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

Research output: Contribution to journalArticle


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.


  • Veronika Fedirko
  • Hao Quang Tran
  • Andrew T. Gewirtz
  • Magdalena Stepien
  • Antonia Trichopoulou
  • Krasimira Aleksandrova
  • Anja Olsen
  • Anne Tjønneland
  • Kim Overvad
  • Franck Carbonnel
  • Marie Christine Boutron-Ruault
  • Gianluca Severi
  • Tilman Kühn
  • Rudolf Kaaks
  • Heiner Boeing
  • Christina Bamia
  • Pagona Lagiou
  • Sara Grioni
  • Salvatore Panico
  • Domenico Palli
  • Rosario Tumino
  • Alessio Naccarati
  • Petra H. Peeters
  • H B Bueno-de-Mesquita
  • Elisabete Weiderpass
  • José María Huerta Castaño
  • Aurelio Barricarte
  • María-José Sánchez
  • Miren Dorronsoro,
  • J Ramón Quirós
  • Antonio Agudo
  • Oskar Hemmingsson
  • Mårten Werner
  • Kathryn E Bradbury
  • Kay-Tee Khaw
  • Nick Wareham
  • Konstantinos K Tsilidis
  • Dagfinn Aune
  • Augustin Scalbert
  • Isabelle Romieu
  • Elio Riboli
  • Mazda Jenab
External organisations
  • Emory University
  • Georgia State University
  • International Agency for Research on Cancer, World Health Organization
  • National and Kapodistrian University of Athens
  • German Institute of Human Nutrition
  • Danish Cancer Society Research Center
  • Aarhus University
  • University of Paris-Sud
  • German Cancer Research Centre
  • Istituto Nazionale dei Tumori
  • University of Naples Federico II
  • Cancer Research and Prevention Institute (ISPO)
  • Civic and M.P Arezzo Hospital
  • University of Malaya
  • Karolinska Institutet
  • CIBER Epidemiology and Public Health (CIBERESP)
  • Public Health Directorate
  • Catalan Institute of Oncology
  • Skåne University Hospital
  • Norrland University Hospital
  • University of Oxford
  • University of Cambridge
  • University of Ioannina
  • University of Paris-Saclay
  • Human Genetics Foundation (HuGeF)
  • University Medical Center Utrecht
  • Imperial College London
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Public Health, Global Health, Social Medicine and Epidemiology


  • Endotoxins, Flagellin, Hepatocellular carcinoma, Lipopolysaccharide, Prospective studies
Original languageEnglish
Article number72
JournalBMC Medicine
Issue number1
Publication statusPublished - 2017 Apr 4
Publication categoryResearch