Both pathogenic and good bacteria produce toxins that break eukaryotic DNA
By Melissa Lee Phillips | August 10, 2006
Commensal strains of bacteria may establish themselves in the intestine by damaging eukaryotic cells, just like pathogenic bacteria, according to a new study in Science. The researchers found that both pathogenic and commensal strains of Escherichia coli possess a set of genes that lead to double-strand breaks in host cell DNA -- a mechanism that could also trigger intestinal cancer, the authors say.
"It is a clear example of something that we think of as a virulence factor when we find it in pathogens that may be present in commensals as well," said David Schauer of MIT in Cambridge, Mass., who was not involved in the study. "That's really an exciting idea."
Researchers led by Jean-Philippe Nougayrède of the National Institute for Agronomic Research in Toulouse, France, observed that some E. coli strains induce in eukaryotic cells a process called megalocytosis, in which the cell body and nucleus become enlarged and mitosis stops. Using a variety of mutant screens, they found that a particular genomic island in the bacteria was likely behind this toxic effect.
The authors did not find this genomic island in E. coli strains that cause intestinal infection, but saw it in 53% of strains that cause extra-intestinal infection, along with 34% of strains found in healthy human intestines. Screening of an E. coli reference collection confirmed that this island is found only in commensals and extra-intestinal pathogens of one E. coli phylogenetic group.
The genomic island that the authors discovered contains instructions for synthesizing hybrid compounds produced in many bacteria and fungi. Many natural products have been derived from these compounds, including antitumor, antibiotic, and immunosupressive drugs, senior author Eric Oswald, also of the National Institute for Agronomic Research, told The Scientist in an Email.
To find the mechanism by which this set of genes, which the researchers named the pks island, could kill host cells, they examined the cell cycle of eukaryotic cells exposed to the toxin. They found that toxin exposure activated a DNA damage signaling cascade, stopping the normal cell cycle.
Within four hours of contact with bacteria containing the pks island, eukaryotic cells also showed increased levels of a marker of DNA double-strand breaks. And the more bacteria, the greater the damage -- with a small number of bacterial cells, only a few DNA foci were injured; in contrast, exposure to 100 bacteria per cell broke most nuclear DNA.
"The damage induced by the cytotoxin is quite intense," Oswald said, "similar to that induced by gamma radiation."
"The genetic correlation [between the pks island and cytotoxicity] is pretty clear, but how that translates into DNA damage will need to be followed up," noted Jorge Galán of Yale University Medical School in New Haven, Conn, who didn't participate in the study.
The biggest surprise, according to Oswald, was that the toxin was found in both pathogenic and commensal strains of E. coli -- including a commensal strain called Nissle 1917, a prominent member of the human and mice microbiota that acts as a probiotic treatment for intestinal disorders.
Commensal bacteria like Nissle 1917 could promote their own coloniziation by blocking the host cell cycle and therefore limiting epithelial renewal, Oswald suggested. "A good probiotic needs to be a good colonizer."
However, "surface epithelial cells in the gut are post-mitotic," MIT's Schauer told The Scientist. It may be possible for the pks genotoxin to affect epithelial stem cells, but it may instead affect "another cell type entirely," he said. "There are many cell types in the environment ... that may be likely true targets."
Because the pks island contributes to genomic instability in host cells, bacteria containing this island may predispose a host to intestinal cancer, Oswald said. It's possible that E. coli strains traditionally considered commensals could "silently insult our DNA for decades," Oswald said, but cautioned that "we do not know yet if these bacteria can induce DNA damage in vivo."
If the pks island does prove to cause DNA damage in vivo, the discovery will be an intriguing addition to cancers caused by bacteria, such as stomach cancers caused by Helicobacter pylori, Galán told The Scientist. "When people think about cancer, they don't think about infections," he said. "When it comes to predisposing causes of cancer, the microbial origin will have to be increasingly considered."
Melissa Lee Phillips
Links within this article
J-P Nougayrède et al., "Escherichia coli induces DNA double-strand breaks in
eukaryotic cells," Science, August 11, 2006.
T.M. Powledge, "Microbes do vital work in human gut," The Scientist, June 2, 2006.
C.R. Hutchinson et al., "Polyketide and non-ribosomal peptide synthases: falling together by coming apart," PNAS, March 18, 2003.
W. Kruis et al., "Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine," Gut, November 2004.
B. Beale, "Probiotics: Their tiny worlds are under scrutiny," The Scientist, July 22, 2002.
S. Pincock, "H. pylori researchers win Nobel," The Scientist, October 3, 2005.
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