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Cited by 256Gut microbiota and healthEscherichia coli research studiesOral microbiology and periodontitis research

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Quantitative Profiling of Colorectal Cancer-Associated Bacteria Reveals Associations between Fusobacterium spp., Enterotoxigenic Bacteroides fragilis (ETBF) and Clinicopathological Features of Colorectal Cancer

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Viljoen, Katie S., Dakshinamurthy, Amirtha, Goldberg, Paul, Blackburn, Jonathan M.·2015·PLoS ONE
DOI 10.1371/journal.pone.0119462PMC PMC4353626
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Abstract

Various studies have presented clinical or in vitro evidence linking bacteria to colorectal cancer, but these bacteria have not previously been concurrently quantified by qPCR in a single cohort. We quantify these bacteria (Fusobacterium spp., Streptococcus gallolyticus, Enterococcus faecalis, Enterotoxigenic Bacteroides fragilis (ETBF), Enteropathogenic Escherichia coli (EPEC), and afaC- or pks-positive E. coli) in paired tumour and normal tissue samples from 55 colorectal cancer patients. We further investigate the relationship between a) the presence and b) the level of colonisation of each bacterial species with site and stage of disease, age, gender, ethnicity and MSI-status. With the exception of S. gallolyticus, we detected all bacteria profiled here in both tumour and normal samples at varying frequencies. ETBF (FDR = 0.001 and 0.002 for normal and tumour samples) and afaC-positive E. coli (FDR = 0.03, normal samples) were significantly enriched in the colon compared to the rectum. ETBF (FDR = 0.04 and 0.002 for normal and tumour samples, respectively) and Fusobacterium spp. (FDR = 0.03 tumour samples) levels were significantly higher in late stage (III/IV) colorectal cancers. Fusobacterium was by far the most common bacteria detected, occurring in 82% and 81% of paired tumour and normal samples. Fusobacterium was also the only bacterium that was significantly higher in tumour compared to normal samples (p = 6e-5). We also identified significant associations between high-level colonisation by Fusobacterium and MSI-H (FDR = 0.05), age (FDR = 0.03) or pks-positive E. coli (FDR = 0.01). Furthermore, we exclusively identified atypical EPEC in our cohort, which has not been previously reported in association with colorectal cancer. By quantifying colorectal cancer-associated bacteria across a single cohort, we uncovered inter- and intra-individual patterns of colonization not previously recognized, as well as important associations with clinicopathological features, especially in the case of Fusobacterium and ETBF.

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Crossref · 10.1371/journal.pone.0119462

