Search resultsEthanol impairs intestinal barrier function in humans through mitogen activated protein kinase signaling: A combined in vivo and in vitro approach
Title
Ethanol impairs intestinal barrier function in humans through mitogen activated protein kinase signaling: A combined in vivo and in vitro approach
Publication type
Journal Article
Year of Publication
2014
Authors
Journal
PLoS ONE
Volume
9
Issue
9
Date published
2014
ISBN
19326203 (ISSN)
Keywords
Adult, alcohol, alcohol consumption, article, CACO 2 cell line, controlled study, cysteine, down regulation, duodenum biopsy, enzyme activation, enzyme phosphorylation, F actin, gene expression, human, human cell, human experiment, human tissue, in vitro study, in vivo study, intestine mucosa permeability, large intestine, male, messenger RNA, mitogen activated protein kinase, mitogen activated protein kinase inhibitor, mitogen activated protein kinase p38, myosin light chain, myosin light chain kinase, normal human, occludin, protein function, protein localization, protein ZO1, signal transduction, small intestine, stress activated protein kinase, tight junction, tight junction protein, upregulation
Abstract
Background: Ethanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders. Aim: Since human data on effects of moderate ethanol consumption on intestinal barrier integrity and involved mechanisms are limited, the objectives of this study were to investigate effects of a single moderate ethanol dose on small and large intestinal permeability and to explore the role of mitogen activated protein kinase (MAPK) pathway as a primary signaling mechanism. Methods: Intestinal permeability was assessed in 12 healthy volunteers after intraduodenal administration of either placebo or 20 g ethanol in a randomised cross-over trial. Localization of the tight junction (TJ) and gene expression, phosphorylation of the MAPK isoforms p38, ERK and JNK as indicative of activation were analyzed in duodenal biopsies. The role of MAPK was further examined in vitro using Caco-2 monolayers. Results: Ethanol increased small and large intestinal permeability, paralleled by redistribution of ZO-1 and occludin, downregulation of ZO-1 and up-regulation of myosin light chain kinase (MLCK) mRNA expression, and increased MAPK isoforms phosphorylation. In Caco-2 monolayers, ethanol increased permeability, induced redistribution of the junctional proteins and F-actin, and MAPK and MLCK activation, as indicated by phosphorylation of MAPK isoforms and myosin light chain (MLC), respectively, which could be reversed by pretreatment with either MAPK inhibitors or the anti-oxidant L-cysteine. Conclusions: Administration of moderate ethanol dosage can increase both small and colon permeability. Furthermore, the data indicate a pivotal role for MAPK and its crosstalk with MLCK in ethanol-induced intestinal barrier disruption. Trial Registration: ClinicalTrials.gov NCT00928733.