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Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort

Butt J 1 , Jenab M 2 , Werner J 1 , Fedirko V 3 , Weiderpass E 4 , Dahm CC 3 Show all authors , Tjønneland A 5 , Olsen A 5 , Boutron-Ruault MC 6 , Rothwell JA 6 , Severi G 6 , Kaaks R 7 , Turzanski-Fortner R 7 , Aleksandrova K 8 , Schulze M 9 , Palli D 10 , Pala V 11 , Panico S 12 , Tumino R 13 , Sacerdote C 14 , Bueno-de-Mesquita B 15 , Van Gils CH 16 , Gram IT 17 , Lukic M 18 , Sala N 19 , Sánchez Pérez MJ 20 , Ardanaz E 21 , Chirlaque MD 22 , Palmquist R 23 , Löwenmark T 23 , Travis RC 24 , Heath A 25 , Cross AJ 25 , Freisling H 2 , Zouiouich S 2 , Aglago E 2 , Waterboer T 1 , Hughes DJ 2

Affiliations 

  • 1 Infections and Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 2 Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France
  • 3 Department of Public Health, Aarhus University, Aarhus, Denmark
  • 4 Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
  • 5 Exposome and Heredity Team, CESP (Centre de Recherche en Epidemiologie et Santé des Populations), Danish Cancer Society Research Center, Diet, Genes and Environment, Nutrition and Biomarkers (NAB), Copenhagen, Denmark
  • 6 Cesp (Umr1018), Médecine Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France
  • 7 Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 8 Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany
  • 9 Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
  • 10 Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy
  • 11 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy
  • 12 Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy
  • 13 Cancer Registry and Histopathology Department, Provincial Health Authority (ASP 7), Ragusa, Italy
  • 14 Unit of Cancer Epidemiology, Città Della Salute E Della Scienza University-Hospital, Turin, Italy
  • 15 Former Senior Scientist, Dept. For Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
  • 16 Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands
  • 17 Department of Community Medicine, University of Tromsø, the Arctic University of Norway, Tromsø, Norway
  • 18 Department of Community Medicine, UiT, The Arctic University of Norway, Tromsø, Norway
  • 19 Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program and Translational Research Laboratory, Catalan Institute of Oncology (ICO), Biomedical Research Institute (IDIBELL), Barcelona, Spain
  • 20 Escuela Andaluza De Salud Pública (EASP), Granada, Spain
  • 21 Navarra Public Health Institute, Pamplona, Spain
  • 22 Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain
  • 23 Department of Medical Biosciences, Pathology, Umeå University, Ireland
  • 24 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
  • 25 Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
Gut Microbes, 2021;13(1):1-14.
PMID: 33874856 DOI: 10.1080/19490976.2021.1903825

Abstract

Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC.The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.

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