Cargando…

Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition

BACKGROUND AND AIMS: The aetiology of Crohn’s disease is poorly understood. By investigating twin pairs discordant for Crohn’s disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barr...

Descripción completa

Detalles Bibliográficos
Autores principales: Keita, Åsa V, Lindqvist, Carl Mårten, Öst, Åke, Magana, Carlos D L, Schoultz, Ida, Halfvarson, Jonas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225972/
https://www.ncbi.nlm.nih.gov/pubmed/29659773
http://dx.doi.org/10.1093/ecco-jcc/jjy045
_version_ 1783369884279767040
author Keita, Åsa V
Lindqvist, Carl Mårten
Öst, Åke
Magana, Carlos D L
Schoultz, Ida
Halfvarson, Jonas
author_facet Keita, Åsa V
Lindqvist, Carl Mårten
Öst, Åke
Magana, Carlos D L
Schoultz, Ida
Halfvarson, Jonas
author_sort Keita, Åsa V
collection PubMed
description BACKGROUND AND AIMS: The aetiology of Crohn’s disease is poorly understood. By investigating twin pairs discordant for Crohn’s disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. METHODS: Ileal biopsies from 15 twin pairs discordant for Crohn’s disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to (51)Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. RESULTS: Healthy co-twins and affected twins displayed increased (51)Cr-EDTA permeability at 120 min, both with acetylsalicylic acid [p < 0.001] and without [p < 0.001] when compared with controls. A significant increase in (51)Cr-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p≤0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p < 0.05] and affected twins [p < 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohn’s disease twins [p < 0.05]. CONCLUSION: Our results suggest that barrier dysfunction is a primary defect in Crohn’s disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect.
format Online
Article
Text
id pubmed-6225972
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Oxford University Press
record_format MEDLINE/PubMed
spelling pubmed-62259722018-11-14 Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition Keita, Åsa V Lindqvist, Carl Mårten Öst, Åke Magana, Carlos D L Schoultz, Ida Halfvarson, Jonas J Crohns Colitis Original Articles BACKGROUND AND AIMS: The aetiology of Crohn’s disease is poorly understood. By investigating twin pairs discordant for Crohn’s disease, we aimed to assess whether the dysregulated barrier represents a cause or a consequence of inflammation and to evaluate the impact of genetic predisposition on barrier function. METHODS: Ileal biopsies from 15 twin pairs discordant for Crohn’s disease [monozygotic n = 9, dizygotic n = 6] and 10 external controls were mounted in Ussing chambers to assess paracellular permeability to (51)Chromium [Cr]-EDTA and trancellular passage to non-pathogenic E. coli K-12. Experiments were performed with and without provocation with acetylsalicylic acid. Immunofluorescence and ELISA were used to quantify the expression level of tight junction proteins. RESULTS: Healthy co-twins and affected twins displayed increased (51)Cr-EDTA permeability at 120 min, both with acetylsalicylic acid [p < 0.001] and without [p < 0.001] when compared with controls. A significant increase in (51)Cr-EDTA flux was already seen at 20 min in healthy monozygotic co-twins compared with controls [p≤0.05] when stratified by zygosity, but not in healthy dizygotic co-twins. No difference in E. coli passage was observed between groups. Immunofluorescence of the tight junction proteins claudin-5 and tricellulin showed lower levels in healthy co-twins [p < 0.05] and affected twins [p < 0.05] compared with external controls, while ELISA only showed lower tricellulin in Crohn’s disease twins [p < 0.05]. CONCLUSION: Our results suggest that barrier dysfunction is a primary defect in Crohn’s disease, since changes were predominantly seen in healthy monozygotic co-twins. Passage of E. coli seems to be a consequence of inflammation, rather than representing a primary defect. Oxford University Press 2018-11 2018-04-12 /pmc/articles/PMC6225972/ /pubmed/29659773 http://dx.doi.org/10.1093/ecco-jcc/jjy045 Text en © European Crohn’s and Colitis Organisation (ECCO) 2018. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Original Articles
Keita, Åsa V
Lindqvist, Carl Mårten
Öst, Åke
Magana, Carlos D L
Schoultz, Ida
Halfvarson, Jonas
Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition
title Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition
title_full Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition
title_fullStr Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition
title_full_unstemmed Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition
title_short Gut Barrier Dysfunction—A Primary Defect in Twins with Crohn’s Disease Predominantly Caused by Genetic Predisposition
title_sort gut barrier dysfunction—a primary defect in twins with crohn’s disease predominantly caused by genetic predisposition
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225972/
https://www.ncbi.nlm.nih.gov/pubmed/29659773
http://dx.doi.org/10.1093/ecco-jcc/jjy045
work_keys_str_mv AT keitaasav gutbarrierdysfunctionaprimarydefectintwinswithcrohnsdiseasepredominantlycausedbygeneticpredisposition
AT lindqvistcarlmarten gutbarrierdysfunctionaprimarydefectintwinswithcrohnsdiseasepredominantlycausedbygeneticpredisposition
AT ostake gutbarrierdysfunctionaprimarydefectintwinswithcrohnsdiseasepredominantlycausedbygeneticpredisposition
AT maganacarlosdl gutbarrierdysfunctionaprimarydefectintwinswithcrohnsdiseasepredominantlycausedbygeneticpredisposition
AT schoultzida gutbarrierdysfunctionaprimarydefectintwinswithcrohnsdiseasepredominantlycausedbygeneticpredisposition
AT halfvarsonjonas gutbarrierdysfunctionaprimarydefectintwinswithcrohnsdiseasepredominantlycausedbygeneticpredisposition