Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype

Publication type:
Journal article
Metadata:
Autoren
  • Wolfgang Stremmel
  • Simone Staffer
  • Mathias Jochen Schneider
  • Hongying Gan-Schreier
  • Andreas Wannhoff
  • Nicole Stuhrmann
  • Annika Gauss
  • Hartwig Wolburg
  • Anne Mahringer
  • Alexander Swidsinski
  • Thomas Efferth
Autoren-URL
https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=fis-test-1&SrcAuth=WosAPI&KeyUT=WOS:000412211500012&DestLinkType=FullRecord&DestApp=WOS_CPL
DOI
10.1093/ecco-jcc/jjx075
eISSN
1876-4479
Externe Identifier
  • Clarivate Analytics Document Solution ID: FI7WX
  • PubMed Identifier: 28575164
ISSN
1873-9946
Ausgabe der Veröffentlichung
10
Zeitschrift
JOURNAL OF CROHNS & COLITIS
Schlüsselwörter
  • Mucosal barrier
  • mucus
  • phosphatidylcholine
  • hydrophobicity
  • ulcerative colitis
Paginierung
1247 - 1257
Datum der Veröffentlichung
2017
Status
Published
Titel
Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype
Sub types
  • Article
Ausgabe der Zeitschrift
11

Data source: Web of Science (Lite)

Other metadata sources:
Autoren
  • Wolfgang Stremmel
  • Simone Staffer
  • Mathias Jochen Schneider
  • Hongying Gan-Schreier
  • Andreas Wannhoff
  • Nicole Stuhrmann
  • Annika Gauss
  • Hartwig Wolburg
  • Anne Mahringer
  • Alexander Swidsinski
  • Thomas Efferth
DOI
10.1093/ecco-jcc/jjx075
eISSN
1876-4479
ISSN
1873-9946
Ausgabe der Veröffentlichung
10
Zeitschrift
Journal of Crohn's and Colitis
Sprache
en
Online publication date
2017
Paginierung
1247 - 1257
Datum der Veröffentlichung
2017
Status
Published
Herausgeber
Oxford University Press (OUP)
Herausgeber URL
http://dx.doi.org/10.1093/ecco-jcc/jjx075
Datum der Datenerfassung
2020
Titel
Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype
Ausgabe der Zeitschrift
11

Data source: Crossref

Abstract
<h4>Background and aims</h4>A key pathogenetic feature of ulcerative colitis [UC] is an intrinsic low mucus phosphatidylcholine[PC] content. Recently, a paracellular transport for PC across tight junctions[TJs] was described, suggesting TJ disturbance as a cause of diminished luminal PC transport. Therefore, we aimed to generate mutant mice with TJ deletion to evaluate whether a UC phenotype developed.<h4>Methods</h4>CL57BL/6 control wild-type mice were compared to mutant mice with tamoxifen-induced villin-Cre-dependent intestinal deletion of kindlin 1 and 2.<h4>Results</h4>Electron microscopy of mucosal biopsies obtained from both mutants before overt inflammation following only 2 days of tamoxifen exposure revealed a defective TJ morphology with extended paracellular space and, by light microscopy, expanded mucosal crypt lumina. PC secretion into mucus was reduced by >65% and the mucus PC content dropped by >50%, causing a >50 % decrease of mucus hydrophobicity in both mutants. Consequently, the microbiota was able to penetrate the submucosa. After 3 days of tamoxifen exposure, intestinal inflammation was present in both mutants, with loose bloody stools as well as macroscopic and histological features of colitis. Oral PC supplementation was able to suppress inflammation. By analogy, colonic biopsies obtained from patients with UC in remission also showed a defective epithelium with widened intercellular clefts, and enlarged crypt luminal diameters with functionally impaired luminal PC secretion.<h4>Conclusions</h4>Genetic mouse models with intestinal deletion of kindlin 1 and 2 resulted in TJ deletion and revealed pathophysiological features of impaired PC secretion to the mucus leading to mucosal inflammation compatible with human UC.
Addresses
  • Department of Internal Medicine IV, University Clinics of Heidelberg, Heidelberg, Germany.
Autoren
  • Wolfgang Stremmel
  • Simone Staffer
  • Mathias Jochen Schneider
  • Hongying Gan-Schreier
  • Andreas Wannhoff
  • Nicole Stuhrmann
  • Annika Gauss
  • Hartwig Wolburg
  • Anne Mahringer
  • Alexander Swidsinski
  • Thomas Efferth
  • Thomas Efferth
DOI
10.1093/ecco-jcc/jjx075
eISSN
1876-4479
Externe Identifier
  • PubMed Identifier: 28575164
  • PubMed Central ID: PMC5881657
Open access
true
ISSN
1873-9946
Ausgabe der Veröffentlichung
10
Zeitschrift
Journal of Crohn's & colitis
Schlüsselwörter
  • Tight Junctions
  • Animals
  • Mice, Inbred C57BL
  • Mice
  • Colitis, Ulcerative
  • Disease Models, Animal
  • Carrier Proteins
  • Muscle Proteins
  • Cytoskeletal Proteins
  • Sequence Deletion
  • Phenotype
  • Models, Genetic
  • Male
Sprache
eng
Medium
Print
Open access status
Open Access
Paginierung
1247 - 1257
Datum der Veröffentlichung
2017
Status
Published
Publisher licence
CC BY-NC
Datum der Datenerfassung
2017
Titel
Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype.
Sub types
  • research-article
  • Journal Article
Ausgabe der Zeitschrift
11

