Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study.
Fedirko V., Tran HQ., Gewirtz AT., Stepien M., Trichopoulou A., Aleksandrova K., Olsen A., Tjønneland A., Overvad K., Carbonnel F., Boutron-Ruault M-C., Severi G., Kühn T., Kaaks R., Boeing H., Bamia C., Lagiou P., Grioni S., Panico S., Palli D., Tumino R., Naccarati A., Peeters PH., Bueno-de-Mesquita HB., Weiderpass E., Castaño JMH., Barricarte A., Sánchez M-J., Dorronsoro M., Quirós JR., Agudo A., Sjöberg K., Ohlsson B., Hemmingsson O., Werner M., Bradbury KE., Khaw K-T., Wareham N., Tsilidis KK., Aune D., Scalbert A., Romieu I., Riboli E., Jenab M.
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; 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. 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.