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; P trend = 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-017-0830-8) contains supplementary material, which is available to authorized users.

Identification of Aberrantly Methylated Differentially CpG Sites in Hepatocellular Carcinoma and Their Association With Patient Survival

“…that LBP in live cancer cells may engage in the local immune response to gut-derived bacterial translocation, which was an etiological factor of HCC according to current reports (29,30). The association of LBP and clinicopathological parameters was further investigated by analyzing the LIHC cohort from TCGA.…”

Bacterial Translocation and Risk of Liver Cancer in a Finnish Cohort

“…Murine studies have reported that exposure to the bacterial products lipopolysaccharide (LPS) and flagellin can cause inflammation and oxidative stress in the liver and may promote HCC (9)(10)(11). Similarly, evidence from human studies suggests that systemic exposure to these bacterial products may be positively associated with systemic inflammation (12,13) and chronic liver disease (14)(15)(16)(17). Thus far, the only study in humans to examine the association between antibodies (IgA and IgG, jointly) to LPS and flagellin and the risk of liver cancer reported a positive association (13).…”

“…Similarly, evidence from human studies suggests that systemic exposure to these bacterial products may be positively associated with systemic inflammation (12,13) and chronic liver disease (14)(15)(16)(17). Thus far, the only study in humans to examine the association between antibodies (IgA and IgG, jointly) to LPS and flagellin and the risk of liver cancer reported a positive association (13). Whether individual immunoglobins (IgA vs. IgG vs. IgM) were associated with risk, however, has not been studied.…”

Pseudomonas aeruginosaStimulates Inflammation and Enhances KSHV-Induced Cell Proliferation and Cellular Transformation through Both LPS and Flagellin

“…Moreover, some studies suggest that LPS and flagellin blood levels may be correlated with a higher cancer risk (50,51). However, contradictory studies show decreased cell proliferation in LPS-or flagellin-stimulated cells (52)(53)(54).…”