Colon Macrophages Polarized by Commensal Bacteria Cause Colitis and Cancer through the Bystander Effect.

Intestinal commensal bacteria have recently been shown to trigger macrophages to produce diffusible clastogens (or chromosome-breaking factors) through a bystander effect (BSE) that mediates DNA damage and induces chromosomal instability in neighboring cells. Colon macrophages appear central to colon carcinogenesis and BSE through the expression of tumor necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2). The former induces netrin-1, a regulator of intestinal epithelial cell apoptosis, and the latter generates trans-4-hydroxy-2-nonenal (4-HNE), an endogenous mutagen.

Cyclooxygenase-2 generates the endogenous mutagen trans-4-hydroxy-2-nonenal in Enterococcus faecalis-infected macrophages.

Infection of macrophages by the human intestinal commensal Enterococcus faecalis generates DNA damage and chromosomal instability in mammalian cells through bystander effects. These effects are characterized by clastogenesis and damage to mitotic spindles in target cells and are mediated, in part, by trans-4-hydroxy-2-nonenal (4-HNE). In this study, we investigated the role of COX and lipoxygenase (LOX) in producing this reactive aldehyde using E.

TNF-α mediates macrophage-induced bystander effects through Netrin-1.

Macrophage-induced bystander effects have been implicated as an important mediator of chromosomal instability and colon cancer triggered by Enterococcus faecalis, a human intestinal commensal bacteria. There is little understanding about how inflammatory cytokines mediate bystander effects, but questions in this area are important because of the pivotal contributions made by inflammatory processes to cancer initiation and progression. Here, we report that the central proinflammatory cytokine TNF-α acts as a diffusible mediator of the bystander effects induced by macrophages, an effect caused by a proliferation of macrophages that trigger epithelial cell production of Netrin-1, a neuronal guidance molecule.

4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages.

Background & Aims: Enterococcus faecalis is a human intestinal commensal that produces extracellular superoxide and promotes chromosome instability via macrophage-induced bystander effects. We investigated the ability of 4-hydroxy-2-nonenal (4-HNE), a diffusible breakdown product of ω-6 polyunsaturated fatty acids, to mediate these effects.

Methods: 4-HNE was purified from E faecalis-infected macrophages; its genotoxicity was assessed in human colon cancer (HCT116) and primary murine colon epithelial (YAMC) cell lines.

Dichotomous metabolism of Enterococcus faecalis induced by haematin starvation modulates colonic gene expression.

Enterococcus faecalis is an intestinal commensal that cannot synthesize porphyrins and only expresses a functional respiratory chain when provided with exogenous haematin. In the absence of haematin, E. faecalis reverts to fermentative metabolism and produces extracellular superoxide that can damage epithelial-cell DNA.

Effects of iron and phytic acid on production of extracellular radicals by Enterococcus faecalis.

Enterococcus faecalis is a human intestinal commensal that produces extracellular superoxide, hydrogen peroxide, and hydroxyl radical while colonizing the intestinal tract. To determine whether dietary factors implicated in colorectal cancer affect oxidant production by E. faecalis, radicals were measured in rats colonized with this microorganism while on diets supplemented with iron or phytic acid.

Free radicals and the pathogenesis of type 1 diabetes: beta-cell cytokine-mediated free radical generation via cyclooxygenase-2.

Free radical formation evoked by proinflammatory cytokines has been suggested to be involved in the destruction of beta-cells in the course of type 1 diabetes development. However, there is no direct evidence to support this hypothesis. In this study, we used electron paramagnetic resonance spectroscopy in conjunction with spin-trapping methodology to directly determine whether cytokines give rise to free radical formation in the islets.

Antioxidant amplifies antibiotic protection in the cecal ligation and puncture model of microbial sepsis through interleukin-10 production.

Preadministration of antioxidants such as pyrrolidine dithiocarbamate (PDTC) and phenyl N-tert-butyl nitrone (PBN) protects animals from lethality in sepsis models. However, the requirement of preadministration greatly diminishes the clinical significance of these studies. Although the synthetic antioxidant PBN has been shown to effectively protect rodents from lethality in endotoxemia (lipopolysaccharide [LPS] model), preliminary screening indicates that pre- or postadministration of PBN does not protect in the rat cecal ligation and puncture (CLP) model.

In vivo production of hydroxyl radical by Enterococcus faecalis colonizing the intestinal tract using aromatic hydroxylation.

Enterococcus faecalis is an intestinal commensal that produces extracellular superoxide (O(2)(*-)) through autoxidation of membrane-associated demethylmenaquinone. To assess free radical production by E. faecalis in vivo, intestinal tracts of rats were colonized using wild-type E.

Interleukin-10 overexpression mediates phenyl-N-tert-butyl nitrone protection from endotoxemia.

The free radical trapping compound phenyl N-tert-butylnitrone (PBN) provides potent protection against lethal endotoxemia in rodents, but the mechanism of this protection is not well understood. The objective of this study was to show that PBN administration in lipopolysaccharide- (LPS) induced endotoxemia promotes enhanced production of endogenous interleukin 10 (IL-10), and the expressed IL-10 is a causal factor in the protection from endotoxemia. We show the amplified expression of IL-10 in liver and plasma in PBN- (150 mg/kg) plus LPS- (4 mg/kg) treated rats using ribonuclease protection assay (RPA) and ELISA.

Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA.

Enterococcus faecalis is a commensal microorganism of the human intestinal tract that produces substantial extracellular superoxide (O(-)(2)), and derivative reactive oxygen species such as H(2)O(2) and hydroxyl radical, through autoxidation of membrane-associated demethylmenaquinone. Because these oxidants may be important as a cause of chromosomal instability (CIN) associated with sporadic adenomatous polyps and colorectal cancer, the ability of E.faecalis to damage eukaryotic cell DNA was examined using the alkaline lysis single cell gel electrophoresis (comet) assay.