High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer - PubMed (original) (raw)

High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer

Emmanuel Buc et al. PLoS One. 2013.

Abstract

Some Escherichia coli strains produce toxins designated cyclomodulins (CMs) which interfere with the eukaryotic cell cycle of host cells, suggesting a possible link between these bacteria and cancers. There are relatively few data available concerning the colonization of colon tumors by cyclomodulin- and genotoxic-producing E. coli. We did a qualitative and phylogenetic analysis of mucosa-associated E. coli harboring cyclomodulin-encoding genes from 38 patients with colorectal cancer (CRC) and 31 with diverticulosis. The functionality of these genes was investigated on cell cultures and the genotoxic activity of strains devoid of known CM-encoding gene was investigated. Results showed a higher prevalence of B2 phylogroup E. coli harboring the colibatin-producing genes in biopsies of patients with CRC (55.3%) than in those of patients with diverticulosis (19.3%), (p<0.01). Likewise, a higher prevalence of B2 E. coli harboring the CNF1-encoding genes in biopsies of patients with CRC (39.5%) than in those of patients with diverticulosis (12.9%), (p = 0.01). Functional analysis revealed that the majority of these genes were functional. Analysis of the ability of E. coli to adhere to intestinal epithelial cells Int-407 indicated that highly adherent E. coli strains mostly belonged to A and D phylogroups, whatever the origin of the strains (CRC or diverticulosis), and that most E. coli strains belonging to B2 phylogroup displayed very low levels of adhesion. In addition, 27.6% (n = 21/76) E. coli strains devoid of known cyclomodulin-encoding genes induced DNA damage in vitro, as assessed by the comet assay. In contrast to cyclomodulin-producing E. coli, these strains mainly belonged to A or D E. coli phylogroups, and exhibited a non significant difference in the distribution of CRC and diverticulosis specimens (22% versus 32.5%, p = 0.91). In conclusion, cyclomodulin-producing E. coli belonging mostly to B2 phylogroup colonize the colonic mucosa of patients with CRC.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1

Figure 1. Cytopathic effect induced by E. coli live bacteria or protein extracts on epithelial cells at three-day post-infection.

For CNF and CDT, the cytopathic effect is only observable with bacterial lysates. In contrast, for colibactin and CIF, a contact between bacteria and host cells is required. Colibactin, CDT and CIF induced cytopathic effects as seen by enlarged nuclei and cell distension (megalocytosis), while CNF induced multinucleation and enlargement of HeLa cells.

Figure 2

Figure 2. Distribution of E. coli strains producing various cyclomodulins according to phylogroups and specimen origins.

A, E. coli strains (n = 70) isolated from CRC samples (n = 38), and B, E. coli strains (n = 46) isolated from diverticulosis samples (n = 31).

Figure 3

Figure 3. DNA damage was detected by the comet assay in HeLa cells exposed to E. coli for 3 h.

DNA damage was not detected in HeLa cells infected with the E. coli strain IHE3034 Δ_clbP_ harboring a defective pks island (A). Comet assay was positive in HeLa cells infected with the E. coli strain IHE3034 harboring pks island (B) or with E. coli devoid of known cyclomodulin-encoding genes (C).

Figure 4

Figure 4. Adhesion ability of E. coli strains isolated from diverticulosis and CRC (proximal and distal) samples to Int-407 intestinal epithelial cells.

A, adhesion ability according to the specimen origin and E. coli phylogroup. B, Adhesion ability of E. coli strains isolated from diverticulosis and CRC (proximal and distal) samples and belonging to A and D phylogroups according to their ability to produce or not a cyclomodulin/genotoxin. The results are expressed as number of adherent bacteria per cell after 3 h infection period. Data are means+/−SEM for at least 3 independent experiments.

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This work was supported by the Ministère Français de l'Education Nationale, de la Recherche et de la Technologie, l'Institut national de la santé et de la recherche médicale (Inserm U1071), l'Institut National de la Recherche Agronomique (USC-2018) and la Ligue contre le cancer. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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