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

Fedirko V 1 , Tran HQ 2 , Gewirtz AT 2 , Stepien M 3 , Trichopoulou A 4 , Aleksandrova K 5 Show all authors , Olsen A 6 , Tjønneland A 6 , Overvad K 7 , Carbonnel F 8 , Boutron-Ruault MC 8 , Severi G 8 , Kühn T 9 , Kaaks R 9 , Boeing H 10 , Bamia C 4 , Lagiou P 4 , Grioni S 11 , Panico S 12 , Palli D 13 , Tumino R 14 , Naccarati A 15 , Peeters PH 16 , Bueno-de-Mesquita HB 17 , Weiderpass E 18 , Castaño JM 19 , Barricarte A 20 , Sánchez MJ 20 , Dorronsoro M 20 , Quirós JR 21 , Agudo A 22 , Sjöberg K 23 , Ohlsson B 24 , Hemmingsson O 25 , Werner M 26 , Bradbury KE 27 , Khaw KT 28 , Wareham N 29 , Tsilidis KK 30 , Aune D 31 , Scalbert A 3 , Romieu I 3 , Riboli E 31 , Jenab M 32

Affiliations 

  • 1 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. vfedirk@emory.edu
  • 2 Center for Inflammation, Immunity, and Infection Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA
  • 3 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
  • 4 Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece
  • 5 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nutrition, Immunity and Metabolism Start-up Lab, Nuthetal, Germany
  • 6 Danish Cancer Society Research Center, Copenhagen, Denmark
  • 7 Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
  • 8 Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France
  • 9 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 10 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 11 Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian, 1 20133, Milano, Italy
  • 12 Dipartimento di Medicina Clinica Echirurgia Federico II University, Naples, Italy
  • 13 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
  • 14 Cancer Registry and Histopathology Unit, "Civic -M.P. Arezzo" Hospital, ASP, Ragusa, Italy
  • 15 Molecular and Genetic Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino, Italy
  • 16 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
  • 17 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 18 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway
  • 19 Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
  • 20 CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
  • 21 Public Health Directorate, Asturias, Spain
  • 22 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
  • 23 Department of Clinical Sciences, Lund University, Malmö, Sweden
  • 24 Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Malmö, Lund University, Lund, Sweden
  • 25 Department of Surgical and Perioperative Sciences, Kirurgcentrum, Norrlands Universitetssjukhus, Umeå, Sweden
  • 26 Department of Medicine Sections for Hepatology and Gastroenterology, Umeå University Hospital, SE-90185, Umeå, Sweden
  • 27 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 28 Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK
  • 29 MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
  • 30 Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
  • 31 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
  • 32 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France. jenabm@iarc.fr
BMC Med, 2017 04 04;15(1):72.
PMID: 28372583 DOI: 10.1186/s12916-017-0830-8

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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