title: Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation.
abstract: OBJECTIVE
  Matrix metalloproteases (MMPs) mediate pathogenesis of chronic intestinal inflammation. We characterized the role of the gelatinase (GelE), a metalloprotease from Enterococcus faecalis, in the development of colitis in mice.
  
  
  METHODS
  Germ-free, interleukin-10-deficient (IL-10(-/-)) mice were monoassociated with the colitogenic E faecalis strain OG1RF and isogenic, GelE-mutant strains. Barrier function was determined by measuring E-cadherin expression, transepithelial electrical resistance (TER), and translocation of permeability markers in colonic epithelial cells and colon segments from IL-10(-/-) and TNF(ΔARE/Wt) mice. GelE specificity was shown with the MMP inhibitor marimastat.
  
  
  RESULTS
  Histologic analysis (score 0-4) of E faecalis monoassociated IL-10(-/-) mice revealed a significant reduction in colonic tissue inflammation in the absence of bacteria-derived GelE. We identified cleavage sites for GelE in the sequence of recombinant mouse E-cadherin, indicating that it might be degraded by GelE. Experiments with Ussing chambers and purified GelE revealed the loss of barrier function and extracellular E-cadherin in mice susceptible to intestinal inflammation (IL-10(-/-) and TNF(ΔARE/Wt) mice) before inflammation developed. Colonic epithelial cells had reduced TER and increased translocation of permeability markers after stimulation with GelE from OG1RF or strains of E faecalis isolated from patients with Crohn's disease and ulcerative colitis.
  
  
  CONCLUSIONS
  The metalloprotease GelE, produced by commensal strains of E faecalis, contributes to development of chronic intestinal inflammation in mice that are susceptible to intestinal inflammation (IL-10(-/-) and TNF(ΔARE/Wt) mice) by impairing epithelial barrier integrity.
authors.affiliation: Chair for Biofunctionality, ZIEL-Research Center for Nutrition and Food Science, CDD Center for Diet and Disease, Technische Universität München, Freising-Weihenstephan, Germany.
authors.forename: Natalie
authors.initials: N
authors.lastname: Steck
authors.forename: Micha
authors.initials: M
authors.lastname: Hoffmann
authors.forename: Irina G
authors.initials: IG
authors.lastname: Sava
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Kim
authors.forename: Hannes
authors.initials: H
authors.lastname: Hahne
authors.forename: Susan L
authors.initials: SL
authors.lastname: Tonkonogy
authors.forename: Katrin
authors.initials: K
authors.lastname: Mair
authors.forename: Dagmar
authors.initials: D
authors.lastname: Krueger
authors.forename: Mihaela
authors.initials: M
authors.lastname: Pruteanu
authors.forename: Fergus
authors.initials: F
authors.lastname: Shanahan
authors.forename: Roger
authors.initials: R
authors.lastname: Vogelmann
authors.forename: Michael
authors.initials: M
authors.lastname: Schemann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Kuster
authors.forename: R Balfor
authors.initials: RB
authors.lastname: Sartor
authors.forename: Dirk
authors.initials: D
authors.lastname: Haller
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D015820:Cadherins / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000502:physiology*; D003092:Colitis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D013293:Enterococcus faecalis / Q000378:metabolism*; D018093:Gelatinases / Q000378:metabolism*; D016908:Gram-Positive Bacterial Infections / Q000150:complications / Q000378:metabolism / Q000503:physiopathology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism*; D045726:Metalloproteases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D015820:Cadherins; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D045726:Metalloproteases; D018093:Gelatinases