Enrichment of Bacteroides fragilis and enterotoxigenic Bacteroides fragilis in CpG island methylator phenotype-high colorectal carcinoma

Yasutoshi Takashima; Hidetaka Kawamura; Kazuo Okadome; Satoko Ugai; Koichiro Haruki; Kota Arima; Kosuke Mima; Naohiko Akimoto; Jonathan A Nowak; Marios Giannakis; Wendy S Garrett; Cynthia L Sears; Mingyang Song; Tomotaka Ugai; Shuji Ogino

doi:10.1016/j.cmi.2024.01.013

Enrichment of Bacteroides fragilis and enterotoxigenic Bacteroides fragilis in CpG island methylator phenotype-high colorectal carcinoma

Clin Microbiol Infect. 2024 May;30(5):630-636. doi: 10.1016/j.cmi.2024.01.013. Epub 2024 Jan 22.

Authors

Affiliations

¹ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
² Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.
³ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
⁷ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Cancer Immunology Program, Dana-Farber Harvard Cancer Centre, Boston, MA, USA. Electronic address: sogino@bwh.harvard.edu.

PMID: 38266708
PMCID: PMC11043012 (available on 2025-05-01)
DOI: 10.1016/j.cmi.2024.01.013

Abstract

Objectives: Data support that enterotoxigenic Bacteroides fragilis (ETBF) harbouring the Bacteroides fragilis toxin (bft) gene may promote colorectal tumourigenesis through the serrated neoplasia pathway. We hypothesized that ETBF may be enriched in colorectal carcinoma subtypes with high-level CpG island methylator phenotype (CIMP-high), BRAF mutation, and high-level microsatellite instability (MSI-high).

Methods: Quantitative PCR assays were designed to quantify DNA amounts of Bacteroides fragilis, ETBF, and each bft gene isotype (bft-1, bft-2, or bft-3) in colorectal carcinomas in the Health Professionals Follow-up Study and Nurses' Health Study. We used multivariable-adjusted logistic regression models with the inverse probability weighting method.

Results: We documented 4476 colorectal cancer cases, including 1232 cases with available bacterial data. High DNA amounts of Bacteroides fragilis and ETBF were positively associated with BRAF mutation (p ≤ 0.0003), CIMP-high (p ≤ 0.0002), and MSI-high (p < 0.0001 and p = 0.01, respectively). Multivariable-adjusted odds ratios (with 95% confidence interval) for high Bacteroides fragilis were 1.40 (1.06-1.85) for CIMP-high and 2.14 (1.65-2.77) for MSI-high, but 1.02 (0.78-1.35) for BRAF mutation. Multivariable-adjusted odds ratios for high ETBF were 2.00 (1.16-3.45) for CIMP-high and 2.86 (1.64-5.00) for BRAF mutation, but 1.09 (0.67-1.76) for MSI-high. Neither Bacteroides fragilis nor ETBF was associated with colorectal cancer-specific or overall survival.

Discussion: The tissue abundance of Bacteroides fragilis is associated with CIMP-high and MSI-high, whereas ETBF abundance is associated with CIMP-high and BRAF mutation in colorectal carcinoma. Our findings support the aetiological relevance of Bacteroides fragilis and ETBF in the serrated neoplasia pathway.

Keywords: DNA methylation; Dysbiosis; Epigenetics; Microbiota; Molecular pathological epidemiology; Pathogen.

MeSH terms

Adult
Aged
Bacterial Toxins / genetics
Bacteroides Infections / microbiology
Bacteroides fragilis* / genetics
Bacteroides fragilis* / isolation & purification
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / microbiology
CpG Islands* / genetics
DNA Methylation*
Female
Humans
Male
Metalloendopeptidases* / genetics
Microsatellite Instability
Middle Aged
Mutation
Phenotype
Proto-Oncogene Proteins B-raf / genetics

Substances

Bacteroides fragilis toxin
Metalloendopeptidases
Bacterial Toxins
Proto-Oncogene Proteins B-raf
BRAF protein, human

Abstract

MeSH terms

Substances

Grants and funding