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 MC., 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 JM., Barricarte A., Sánchez MJ., Dorronsoro M., Quirós JR., Agudo A., Sjöberg K., Ohlsson B., Hemmingsson O., Werner M., Bradbury KE., Khaw KT., 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.