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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)630-636
Number of pages7
JournalClinical Microbiology and Infection
Volume30
Issue number5
DOIs
StatePublished - May 2024

Keywords

  • DNA methylation
  • Dysbiosis
  • Epigenetics
  • Microbiota
  • Molecular pathological epidemiology
  • Pathogen

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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