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Serum Endotoxins and Flagellin and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort

Kong SY 1 , Tran HQ 2 , Gewirtz AT 2 , McKeown-Eyssen G 3 , Fedirko V 4 , Romieu I 1 Show all authors , Tjønneland A 5 , Olsen A 5 , Overvad K 6 , Boutron-Ruault MC 7 , Bastide N 7 , Affret A 7 , Kühn T 8 , Kaaks R 8 , Boeing H 9 , Aleksandrova K 9 , Trichopoulou A 10 , Kritikou M 11 , Vasilopoulou E 12 , Palli D 13 , Krogh V 14 , Mattiello A 15 , Tumino R 16 , Naccarati A 17 , Bueno-de-Mesquita HB 18 , Peeters PH 19 , Weiderpass E 20 , Quirós JR 21 , Sala N 22 , Sánchez MJ 23 , Castaño JM 24 , Barricarte A 25 , Dorronsoro M 26 , Werner M 27 , Wareham NJ 28 , Khaw KT 29 , Bradbury KE 30 , Freisling H 1 , Stavropoulou F 1 , Ferrari P 1 , Gunter MJ 31 , Cross AJ 31 , Riboli E 31 , Bruce WR 32 , Jenab M 33

Affiliations 

  • 1 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France
  • 2 Center for Inflammation, Immunity, and Infection, Department of Biology, Georgia State University, Atlanta, Georgia
  • 3 Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
  • 4 Department of Epidemiology, Rollins School of Public Health, Winship Cancer Institute, Emory University, Atlanta, Georgia
  • 5 Diet, Genes, and Environment, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 6 Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus C, Denmark
  • 7 INSERM, CESP Centre for Research in Epidemiology and Population Health, Lifestyle, Genes, and Health: Integrative Trans-Generational Epidemiology, Villejuif, France. University of Paris-South, Villejuif, France. Institute Gustave Roussy, Villejuif, France
  • 8 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 9 Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
  • 10 Hellenic Health Foundation, Athens, Greece. Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece
  • 11 Hellenic Health Foundation, Athens, Greece
  • 12 Department of Hygiene, Epidemiology, and Medical Statistics, University of Athens Medical School, Athens, Greece
  • 13 Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute - ISPO, Florence, Italy
  • 14 Epidemiology and Prevention Unit, IRCCS Foundation, National Cancer Institute, Milano, Italy
  • 15 Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy
  • 16 Cancer Registry and Histopathology Unit, "Civic - MP Arezzo" Hospital, Ragusa, Italy
  • 17 Human Genetics Foundation, Torino Molecular and Genetic Epidemiology Unit, Torino, Italy
  • 18 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and Environment (RIVM), Bilthoven, the Netherlands. Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. Department of Epidemiology and Biostatistics, School of Public Health, Imperil College London, London, United Kingdom. Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 19 Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands. MRC-PHE Centre for Environment and Health, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom
  • 20 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, Oslo, Norway. Department of Medical Epidemiology and Biostatistics, Karolinska Instituet, Stockholm, Sweden. Department of Genetic Epidemiology, Folkhälsan Research Center, Helsinki, Finland
  • 21 Public Health Directorate, Asturias, Spain
  • 22 Unit of Nutrition, Environment, and Cancer, Cancer Epidemiology Research Program, and Translational Research Laboratory, Catalan Institute of Oncology (IDIBELL), Barcelona, Spain
  • 23 Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs, GRANADA, Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain. CIBER de Epidemiología y Salud Pública (CIBERESP), Spain
  • 24 CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain
  • 25 CIBER de Epidemiología y Salud Pública (CIBERESP), Spain. Navarra Public Health Institute, Pamplona, Spain. Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
  • 26 Public Health Direction and CIBERESP-Biodonostia Research Institute, Basque Regional Health Department, San Sebastian, Spain
  • 27 Institution of Public Health and Medicine, Medicine Umeå University, Umeå, Sweden
  • 28 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom
  • 29 Clinical Gerontology Unit, Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, United Kingdom
  • 30 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
  • 31 Department of Epidemiology and Biostatistics, School of Public Health, Imperil College London, London, United Kingdom
  • 32 Department of Nutritional Sciences, University of Toronto, Toronto, Canada. jenabm@iarc.fr wrbruce@utoronto.ca
  • 33 Section of Nutrition and Metabolism, International Agency for Research on Cancer (IARC-WHO), Lyon, France. jenabm@iarc.fr wrbruce@utoronto.ca
Cancer Epidemiol Biomarkers Prev, 2016 Feb;25(2):291-301.
PMID: 26823475 DOI: 10.1158/1055-9965.EPI-15-0798

Abstract

BACKGROUND: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk.

METHODS: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors.

RESULTS: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10-2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47-1.02; Ptrend, 0.18).

CONCLUSION: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist.

IMPACT: Further studies are warranted to better clarify these preliminary observations.

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

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