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

V. Fedirko, H. Q. Tran, A. T. Gewirtz, M. Stepien, A. Trichopoulou, K. Aleksandrova, A. Olsen, A. Tjonneland, K. Overvad, F. Carbonnel, M. C. Boutron-Ruault, G. Severi, T. Kuhn, R. Kaaks, H. Boeing, C. Bamia, P. Lagiou, S. Grioni, S. Panico, D. PalliR. Tumino, A. Naccarati, P. H. Peeters, H. B. Bueno-de-Mesquita, E. Weiderpass, J. M. Castano, A. Barricarte, M. J. Sanchez, M. Dorronsoro, J. R. Quiros, A. Agudo, K. Sjoberg, B. Ohlsson, O. Hemmingsson, M. Werner, K. E. Bradbury, K. T. Khaw, N. Wareham, K. K. Tsilidis, D. Aune, A. Scalbert, I. Romieu, E. Riboli, M. Jenab

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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.
Original languageUndefined/Unknown
Article number72
Number of pages12
JournalBMC Medicine
Issue number1
Publication statusPublished - 04 Apr 2017

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