Cytotoxic necrotizing factor 1 hinders colon tumorigenesis induced by colibactin-producing Escherichia coli in ApcMin/+ mice
Héloïse Chat,
Guillaume Dalmasso,
Catherine Godfraind,
Virginie Bonnin,
Racha Beyrouthy,
Mathilde Bonnet,
Nicolas Barnich,
Amel Mettouchi,
Emmanuel Lemichez,
Richard Bonnet,
Julien Delmas
Affiliations
Héloïse Chat
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Guillaume Dalmasso
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Catherine Godfraind
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Virginie Bonnin
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Racha Beyrouthy
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Mathilde Bonnet
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Nicolas Barnich
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Amel Mettouchi
Institut Pasteur, University of Paris, CNRS UMR2001, Paris, France
Emmanuel Lemichez
Institut Pasteur, University of Paris, CNRS UMR2001, Paris, France
Richard Bonnet
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
Julien Delmas
Centre de Recherche en Nutrition Humaine Auvergne, University Clermont Auvergne, Inserm U1071, INRAE USC 1382, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Clermont-Ferrand, France
ABSTRACTColorectal cancer (CRC) patients are frequently colonized by colibactin-producing Escherichia coli (CoPEC) (>40%), which enhances tumorigenesis in mouse models of CRC. We observed that 50% of CoPEC also contains the cnf1 gene, which encodes cytotoxic necrotizing factor-1 (CNF1), an enhancer of the eukaryotic cell cycle. The impact of its co-occurrence with colibactin (Clb) has not yet been investigated. We evaluated the impact of CNF1 on colorectal tumorigenesis using human colonic epithelial HT-29 cells and CRC-susceptible ApcMin/+ mice inoculated with the CoPEC 21F8 clinical strain (Clb+Cnf+) or 21F8 isogenic mutants (Clb+Cnf-, Clb-Cnf+ and Clb-Cnf-). Infection with the Clb+Cnf- strain induced higher levels of inflammatory cytokines and senescence markers both in vitro and in vivo compared to those induced by infection with the Clb+Cnf+ strain. In contrast, the Clb+Cnf- and Clb+Cnf+ strains generated similar levels of DNA damage in HT-29 cells and in colonic murine tissues. Furthermore, the ApcMin/+ mice inoculated with the Clb+Cnf- strain developed significantly more tumors than the mice inoculated with the Clb+Cnf+ strain or the isogenic mutants, and the composition of their microbiota was changed. Finally, rectal administration of the CNF1 protein in ApcMin/+ mice inoculated with the Clb+Cnf- strain significantly decreased tumorigenesis and inflammation. Overall, this study provides evidence that CNF1 decreases the carcinogenic effects of CoPEC in ApcMin/+ mice by decreasing CoPEC-induced cellular senescence and inflammation.
