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BMC Med. 2017 Apr 4;15(1):72. doi: 10.1186/s12916-017-0830-8.

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

Author information

1
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA. vfedirk@emory.edu.
2
Winship Cancer Institute, Emory University, Atlanta, GA, USA. vfedirk@emory.edu.
3
Center for Inflammation, Immunity, and Infection Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, 30303, USA.
4
Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
5
Hellenic Health Foundation, 13 Kaisareias Street, Athens, GR-115 27, Greece.
6
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.
7
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nutrition, Immunity and Metabolism Start-up Lab, Nuthetal, Germany.
8
Danish Cancer Society Research Center, Copenhagen, Denmark.
9
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark.
10
Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.
11
Gustave Roussy, Villejuif, F-94805, France.
12
Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris (AP-HP), University hospitals Paris-Sud, Site de Bicêtre, Paris Sud University, Paris XI, Le Kremlin Bicêtre, Villejuif, France.
13
Human Genetics Foundation (HuGeF), Torino, Italy.
14
Cancer Council Victoria and University of Melbourne, Melbourne, Australia.
15
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
16
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
17
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
18
Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Via Venezian, 1 20133, Milano, Italy.
19
Dipartimento di Medicina Clinica Echirurgia Federico II University, Naples, Italy.
20
Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy.
21
Cancer Registry and Histopathology Unit, "Civic -M.P. Arezzo" Hospital, ASP, Ragusa, Italy.
22
Molecular and Genetic Epidemiology Unit, HuGeF, Human Genetics Foundation, Torino, Italy.
23
Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
24
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
25
Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
26
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.
27
Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
28
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway.
29
Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway.
30
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
31
Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki, Finland.
32
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
33
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
34
Navarra Public Health Institute, Pamplona, Spain.
35
Navarra Institute for Health Research (IdiSNA), Pamplona, Spain.
36
Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA. Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain.
37
Basque Regional Health Department, San Sebastian, Spain.
38
Public Health Directorate, Asturias, Spain.
39
Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
40
Department of Clinical Sciences, Lund University, Malmö, Sweden.
41
Department of Gastroenterology and Nutrition, Skåne University Hospital, Malmö, Sweden.
42
Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Malmö, Lund University, Lund, Sweden.
43
Department of Surgical and Perioperative Sciences, Kirurgcentrum, Norrlands Universitetssjukhus, Umeå, Sweden.
44
Department of Medicine Sections for Hepatology and Gastroenterology, Umeå University Hospital, SE-90185, Umeå, Sweden.
45
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
46
Clinical Gerontology Unit, University of Cambridge School of Clinical Medicine, Cambridge, UK.
47
MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
48
Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
49
Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
50
Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France. jenabm@iarc.fr.

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.

KEYWORDS:

Endotoxins; Flagellin; Hepatocellular carcinoma; Lipopolysaccharide; Prospective studies

PMID:
28372583
PMCID:
PMC5379669
DOI:
10.1186/s12916-017-0830-8
[Indexed for MEDLINE]
Free PMC Article

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