Press release. 11/08/2006

Genotoxic bacteria in the digestive tract

INRA - Bayerische Julius-Maximilians Universität Würzburg - Georg-August-Universität Göttingen - Institut Pasteur

Escherichia coli is a commensal bacterium, which lives peacefully in our digestive tract. However, certain strains are pathogenic and are frequently incriminated in a broad spectrum of infections, affecting both farmed animals and humans (diarrhoea, urinary tract infections, food poisoning, septicaemia, neonatal meningitis, etc.). In this respect, E. coli is a model bacterium to study the continuum between commensal and pathogenic bacteria. Researchers at INRA in Toulouse, in collaboration with German universities in Würzburg and Göttingen and the Institut Pasteur in Paris, have shown for the first time that both commensal and pathogenic E. coli produce a substance which is toxic to the DNA in eukaryotic cells. The bacteria producing this toxin thus induce DNA breaks in host cells and disturb the cell cycle. This slowdown of eukaryotic cell proliferation may enhance bacterial colonization of the intestine. On the other hand, if these breaks are not repaired, they could give rise to a high level of mutations, which are the principal factors triggering cancer in man. The details of this work have been published in Science, August 11th 2006.

© INRA / R. Ducluzeau

Certain strains of E. coli produce a toxin, which induces a toxic effect in host cells, characterised by gradual cell enlargement following the arrest of cell proliferation.  INRA researchers in Toulouse, in collaboration with teams at the German universities of Würzburg and Göttingen and the Institut Pasteur in Paris, have demonstrated that these bacterial strains possess a "genomic island" in their genome, which contains all genes allowing the biosynthesis of a new toxin, which they have called "Colibactin".  The researchers have shown that the bacteria producing this toxin induce serious lesions to the DNA of host cells, causing a blockade of the cell cycle of infected cells.  Colibactin belongs to a new family of bacterial toxins, which are able to act on the cell cycle of eukaryotic cells.  The INRA researchers have proposed to call this family the "cyclomodulins".  

Colibactin is a non-protein toxin.  The genes carried by the genomic island code for several enzymes belonging to the family of "polyketide synthetases" (PKS) and "nonribosomal polypeptide synthetases" (NRPS).  Compounds arising from these biosynthetic pathways constitute a large family of natural products with a very broad range of biological activities and pharmacological properties.  This family comprises numerous molecules which are of importance both agronomically (anti-parasite substances, such as avermectin) and medically (e.g. immunosuppressants, cholesterol-lowering agents, anticancer compounds and antibiotics (cyclosporine, lovastatin, bleomycin, erythromycin, etc.).  This is the first time that an enzyme system of this type, producing a molecule active on eukaryote cells, has been characterised in E. coli, a bacterial species where genetic engineering is well mastered.  This discovery provides a biotechnological key to producing new compounds of interest, and has been the subject of a patent application.  It opens the way to novel therapeutic approaches as well as preventive opportunities.

Infectious diseases, cancer and anti-proliferative effects: is there a role for bacteria producing cyclomodulins?

The work reported in Science also raises an important question for public health.  DNA double strand breaks are dangerous lesions affecting eukaryotic cells; if these are not repaired, they give rise to a high level of mutations, which are the principal triggers of cancer in man.  Colibactin is produced by both commensal E. coli in the intestinal flora and pathogenic strains which are responsible for septicaemia, urinary tract infections and meningitis.  The presence of these bacteria in the commensal flora may therefore constitute a predisposing factor for the development of certain cancers.  Thus bacterial flora may participate in the development, differentiation and homeostasis of mucosa and hence the development of certain types of cancer, or protection against them. 

References:

Escherichia coli induces DNA double strand breaks in eukaryotic cells 
in Science, August 11th 2006, vol.313, n°5788, pp 848-851, DOI: 10.1126/science.1127059
http://www.sciencemag.org/cgi/content/abstract/313/5788/848
Jean-Philippe Nougayrède1, Stefan Homburg2, Frédéric Taieb1, Michèle Boury1, Elzbieta Brzuszkiewicz3, Gerhard Gottschalk3, Carmen Buchrieser4, Jörg Hacker2, Ulrich Dobrindt2, Eric Oswald1
1INRA, UMR1225, Ecole Nationale Vétérinaire de Toulouse, Toulouse, France.
2Institut für Molekulare Infektionsbiologie, Universität Würzburg, Würzburg, Germany.
3Göttingen Genomics Laboratory, Universität Göttingen, Göttingen, Germany.
4Institut Pasteur, Unité de Génomique des Microorganismes Pathogènes et CNRS URA 2171, Paris, France.

Other publications by the team on cyclomodulins:
Taieb et al Cellular Microbiology 2006
Nougayrede et al Trends in Microbiology 2005
Oswald et al Current Opinion in Microbiology 2005

Other publications by the team on genome plasticity and bacterial evolution:
Brzuszkiewicz et al, PNAS 2006
Dobrindt et al Nature Rev. Microbiology 2004
Hacker et al Science 2003

European Patent application dated May 10, 2006
French registration number: 06 290 742.3.
In the name of: INRA and Bayerische Julius-Maximilians-Universitat Wurzburg
Titre: Use of cells containing a specific DNA molecule as cytopathic agents to inhibit the proliferation of cells.

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