Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation

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

doi:10.1053/j.gastro.2011.05.035

Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation

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

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234 Scopus citations

Abstract

Background & Aims: 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-10deficient (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 04) 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.

Original language	English
Pages (from-to)	959-971
Number of pages	13
Journal	Gastroenterology
Volume	141
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2011.05.035
State	Published - Sep 2011

Keywords

Bacteria-Host Interactions
Bacterial Protease
IBD
Intestinal Barrier Function

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10.1053/j.gastro.2011.05.035

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Steck, N., Hoffmann, M., Sava, I. G., Kim, S. C., Hahne, H., Tonkonogy, S. L., Mair, K., Krueger, D., Pruteanu, M., Shanahan, F., Vogelmann, R., Schemann, M., Kuster, B., Sartor, R. B., & Haller, D. (2011). Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation. Gastroenterology, 141(3), 959-971. https://doi.org/10.1053/j.gastro.2011.05.035

@article{d54c3eac8ac14207b9a5413b93c4a857,

title = "Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation",

abstract = "Background & Aims: 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-10deficient (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 TNFΔARE/Wt mice. GelE specificity was shown with the MMP inhibitor marimastat. Results: Histologic analysis (score 04) 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 TNFΔARE/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 TNFΔARE/Wt mice) by impairing epithelial barrier integrity.",

keywords = "Bacteria-Host Interactions, Bacterial Protease, IBD, Intestinal Barrier Function",

author = "Natalie Steck and Micha Hoffmann and Sava, {Irina G.} and Kim, {Sandra C.} and Hannes Hahne and Tonkonogy, {Susan L.} and Katrin Mair and Dagmar Krueger and Mihaela Pruteanu and Fergus Shanahan and Roger Vogelmann and Michael Schemann and Bernhard Kuster and Sartor, {R. Balfor} and Dirk Haller",

year = "2011",

month = sep,

doi = "10.1053/j.gastro.2011.05.035",

language = "English",

volume = "141",

pages = "959--971",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

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Steck, N, Hoffmann, M, Sava, IG, Kim, SC, Hahne, H, Tonkonogy, SL, Mair, K, Krueger, D, Pruteanu, M, Shanahan, F, Vogelmann, R, Schemann, M , Kuster, B, Sartor, RB & Haller, D 2011, 'Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation', Gastroenterology, vol. 141, no. 3, pp. 959-971. https://doi.org/10.1053/j.gastro.2011.05.035

TY - JOUR

T1 - Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation

AU - Steck, Natalie

AU - Hoffmann, Micha

AU - Sava, Irina G.

AU - Kim, Sandra C.

AU - Hahne, Hannes

AU - Tonkonogy, Susan L.

AU - Mair, Katrin

AU - Krueger, Dagmar

AU - Pruteanu, Mihaela

AU - Shanahan, Fergus

AU - Vogelmann, Roger

AU - Schemann, Michael

AU - Kuster, Bernhard

AU - Sartor, R. Balfor

AU - Haller, Dirk

PY - 2011/9

Y1 - 2011/9

N2 - Background & Aims: 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-10deficient (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 TNFΔARE/Wt mice. GelE specificity was shown with the MMP inhibitor marimastat. Results: Histologic analysis (score 04) 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 TNFΔARE/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 TNFΔARE/Wt mice) by impairing epithelial barrier integrity.

AB - Background & Aims: 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-10deficient (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 TNFΔARE/Wt mice. GelE specificity was shown with the MMP inhibitor marimastat. Results: Histologic analysis (score 04) 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 TNFΔARE/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 TNFΔARE/Wt mice) by impairing epithelial barrier integrity.

KW - Bacteria-Host Interactions

KW - Bacterial Protease

KW - IBD

KW - Intestinal Barrier Function

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U2 - 10.1053/j.gastro.2011.05.035

DO - 10.1053/j.gastro.2011.05.035

M3 - Article

AN - SCOPUS:80052130713

SN - 0016-5085

VL - 141

SP - 959

EP - 971

JO - Gastroenterology

JF - Gastroenterology

IS - 3

ER -

Enterococcus faecalis metalloprotease compromises epithelial barrier and contributes to intestinal inflammation

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