Cited by 72Alcohol Consumption and Health EffectsGastrointestinal motility and disordersBarrier Structure and Function Studies

Ethanol disrupts intestinal epithelial tight junction integrity through intracellular calcium-mediated Rho/ROCK activation

Elamin, Elhaseen, Masclee, Ad, Dekker, Jan, Jonkers, Daisy·2014·American Journal of Physiology-Gastrointestinal and Liver Physiology

Abstract

Evidence indicates that ethanol-induced intestinal barrier dysfunction and subsequent endotoxemia plays a key role in the pathogenesis of alcoholic liver disease. Recently, it has been demonstrated that ethanol induces RhoA kinase activation in intestinal epithelium, thereby disrupting barrier integrity. In this study, the role of a rise in intracellular calcium concentration ([Ca 2+]i) in ethanol-induced Rho-associated coiled coil-forming kinase (Rho/ROCK) activation and barrier disruption was investigated in Caco-2 cell monolayers. Treatment of Caco-2 monolayers with 40 mmol/l ethanol induced [Ca 2+]i release as indicated by increased relative fluorescent units of Fluo-3 from 0.06 ± 0.02 to 2.27 ± 1.96 ( P < 0.0001). Pretreatment with 1,2-bis(2-aminophenoxy) ethane- N,N,N′,N′-tetraacetic acid (BAPTA-AM) completely inhibited the release, whereas the inositol 1,4,5-triphosphate receptor (IP 3 R)-antagonist, Xestospongin C, partially inhibited the ethanol-induced [Ca 2+]i release (from 2.27 ± 1.96 to 0.03 ± 0.01; P < 0.0001 and from 2.27 ± 1.96 to 1.19 ± 1.80; P < 0.001, respectively). The rise in [Ca 2+]i was paralleled with increased intestinal permeability, which could be attenuated by either BAPTA-AM or Xestospongin C. Furthermore, ethanol induced Rho/ROCK activation, as indicated by increased phosphorylation of myosin-binding subunit, which could be prevented either by BAPTA, Xestospongin C, or the specific Rho/ROCK inhibitor Y27632. Finally, inhibition of Rho/ROCK kinase by Y27632 ameliorated the ethanol-induced redistribution of zonula occluden-1, adherens junction proteins including E-cadherin and β-catenin, and also disorganization of F-actin. These findings suggest that ethanol-induced [Ca 2+]i release, mediated by stimulating IP 3 R-gated Ca 2+channel, activates Rho/ROCK in Caco-2 cells, thereby contributing to ethanol-induced intestinal barrier dysfunction.

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Crossref · 10.1152/ajpgi.00236.2013

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  • Endotoxemia may occur secondary to increased intestinal permeability resulting from extreme physiologic stress, ethanol exposure, or a Western diet high in carbohydrate and saturated fat.

    “and secondary to increased intestinal permeability resulting from extreme physiologic stress,32 ethanol exposure,33 or a “fast-food style” Western diet, high in both carbohydrate and saturated fat.34”

    From The Gut Microbiome and the Brain (2014) · cites this paper as [33]

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Authors
Elamin, E., Masclee, A., Dekker, J., & Jonkers, D.
Affiliations
  • Maastricht University Medical Centre (NL)
  • TiFN (NL)
Corresponding author
Elamin, Elhaseen
Venue
American Journal of Physiology-Gastrointestinal and Liver Physiology
Published
2014-04-15
Volume
306
Issue
8
Pages
G677-G685
ISSN
  • 0193-1857 (ISSN-L)
  • 1522-1547
OpenAlex
W2021779148
Cited by
72
References
64
Citations by year
2026: 2 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 6 · 2021: 5 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 13 · 2014: 4
FWCI
7.18
Type
journal article
Language
en
Open access
closed
Locations
  • American Journal of Physiology-Gastrointestinal and Liver Physiology (publishedVersion)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (submittedVersion)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
ethanol, intestinal barrier dysfunction, tight junction integrity, intracellular calcium, Rho kinase, IP3 receptor, intestinal permeability, zonula occludens-1, E-cadherin, β-catenin, F-actin, Caco-2 cell monolayers, alcoholic liver disease, endotoxemia, BAPTA
MeSH terms
Ethanol, Calcium, Cells, Cultured, Chelating Agents, Egtazic Acid, Humans, Intestinal Mucosa, Liver Diseases, Alcoholic, Permeability, Phosphorylation, Solvents, Caco-2 Cells, Tight Junctions, rho-Associated Kinases

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