FXR modulates the gut-vascular barrier by regulating the entry sites for bacterial translocation in experimental cirrhosis.
Animals
Bacterial Translocation
/ drug effects
Bile Acids and Salts
/ metabolism
Capillary Permeability
/ drug effects
Dextrans
/ pharmacokinetics
Disease Models, Animal
Escherichia coli
/ isolation & purification
Gastrointestinal Microbiome
/ physiology
Hypertension, Portal
/ metabolism
Intestinal Mucosa
/ drug effects
Liver Cirrhosis, Experimental
/ metabolism
Mice
Receptors, Cytoplasmic and Nuclear
/ agonists
FXR
Gut-liver axis
Gut-vascular barrier
Intestinal permeability
Liver cirrhosis
Mucus
Portal hypertension
Journal
Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
14
12
2018
revised:
26
05
2019
accepted:
19
06
2019
pubmed:
12
7
2019
medline:
20
3
2021
entrez:
12
7
2019
Statut:
ppublish
Résumé
Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria. Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route. For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis.
Sections du résumé
BACKGROUND & AIMS
Pathological bacterial translocation (PBT) in cirrhosis is the hallmark of spontaneous bacterial infections, increasing mortality several-fold. Increased intestinal permeability is known to contribute to PBT in cirrhosis, although the role of the mucus layer has not been addressed in detail. A clear route of translocation for luminal intestinal bacteria is yet to be defined, but we hypothesize that the recently described gut-vascular barrier (GVB) is impaired in experimental portal hypertension, leading to increased accessibility of the vascular compartment for translocating bacteria.
MATERIALS
Cirrhosis was induced in mouse models using bile-duct ligation (BDL) and CCl
RESULTS
Healthy and pre-hepatic portal-hypertensive (PPVL) mice lack translocation of FITC-dextran and GFP-E. coli from the small intestine to the liver, whereas BDL and CCl
CONCLUSIONS
Cirrhosis, but not portal hypertension per se, grossly impairs the endothelial and muco-epithelial barriers, promoting PBT to the portal-venous circulation. Both barriers appear to be FXR-modulated, with FXR-agonists reducing PBT via the portal-venous route.
LAY SUMMARY
For intestinal bacteria to enter the systemic circulation, they must cross the mucus and epithelial layer, as well as the gut-vascular barrier. Cirrhosis disrupts all 3 of these barriers, giving bacteria access to the portal-venous circulation and thus, the gut-liver axis. Diminished luminal bile acid availability, cirrhosis and the associated reduction in farnesoid x receptor (FXR) signaling seem, at least partly, to mediate these changes, as FXR-agonists reduce bacterial translocation via the portal-venous route to the liver in cirrhosis.
Identifiants
pubmed: 31295531
pii: S0168-8278(19)30389-7
doi: 10.1016/j.jhep.2019.06.017
pii:
doi:
Substances chimiques
Bile Acids and Salts
0
Dextrans
0
Receptors, Cytoplasmic and Nuclear
0
farnesoid X-activated receptor
0C5V0MRU6P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1126-1140Informations de copyright
Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.