title: Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study.
abstract: 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; 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.
  
  
  
  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.
authors.affiliation: Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. vfedirk@emory.edu.|Winship Cancer Institute, Emory University, Atlanta, GA, USA. vfedirk@emory.edu.
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authors.affiliation: Center for Inflammation, Immunity, and Infection Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA.
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authors.affiliation: Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece.|Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, University of Athens Medical School, Athens, Greece.
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authors.forename: Franck
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authors.affiliation: Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, Villejuif, F-94805, France.
authors.forename: Marie-Christine
authors.initials: MC
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authors.affiliation: Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.|Gustave Roussy, Villejuif, F-94805, France.|Human Genetics Foundation (HuGeF), Torino, Italy.|Cancer Council Victoria and University of Melbourne, Melbourne, Australia.
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authors.affiliation: Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece.|Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, University of Athens Medical School, Athens, Greece.
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authors.affiliation: Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece.|Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, University of Athens Medical School, Athens, Greece.|Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
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authors.affiliation: Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.|Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.|Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.|Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
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authors.affiliation: Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.|Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
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authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.|Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
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authors.forename: Isabelle
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mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000097:blood* / Q000276:immunology / Q000382:microbiology; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D005408:Flagellin / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood* / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood* / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology*; D008113:Liver Neoplasms / Q000097:blood* / Q000276:immunology / Q000382:microbiology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D005408:Flagellin
keywords: Endotoxins; Flagellin; Hepatocellular carcinoma; Lipopolysaccharide; Prospective studies