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Gastroenterology. 2007 Feb;132(2):551-61. Epub 2006 Nov 29.

Extracellular superoxide production by Enterococcus faecalis promotes chromosomal instability in mammalian cells.

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The Muchmore Laboratories for Infectious Disease Research, Department of Veterans Affairs Medical Center, University of Oklahoma Health Sciences Center, Oklahoma City, USA.



We investigated whether Enterococcus faecalis, a Gram-positive intestinal commensal that produces extracellular superoxide, could promote chromosomal instability (CIN) in mammalian cells.


We measured the ability of E faecalis to promote CIN using hybrid hamster cells (A(L)N) containing human chromosome 11.


E faecalis promoted CIN in A(L)N cells with average mutant fractions per 10(5) survivors (+/-SD) of 72.3 +/- 6.7 at 1 x 10(9) cfu mL(-1) compared with 22.2 degrees +/- 4.5 for the no bacteria control. Gamma-irradiation at 2 Gray similarly resulted in 74.7 +/- 5.7 mutant clones per 10(5) survivors. Deletions in chromosome 11 consistent with CIN were verified in 80% of mutant clones. E faecalis-treated A(L)N cells were protected from CIN by superoxide dismutase, gamma-tocopherol, and cyclooxygenase-2 (COX-2) inhibitors. In a dual-chamber tissue culture model designed to mimic stromal-epithelial cell interactions, macrophages pretreated with E faecalis grown on permeable supports increased mutant fractions 2.5-fold for A(L)N cells. COX-2 was up-regulated by superoxide from E faecalis and mutant fractions decreased when COX-2 was silenced using short interfering RNA. Escherichia coli, a Gram-negative commensal that produces negligible extracellular superoxide, only modestly promoted CIN in this model.


These findings indicate that macrophage COX-2 is induced by superoxide from E faecalis and promotes CIN in mammalian cells through diffusible factors. This mechanism links the oxidative physiology of E faecalis to propagation of genomic instability through a bystander effect, and offers a novel theory for the role of commensal bacteria in the etiology of sporadic colorectal cancer.

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