Role of defective methylation reactions in ethanol-induced dysregulation of intestinal barrier integrity

Paul G Thomes, Natalia A Osna, Sarah M. Bligh, Dean J. Tuma, Kusum Kharbanda

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Alcoholic liver disease (ALD) is a major healthcare challenge worldwide. Emerging evidence reveals that ethanol administration disrupts the intestinal epithelial tight junction (TJ) complex; this defect allows for the paracellular translocation of gut-derived pathogenic molecules to reach the liver to cause inflammation and progressive liver injury. We have previously demonstrated a causative role of impairments in liver transmethylation reactions in the pathogenesis of ALD. We have further shown that treatment with betaine, a methylation agent that normalizes liver methylation potential, can attenuate ethanol-induced liver injury. Herein, we explored whether alterations in methylation reactions play a causative role in disrupting intestinal mucosal barrier function by employing an intestinal epithelial cell line. Monolayers of Caco-2 cells were exposed to ethanol or a-pan methylation reaction inhibitor, tubercidin, in the presence and absence of betaine. The structural and functional integrity of intestinal epithelial barrier was then examined. We observed that exposure to either ethanol or tubercidin disrupted TJ integrity and function by decreasing the localization of TJ protein occludin-1 to the intracellular junctions, reducing transepithelial electrical resistance and increasing dextran influx. All these detrimental effects of ethanol and tubercidin were attenuated by co-treatment with betaine. We further show that the mechanism of betaine protection was through BHMT-mediated catalysis. Collectively, our data suggest a novel mechanism for alcohol-induced gut leakiness and identifies the importance of normal methylation reactions in maintaining TJ integrity. We also propose betaine as a potential therapeutic option for leaky gut in alcohol-consuming patients who are at the risk of developing ALD.

Original languageEnglish (US)
JournalBiochemical Pharmacology
Volume96
Issue number1
DOIs
StatePublished - Mar 17 2015

Fingerprint

Betaine
Methylation
Liver
Tubercidin
Ethanol
Alcoholic Liver Diseases
Tight Junctions
Zonula Occludens-1 Protein
Alcohols
Occludin
Caco-2 Cells
Wounds and Injuries
Dextrans
Catalysis
Electric Impedance
Tight Junction Proteins
Therapeutics
Epithelial Cells
Acoustic impedance
Inflammation

Keywords

  • Betaine
  • Caco-2
  • Ethanol
  • Methylation
  • Occludin-1
  • Tubercidin

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

Cite this

Role of defective methylation reactions in ethanol-induced dysregulation of intestinal barrier integrity. / Thomes, Paul G; Osna, Natalia A; Bligh, Sarah M.; Tuma, Dean J.; Kharbanda, Kusum.

In: Biochemical Pharmacology, Vol. 96, No. 1, 17.03.2015.

Research output: Contribution to journalArticle

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