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

• Type of Material: Article
• Authors: Veronika Fedirko, Emory University; Hao Quang Tran, Georgia State University; Andrew Gewirtz, Emory University; Magdalena Stepien, International Agency for Research on Cancer; Antonia Trichopoulou, Hellenic Health Foundation; Krasimira Aleksandrova, German Institute of Human Nutrition Potsdam-Rehbruecke; Anja Olsen, Danish Cancer Society Research Center; Anne Tjønneland, Danish Cancer Society Research Center; Kim Overvad, Aarhus University; Franck Carbonnel, Université Paris-Sud
• Language: English
• Date: 2017-04-04
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2017
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12916-017-0830-8
• Title of Journal or Parent Work: BMC Medical Education
• ISSN: 1472-6920
• Volume: 15
• Issue: 1
• Start Page: 72
• End Page: 72
• Grant/Funding Information: This work was supported by the French National Cancer Institute (L’Institut National du Cancer; INCA) (grant number 2009-139; Principal Investigator: M. Jenab).; The national cohorts are supported by the Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, and Institut National de la Santé et de la Recherche Médicale (INSERM) (France); Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, and Federal Ministry of Education and Research (Germany); the Hellenic Health Foundation (Greece); the Sicilian Government, AIRE ONLUS Ragusa, AVIS Ragusa, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), and Statistics Netherlands (the Netherlands); Nordic Centre of Excellence programme on Food, Nutrition and Health. (Norway); Health Research Fund (FIS), PI13/00061 to Granada), Regional Governments of Andalucía, Asturias, Basque Country, Murcia (no. 6236) and Navarra, Regional Government of Asturias (Asturias, Spain), and ISCIII RETIC (RD06/0020) (Spain); Swedish Cancer Society, Swedish Scientific Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 to EPIC-Oxford) and Medical Research Council (1000143 to EPIC-Norfolk) (United Kingdom); and a Girdlers’ New Zealand Health Research Council Fellowship (to Dr. K.E. Bradbury).; The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer.
• Keywords: Flagellin; Lipopolysaccharide; Endotoxins; Hepatocellular carcinoma; Prospective studies
• Research Categories: Health Sciences, Oncology; Health Sciences, Epidemiology; Health Sciences, Immunology

Abstract

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.