Abstract
BackgroundEthanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders.AimSince 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.MethodsIntestinal 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.ResultsEthanol increased small and large intestinal permeability, paralleled by redistribution of ZO-1 and occludin, down-regulation 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.ConclusionsAdministration 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 RegistrationClinicalTrials.gov NCT00928733
Highlights
Ethanol consumption is associated with several gastrointestinal (GI) and liver disorders, especially alcoholic liver disease (ALD) [1]
The data indicate a pivotal role for mitogen activated protein kinase (MAPK) and its crosstalk with myosin light chain kinase (MLCK) in ethanol-induced intestinal barrier disruption
Ethanol and fatty acid ethyl esters (FAEEs) Blood samples collected prior to the intervention were negative for ethanol (i.e. ,10 mg/dl plasma) and FAEEs
Summary
Ethanol (ethyl alcohol) consumption is associated with several gastrointestinal (GI) and liver disorders, especially alcoholic liver disease (ALD) [1]. ALD is a progressive disease initiated by steatosis and inflammation, followed by liver fibrosis and cirrhosis [2]. Ethanol is known to disrupt GI epithelial barrier integrity [5], resulting in translocation of potentially harmful bacteria and their products such as endotoxins [6] and peptidoglycans [7] into the portal circulation and liver injury. Dysfunction of GI mucosal barrier may result in increased susceptibility to infections [8] and to development of ethanol-related GI cancers [9]. Ethanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders
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