Files

https://academic.oup.com/ecco-jcc/article-pdf/11/10/1247/24365244/jjx075.pdf https://europepmc.org/articles/PMC5881657?pdf=render

Data source: Europe PubMed Central

Abstract
BACKGROUND AND AIMS: A key pathogenetic feature of ulcerative colitis [UC] is an intrinsic low mucus phosphatidylcholine[PC] content. Recently, a paracellular transport for PC across tight junctions[TJs] was described, suggesting TJ disturbance as a cause of diminished luminal PC transport. Therefore, we aimed to generate mutant mice with TJ deletion to evaluate whether a UC phenotype developed. METHODS: CL57BL/6 control wild-type mice were compared to mutant mice with tamoxifen-induced villin-Cre-dependent intestinal deletion of kindlin 1 and 2. RESULTS: Electron microscopy of mucosal biopsies obtained from both mutants before overt inflammation following only 2 days of tamoxifen exposure revealed a defective TJ morphology with extended paracellular space and, by light microscopy, expanded mucosal crypt lumina. PC secretion into mucus was reduced by >65% and the mucus PC content dropped by >50%, causing a >50 % decrease of mucus hydrophobicity in both mutants. Consequently, the microbiota was able to penetrate the submucosa. After 3 days of tamoxifen exposure, intestinal inflammation was present in both mutants, with loose bloody stools as well as macroscopic and histological features of colitis. Oral PC supplementation was able to suppress inflammation. By analogy, colonic biopsies obtained from patients with UC in remission also showed a defective epithelium with widened intercellular clefts, and enlarged crypt luminal diameters with functionally impaired luminal PC secretion. CONCLUSIONS: Genetic mouse models with intestinal deletion of kindlin 1 and 2 resulted in TJ deletion and revealed pathophysiological features of impaired PC secretion to the mucus leading to mucosal inflammation compatible with human UC.
Date of acceptance
2017
Autoren
  • Wolfgang Stremmel
  • Simone Staffer
  • Mathias Jochen Schneider
  • Hongying Gan-Schreier
  • Andreas Wannhoff
  • Nicole Stuhrmann
  • Annika Gauss
  • Hartwig Wolburg
  • Anne Mahringer
  • Alexander Swidsinski
  • Thomas Efferth
Autoren-URL
https://www.ncbi.nlm.nih.gov/pubmed/28575164
DOI
10.1093/ecco-jcc/jjx075
eISSN
1876-4479
Externe Identifier
  • PubMed Central ID: PMC5881657
Ausgabe der Veröffentlichung
10
Zeitschrift
J Crohns Colitis
Schlüsselwörter
  • Mucosal barrier
  • hydrophobicity
  • mucus
  • phosphatidylcholine
  • ulcerative colitis
  • Animals
  • Carrier Proteins
  • Colitis, Ulcerative
  • Cytoskeletal Proteins
  • Disease Models, Animal
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Muscle Proteins
  • Phenotype
  • Sequence Deletion
  • Tight Junctions
Sprache
eng
Country
England
Paginierung
1247 - 1257
PII
3855757
Datum der Veröffentlichung
2017
Status
Published
Datum, an dem der Datensatz öffentlich gemacht wurde
2018
Titel
Genetic Mouse Models with Intestinal-Specific Tight Junction Deletion Resemble an Ulcerative Colitis Phenotype.
Sub types
  • Journal Article
Ausgabe der Zeitschrift
11

Data source: PubMed

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