Enterococcus faecalis Metalloprotease Compromises Epithelial Barrier and Contributes to Intestinal Inflammation

Steck, Natalie; Hoffmann, Micha; Sava, Irina G.; Kim, Sandra C.; Hahne, Hannes; Tonkonogy, Susan L.; Mair, Katrin; Krueger, Dagmar; Pruteanu, Mihaela; Shanahan, Fergus; Vogelmann, Roger; Schemann, Michael; Küster, Bernhard; Sartor, Ryan B.; Haller, Dirk

doi:10.1053/j.gastro.2011.05.035

Cited by 256 publications

(191 citation statements)

References 45 publications

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“…For instance, members of the gut microbiota such as Bacteroides spp. [50,51] and Enterococcus faecealis strains [47,52,53] are able to express molecules exerting MMP activity which in turn might affect epithelial barrier function and thus represent potential triggers toward higher susceptibility of the host to inflammatory stimuli [46]. Indeed, mice purchased from different commercial vendors exhibited differences in susceptibility or resistance in inflammation and infection models due to their distinct colonization status [46,48].…”

Section: Discussionmentioning

confidence: 99%

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

Heimesaat¹,

Dunay²,

Fuchs³

et al. 2011

European Journal of Microbiology and Immunology

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Expression of gelatinases A and B, also referred to matrixmetalloproteinases (MMP)-2 and -9, respectively, is increased in inflamed tissues of experimental intestinal inflammation and humans with inflammatory bowel disease (IBDs). Given that we recently reported that treatment with the selective gelatinase inhibitor RO28-2653 ameliorates acute dextrane sulfate sodium (DSS) colitis, we asked whether gelatinase A or B expression is pivotal in mediating large intestinal inflammation. Results from our study reveal that symptoms of acute DSS colitis as well as histopathological colonic changes were ameliorated in MMP-2-, but not MMP-9-deficient mice, and were paralleled by a diminished influx of immune cells. In MMP-2-deficient mice, we observed lower expression of pro-inflammatory cytokines including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-6 in colonic biopsies and less overgrowth of the colonic lumen by potentially pro-inflammatory enterobacteria from the commensal gut microbiota. We conclude that rather MMP-2 than MMP-9 is causative for the establishment of DSS colitis in mice. The discrepancy of these data to prior reports might be due to substantial differences in the intestinal microbiota composition of the mice bred at different animal facilities impacting susceptibility to inflammatory stimuli. Consequently, a detailed survey of the gut microbiota should be implemented in immunological/inflammatory studies in the future in order to allow comparison of data from different facilities.

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Section: Discussionmentioning

confidence: 99%

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

Heimesaat¹,

Dunay²,

Fuchs³

et al. 2011

European Journal of Microbiology and Immunology

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“…GelE is known to contribute to biofilm formation, and contributes also to virulence through degradation of a broad range of host proteinaceous substrates (Hancock & Perego, 2004;Park et al, 2007Park et al, , 2008Steck et al, 2011). The role of the gelE and fsr loci in E. faecalis virulence has been demonstrated in different mammalian infection models (Mohamed & Murray, 2006), in the Caenorhabditis elegans nematode model (Gaspar et al, 2009;Sifri et al, 2002) and in the Arabidopsis thaliana plant model (Jha et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The incongruent gelatinase genotype and phenotype in Enterococcus faecalis are due to shutting off the ability to respond to the gelatinase biosynthesis-activating pheromone (GBAP) quorum-sensing signal

et al. 2012

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The concomitant presence of a complete fsr quorum-sensing system and gelE-sprE operons in Enterococcus faecalis is known to be essential for the detection of gelatinase activity. However, there are reports of the absence of gelatinase activity despite the presence of complete fsr and gelE loci. In order to understand this incongruence between genotype and phenotype we sequenced fsr and gelE loci of the E. faecalis LN68 strain, which was previously found to carry both operons but to lack gelatinase activity. Of the 59 nucleotide differences detected compared with the gelatinase-positive V583 strain, we found a nonsense mutation (a premature STOP codon) predicted to truncate the ATPase sensor domain of the FsrC protein, responsible for sensing and transducing the signal from the quorum-sensing molecule. Strain LN68 was highly affected in the expression of the gelE and sprE genes, further supporting the lack of Fsrdependent gelE induction. When we constructed a V583 mutant with the same premature stop mutation in the fsrC gene the resulting strain was no longer able to degrade gelatin. We conclude that the reduced ability to transduce the quorum-sensing signal of the prematurely truncated FsrC protein is sufficient to explain the negative gelatinase phenotype. As the incongruent genotype and phenotype is detected in natural isolates, we believe that the silencing of the quorum-sensing system Fsr may be beneficial for some E. faecalis strains.

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“…However, it is unclear whether fecal protease-induced intestinal permeability is of mammalian or bacterial origin. Accumulating evidence shows that endogenous enteric microbes produce proteases that possess the ability to disrupt the epithelial barrier (26,27). These commensal proteases may be involved in the pathogenesis of intestinal diseases in the context of a genetically predisposed …”

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confidence: 99%

Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2

et al. 2015

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e Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2 ؊/؊ ) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2 ؊/؊ mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2 ؊/؊ mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2 ؊/؊ mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2.A potential mechanism for the pathogenesis of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS) involves disruption of the intestinal epithelial barrier and exposure of a genetically defective immune system to enteric microbial antigens. Indeed, IBD and IBS patients exhibit a higher level of intestinal permeability than healthy controls (1-7). Additionally, first-degree relatives of IBD patients display elevated levels of enteric permeability (8-10), suggesting that this abnormality is independent of inflammation. Consistent with this hypothesis are animal models of colitis that use chemical disruption of the epithelial barrier with trinitrobenzene sulfonic acid, dextran sodium sulfate, or nonsteroidal anti-inflammatory drugs (NSAIDs) to elicit inflammation (11). Further, disruption of the intestinal epithelial barrier by exposure of susceptible patients to NSAIDs (blockers of prostaglandin synthesis) is a risk factor for intestinal inflammation (12).Enteric proteases can act broadly as catalysts of protein degradation or specifically as selective agents that control physiological processes (13). Additionally, these enzymes can disrupt mucosal barriers and modulate the host immune resp...

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Enterococcus faecalis Metalloprotease Compromises Epithelial Barrier and Contributes to Intestinal Inflammation

Cited by 256 publications

References 45 publications

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

The distinct roles of MMP-2 and MMP-9 in acute DSS colitis

The incongruent gelatinase genotype and phenotype in Enterococcus faecalis are due to shutting off the ability to respond to the gelatinase biosynthesis-activating pheromone (GBAP) quorum-sensing signal

Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2

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