Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures

Iradj Sobhani, Emma Bergsten, Séverine Couffin, Aurélien Amiot, Biba Nebbad, Caroline Barau, Nicola de’Angelis, Sylvie Rabot, Florence Canoui-Poitrine, Denis Mestivier, Thierry Pédron, Khashayarsha Khazaie, Philippe J. Sansonetti

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Sporadic colorectal cancer (CRC) is a result of complex interactions between the host and its environment. Environmental stressors act by causing host cell DNA alterations implicated in the onset of cancer. Here we investigate the stressor ability of CRC-associated gut dysbiosis as causal agent of host DNA alterations. The epigenetic nature of these alterations was investigated in humans and in mice. Germ-free mice receiving fecal samples from subjects with normal colonoscopy or from CRC patients were monitored for 7 or 14 wk. Aberrant crypt foci, luminal microbiota, and DNA alterations (colonic exome sequencing and methylation patterns) were monitored following human feces transfer. CRC-associated microbiota induced higher numbers of hypermethylated genes in murine colonic mucosa (vs. healthy controls’ microbiota recipients). Several gene promoters including SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1 promoters were found hypermethylated in CRC but not in normal tissues or effluents from fecal donors. In a pilot study (n = 266), the blood methylation levels of 3 genes (Wif1, PENK, and NPY) were shown closely associated with CRC dysbiosis. In a validation study (n = 1,000), the cumulative methylation index (CMI) of these genes was significantly higher in CRCs than in controls. Further, CMI appeared as an independent risk factor for CRC diagnosis as shown by multivariate analysis that included fecal immunochemical blood test. Consequently, fecal bacterial species in individuals with higher CMI in blood were identified by whole metagenomic analysis. Thus, CRC-related dysbiosis induces methylation of host genes, and corresponding CMIs together with associated bacteria are potential biomarkers for CRC.

Original languageEnglish (US)
Pages (from-to)24285-24295
Number of pages11
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number48
DOIs
StatePublished - Nov 26 2019

Keywords

  • Biomarker
  • Cancer
  • Colon
  • Gene methylation
  • Microbiota

ASJC Scopus subject areas

  • General

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  • Cite this

    Sobhani, I., Bergsten, E., Couffin, S., Amiot, A., Nebbad, B., Barau, C., de’Angelis, N., Rabot, S., Canoui-Poitrine, F., Mestivier, D., Pédron, T., Khazaie, K., & Sansonetti, P. J. (2019). Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. Proceedings of the National Academy of Sciences of the United States of America, 116(48), 24285-24295. https://doi.org/10.1073/pnas.1912129116