title: Ethanol impairs intestinal barrier function in humans through mitogen activated protein kinase signaling: a combined in vivo and in vitro approach.
abstract: BACKGROUND
  Ethanol-induced gut barrier disruption is associated with several gastrointestinal and liver disorders.
  
  
  OBJECTIVE
  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, 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.
  
  
  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.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00928733.
authors.affiliation: Top Institute Food and Nutrition (TIFN), Wageningen, the Netherlands; Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Elhaseen
authors.initials: E
authors.lastname: Elamin
authors.affiliation: Top Institute Food and Nutrition (TIFN), Wageningen, the Netherlands; Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Ad
authors.initials: A
authors.lastname: Masclee
authors.affiliation: Top Institute Food and Nutrition (TIFN), Wageningen, the Netherlands; Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Freddy
authors.initials: F
authors.lastname: Troost
authors.affiliation: Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Harm-Jan
authors.initials: HJ
authors.lastname: Pieters
authors.affiliation: Top Institute Food and Nutrition (TIFN), Wageningen, the Netherlands; Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Daniel
authors.initials: D
authors.lastname: Keszthelyi
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Canada.
authors.forename: Katarina
authors.initials: K
authors.lastname: Aleksa
authors.affiliation: Top Institute Food and Nutrition (TIFN), Wageningen, the Netherlands; Host microbe interactomics, Department of Animal Sciences, Wageningen University, Wageningen, the Netherlands.
authors.forename: Jan
authors.initials: J
authors.lastname: Dekker
authors.affiliation: Top Institute Food and Nutrition (TIFN), Wageningen, the Netherlands; Division Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
authors.forename: Daisy
authors.initials: D
authors.lastname: Jonkers
mesh_terms: D000199:Actins / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002460:Cell Line; D004789:Enzyme Activation; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D005227:Fatty Acids / Q000378:metabolism; D064368:Healthy Volunteers; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010539:Permeability; D010766:Phosphorylation; D020033:Protein Isoforms; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects*; D062725:Tight Junction Proteins / Q000378:metabolism; D055815:Young Adult
chemical_list: D000199:Actins; D005227:Fatty Acids; D020033:Protein Isoforms; D062725:Tight Junction Proteins; D000431:Ethanol; D020928:Mitogen-Activated Protein Kinases