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Figures

Fig 1 Levels of colonization by each bacterium/gene were categorized using the third quartile (taken across colonisation-positive samples) as a cutoff for high- or low-level colonisation. Categories: 1 (No colonisation), 2 (low colonisation), 3 (high colonisation). In the case of EPEC, because there were so few EPEC-positive patients (N = 6), samples were analysed as positive or negative only. EF: E. faecalis; FB: Fusobacterium.
Fig 1 Levels of colonization by each bacterium/gene were categorized using the third quartile (taken across colonisation-positive samples) as a cutoff for high- or low-level colonisation. Categories: 1 (No colonisation), 2 (low colonisation), 3 (high colonisation). In the case of EPEC, because there were so few EPEC-positive patients (N = 6), samples were analysed as positive or negative only. EF: E. faecalis; FB: Fusobacterium.CC BY · PubMed Central
Fig 2 qPCR quantification of bacteria in paired patient samples, expressed as log10 bacteria/50ng of patient DNA. Each bar represents one samples (either tumour or normal) and the order of samples are the same for each bacterium. Red (tumour); blue (normal); *(Not determined).
Fig 2 qPCR quantification of bacteria in paired patient samples, expressed as log10 bacteria/50ng of patient DNA. Each bar represents one samples (either tumour or normal) and the order of samples are the same for each bacterium. Red (tumour); blue (normal); *(Not determined).CC BY · PubMed Central
Fig 3 ETBF and afaC+ E. coli are significantly more prevalent in colon vs. rectal cancers. This applies to both tumour and normal tissue in the case of ETBF (FDR = 0.002, 0.001, respectively) and normal tissue only in the case of afaC (FDR = 0.03).
Fig 3 ETBF and afaC+ E. coli are significantly more prevalent in colon vs. rectal cancers. This applies to both tumour and normal tissue in the case of ETBF (FDR = 0.002, 0.001, respectively) and normal tissue only in the case of afaC (FDR = 0.03).CC BY · PubMed Central
Fig 4 ETBF and Fusobacterium are found at significantly higher levels in late stage (III/IV) cancers. For Fusobacterium, individual stages were compared in a pairwise manner using Dunn’s test. For ETBF, individual stages were compared in a pairwise manner using Fisher’s exact test. Fusobacterium is found at significantly higher levels in stage III CRCs compared to stage I or II CRCs. ETBF is found more frequently in stage III or IV CRCs compared to stage I or II CRCs; and in the corresponding normal mucosa of stage IV CRCs compared to stage I CRCs.
Fig 4 ETBF and Fusobacterium are found at significantly higher levels in late stage (III/IV) cancers. For Fusobacterium, individual stages were compared in a pairwise manner using Dunn’s test. For ETBF, individual stages were compared in a pairwise manner using Fisher’s exact test. Fusobacterium is found at significantly higher levels in stage III CRCs compared to stage I or II CRCs. ETBF is found more frequently in stage III or IV CRCs compared to stage I or II CRCs; and in the corresponding normal mucosa of stage IV CRCs compared to stage I CRCs.CC BY · PubMed Central
Fig 5 Fusobacterium clinicopathological associations. High-level colonisation by Fusobacterium is significantly more prevalent in younger patients, males and patients of Black ethnicity. Due to the disproportionately high number of young, black patients seen in our cohort the relationship between ethnicity and levels of colonisation by Fusobacterium was assessed using the subset of patients ≤ 50 years. A borderline significant relationship was seen between high-level colonisation by Fusobacterium and MSI-H compared to MSS/MSI-L (In our cohort three MSI-L cases were included with the MSS cohort). The vertical and horizontal dotted lines in the bottom right Fig. represent the cutoff for high-level colonisation by pks+ E. coli and Fusobacterium, respectively (see methods for further detail). FB: Fusobacterium; B: Black; C: Caucasian; I: Indian; M: Mixed Ancestry; N: normal tissue; F: Female; M: Male.
Fig 5 Fusobacterium clinicopathological associations. High-level colonisation by Fusobacterium is significantly more prevalent in younger patients, males and patients of Black ethnicity. Due to the disproportionately high number of young, black patients seen in our cohort the relationship between ethnicity and levels of colonisation by Fusobacterium was assessed using the subset of patients ≤ 50 years. A borderline significant relationship was seen between high-level colonisation by Fusobacterium and MSI-H compared to MSS/MSI-L (In our cohort three MSI-L cases were included with the MSS cohort). The vertical and horizontal dotted lines in the bottom right Fig. represent the cutoff for high-level colonisation by pks+ E. coli and Fusobacterium, respectively (see methods for further detail). FB: Fusobacterium; B: Black; C: Caucasian; I: Indian; M: Mixed Ancestry; N: normal tissue; F: Female; M: Male.CC BY · PubMed Central

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Cites

Research works printed but not linked: 3

  1. E Buc, 2013, High Prevalence of Mucosa-Associated E. coli Producing Cyclomodulin and Genotoxin in Colon Cancer, PLoS One, 8
  2. HM Martin, 2004, Enhanced Escherichia coli adherence and invasion in Crohn’s disease and colon cancer, Gastroenterology, 127, 80
  3. J Dolezel, 2003, Nuclear DNA content and genome size of trout and human, Cytometry A, 51, 127

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Metadata

Authors
Viljoen, K. S., Dakshinamurthy, A., Goldberg, P., & Blackburn, J. M.
Affiliations
  • University of Cape Town (ZA)
  • Groote Schuur Hospital (ZA)
Corresponding author
Blackburn, Jonathan M.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-03-09
Volume
10
Issue
3
Pages
e0119462
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0119462
PMC
PMC4353626
OpenAlex
W2086248022
Cited by
256
References
74
Citations by year
2026: 14 · 2025: 26 · 2024: 25 · 2023: 32 · 2022: 29 · 2021: 34 · 2020: 21 · 2019: 23 · 2018: 21 · 2017: 16 · 2016: 12 · 2015: 1
FWCI
7.24
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • Open University of Cape Town (University of Cape Town) (submittedVersion, cc-by)
Funders
  • National Research Foundation
  • Cancer Association of South Africa
  • Deutscher Akademischer Austauschdienst
  • Harry Crossley Foundation
  • University of Cape Town
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
Keywords
colorectal cancer, Fusobacterium, enterotoxigenic Bacteroides fragilis, Streptococcus bovis, Enterococcus faecalis, enteropathogenic Escherichia coli, tumor microbiome, tumor stage, microsatellite instability, clinicopathological features
MeSH terms
Adenocarcinoma, Adult, Bacterial Infections, Bacteroides fragilis, Colon, Female, Fusobacterium, Genes, Bacterial, Humans, Male, Middle Aged, Neoplasm Staging, Rectum, Colorectal Neoplasms, Case-Control Studies, Enteropathogenic Escherichia coli, Bacterial Load

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