BACKGROUND: Acetaldehyde, the toxic ethanol (EtOH) metabolite, disrupts 
intestinal epithelial barrier function. Aldehyde dehydrogenase (ALDH) detoxifies 
acetaldehyde into acetate. Subpopulations of Asians and Native Americans show 
polymorphism with loss-of-function mutations in ALDH2. We evaluated the effect 
of ALDH2 deficiency on EtOH-induced disruption of intestinal epithelial tight 
junctions and adherens junctions, gut barrier dysfunction, and liver injury.
METHODS: Wild-type and ALDH2-deficient mice were fed EtOH (1 to 6%) in 
Lieber-DeCarli diet for 4 weeks. Gut permeability in vivo was measured by 
plasma-to-luminal flux of FITC-inulin, tight junction and adherens junction 
integrity was analyzed by confocal microscopy, and liver injury was assessed by 
the analysis of plasma transaminase activity, histopathology, and liver 
triglyceride.
RESULTS: EtOH feeding elevated colonic mucosal acetaldehyde, which was 
significantly greater in ALDH2-deficient mice. ALDH2(-/-) mice showed a drastic 
reduction in the EtOH diet intake. Therefore, this study was continued only in 
wild-type and ALDH2(+/-) mice. EtOH feeding elevated mucosal inulin permeability 
in distal colon, but not in proximal colon, ileum, or jejunum of wild-type mice. 
In ALDH2(+/-) mice, EtOH-induced inulin permeability in distal colon was not 
only higher than that in wild-type mice, but inulin permeability was also 
elevated in the proximal colon, ileum, and jejunum. Greater inulin permeability 
in distal colon of ALDH2(+/-) mice was associated with a more severe 
redistribution of tight junction and adherens junction proteins from the 
intercellular junctions. In ALDH2(+/-) mice, but not in wild-type mice, EtOH 
feeding caused a loss of junctional distribution of tight junction and adherens 
junction proteins in the ileum. Histopathology, plasma transaminases, and liver 
triglyceride analyses showed that EtOH-induced liver damage was significantly 
greater in ALDH2(+/-) mice compared to wild-type mice.
CONCLUSIONS: These data demonstrate that ALDH2 deficiency enhances EtOH-induced 
disruption of intestinal epithelial tight junctions, barrier dysfunction, and 
liver damage.