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

• Published in: BMC medicine Vol. 15; no. 1; pp. 72 - 12
• Main Authors: Fedirko, Veronika, Tran, Hao Quang, Gewirtz, Andrew T., Stepien, Magdalena, Trichopoulou, Antonia, Aleksandrova, Krasimira, Olsen, Anja, Tjønneland, Anne, Overvad, Kim, Carbonnel, Franck, Boutron-Ruault, Marie-Christine, Severi, Gianluca, Kühn, Tilman, Kaaks, Rudolf, Boeing, Heiner, Bamia, Christina, Lagiou, Pagona, Grioni, Sara, Panico, Salvatore, Palli, Domenico, Tumino, Rosario, Naccarati, Alessio, Peeters, Petra H., Bueno-de-Mesquita, H. B., Weiderpass, Elisabete, Castaño, José María Huerta, Barricarte, Aurelio, Sánchez, María-José, Dorronsoro, Miren, Quirós, J. Ramón, Agudo, Antonio, Sjöberg, Klas, Ohlsson, Bodil, Hemmingsson, Oskar, Werner, Mårten, Bradbury, Kathryn E., Khaw, Kay-Tee, Wareham, Nick, Tsilidis, Konstantinos K., Aune, Dagfinn, Scalbert, Augustin, Romieu, Isabelle, Riboli, Elio, Jenab, Mazda
• Format: Journal Article
• Language: English
• Published: England BioMed Central 04.04.2017; BMC
• Subjects: Adult; Age; Aged; Amino acids; Antibody response; Bacteria; Biomarkers; Carcinoma, Hepatocellular - blood; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - microbiology; Case-Control Studies; Chronic infection; Cohort Studies; Confidence intervals; Diabetes; Diagnosis; Endotoxins; Exposure; Female; Flagellin; Flagellin - immunology; Gene expression; Health risk assessment; Health risks; Health Sciences; Health sciences: 800; Helsefag: 800; Hepatitis B; Hepatocellular carcinoma; Humans; Hälsovetenskap; Immunoglobulin A; Immunoglobulin A - blood; Immunoglobulin A - immunology; Immunoglobulin G; Immunoglobulin G - blood; Immunoglobulin G - immunology; Immunoglobulins; Inflammation; Insulin resistance; Leakage; Lipopolysaccharide; Lipopolysaccharides; Lipopolysaccharides - immunology; Liver; Liver cancer; Liver diseases; Liver Neoplasms - blood; Liver Neoplasms - immunology; Liver Neoplasms - microbiology; Male; Medical and Health Sciences; Medical disciplines: 700; Medicin och hälsovetenskap; Medisinske Fag: 700; Men; Middle Aged; Multivariable control; Obesity; Prospective Studies; Risk Factors; Rodents; Statistical analysis; VDP; Flagellin; Lipopolysaccharide; Hepatocellular carcinoma; Prospective studies; Endotoxins
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-017-0830-8

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. 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. 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  = 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. 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.