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

Julia Butt¹, Mazda Jenab², Jill Werner¹, Veronika Fedirko³, Elisabete Weiderpass⁴, Christina C Dahm³, Anne Tjønneland^{5

6}, Anja Olsen^{5

7}, Marie-Christine Boutron-Ruault⁸, Joseph A Rothwell⁸, Gianluca Severi^{8

9}, Rudolf Kaaks¹⁰, Renée Turzanski-Fortner¹⁰, Krasimira Aleksandrova¹¹, Matthias Schulze^{12

13}, Domenico Palli¹⁴, Valeria Pala¹⁵, Salvatore Panico¹⁶, Rosario Tumino¹⁷, Carlotta Sacerdote¹⁸, Bas Bueno-de-Mesquita^{19

20

21

22}, Carla H Van Gils²³, Inger Torhild Gram²⁴, Marko Lukic²⁵, Núria Sala²⁶, María José Sánchez Pérez^{27

28

29

30}, Eva Ardanaz^{31

32

33}, María-Dolores Chirlaque^{34

35}, Richard Palmquist³⁶, Thyra Löwenmark³⁶, Ruth C Travis³⁷, Alicia Heath³⁸, Amanda J Cross^{38

39}, Heinz Freisling², Semi Zouiouich², Elom Aglago², Tim Waterboer¹, David J Hughes²

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 Department of Public Health, University of Copenhagen, Denmark.
⁷ Department of Public Health, University of Aarhus, Denmark.
⁸ Cesp (Umr1018), Médecine Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France.
⁹ Department of Statistics, Computer Science and Applications (DISIA), University of Florence, Italy.
¹⁰ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
¹² Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
¹³ Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
¹⁴ Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
¹⁵ Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
¹⁶ Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.
¹⁷ Cancer Registry and Histopathology Department, Provincial Health Authority (ASP 7), Ragusa, Italy.
¹⁸ Unit of Cancer Epidemiology, Città Della Salute E Della Scienza University-Hospital, Turin, Italy.
¹⁹ Former Senior Scientist, Dept. For Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
²⁰ Former Associate Professor, Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
²¹ Former Visiting Professor, Dept. Of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.
²² Former Academic Icon/visiting Professor, Dept. Of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
²³ Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁴ Department of Community Medicine, University of Tromsø, the Arctic University of Norway, Tromsø, Norway.
²⁵ Department of Community Medicine, UiT, The Arctic University of Norway, Tromsø, Norway.
²⁶ 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.
²⁷ Escuela Andaluza De Salud Pública (EASP), Granada, Spain.
²⁸ Instituto De Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
²⁹ Centro De Investigación Biomédica En Red De Epidemiología Y Salud Pública (CIBERESP), Madrid, Spain.
³⁰ Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
³¹ Navarra Public Health Institute, Pamplona, Spain.
³² IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
³³ CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain.
³⁴ Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain.
³⁵ CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
³⁶ Department of Medical Biosciences, Pathology, Umeå University, Ireland.
³⁷ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁸ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁹ Cancer Biology and Therapeutics Group, School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

PMID: 33874856
PMCID: PMC8078709
DOI: 10.1080/19490976.2021.1903825

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

Julia Butt et al. Gut Microbes. 2021 Jan-Dec.

. 2021 Jan-Dec;13(1):1-14.

doi: 10.1080/19490976.2021.1903825.

Authors

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 Department of Public Health, University of Copenhagen, Denmark.
⁷ Department of Public Health, University of Aarhus, Denmark.
⁸ Cesp (Umr1018), Médecine Université Paris-Saclay, Inserm, Gustave Roussy, Villejuif, France.
⁹ Department of Statistics, Computer Science and Applications (DISIA), University of Florence, Italy.
¹⁰ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹¹ Department of Nutrition and Gerontology, German Institute of Human Nutrition Potsdam-Rehbruecke, Germany.
¹² Department of Molecular Epidemiology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany.
¹³ Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany.
¹⁴ Institute for Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
¹⁵ Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.
¹⁶ Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.
¹⁷ Cancer Registry and Histopathology Department, Provincial Health Authority (ASP 7), Ragusa, Italy.
¹⁸ Unit of Cancer Epidemiology, Città Della Salute E Della Scienza University-Hospital, Turin, Italy.
¹⁹ Former Senior Scientist, Dept. For Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
²⁰ Former Associate Professor, Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
²¹ Former Visiting Professor, Dept. Of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK.
²² Former Academic Icon/visiting Professor, Dept. Of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
²³ Julius Centre for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, Utrecht, The Netherlands.
²⁴ Department of Community Medicine, University of Tromsø, the Arctic University of Norway, Tromsø, Norway.
²⁵ Department of Community Medicine, UiT, The Arctic University of Norway, Tromsø, Norway.
²⁶ 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.
²⁷ Escuela Andaluza De Salud Pública (EASP), Granada, Spain.
²⁸ Instituto De Investigación Biosanitaria ibs.GRANADA, Granada, Spain.
²⁹ Centro De Investigación Biomédica En Red De Epidemiología Y Salud Pública (CIBERESP), Madrid, Spain.
³⁰ Department of Preventive Medicine and Public Health, University of Granada, Granada, Spain.
³¹ Navarra Public Health Institute, Pamplona, Spain.
³² IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
³³ CIBER Epidemiology and Public Health CIBERESP, Madrid, Spain.
³⁴ Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain.
³⁵ CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
³⁶ Department of Medical Biosciences, Pathology, Umeå University, Ireland.
³⁷ Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
³⁸ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
³⁹ Cancer Biology and Therapeutics Group, School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

PMID: 33874856
PMCID: PMC8078709
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) (p_{heterogeneity} = 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.

Keywords: Colorectal cancer; Escherichia coli; bacteroides fragilis; prospective; serology.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

**Figure 1.**
IgA and IgG antibody responses (median fluorescence intensities, MFI) to (a) *E. coli* and (b) ETBF proteins in cases and controls in the EPIC study. Boxes represent 25^th to 75^th and whiskers the 5^th to 95^th percentiles, solid lines show the median. Dots represent data points lying outside the 5^th and 95^th percentiles, respectively. Wilcoxon Mann–Whitney test was applied to compare continuous antibody responses [MFI] between sero-positive controls and cases

See this image and copyright information in PMC

References

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous