ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice

Abstract

Background Acetaldehyde, the toxic ethanol metabolite, disrupts intestinal epithelial barrier function. Aldehyde dehydrogenase (ALDH) detoxifies acetaldehyde into acetate. Sub populations of Asians and Native Americans show polymorphism with loss of function mutations in ALDH2. We evaluated the effect of ALDH2 deficiency on ethanol-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 (1–6%) in Lieber-DeCarli diet for 4 weeks. Gut permeability in vivo measured by plasma-to-luminal flux of FITC-inulin, tight junction and adherens junction integrity analyzed by confocal microscopy and liver injury was assessed by analysis of plasma transaminase activity, histopathology and liver triglyceride. Results Ethanol feeding elevated colonic mucosal acetaldehyde, which was significantly greater in ALDH2 deficient mice. ALDH2−/− mice showed a drastic reduction in the ethanol diet intake. Therefore, this study was continued only in wild type and ALDH2+/− mice. Ethanol feeding elevated mucosal inulin permeability in distal colon, but not in proximal colon, ileum or jejunum of wild type mice. In ALDH2+/− mice, ethanol-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, ethanol 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 ethanol-induced liver damage was significantly greater in ALDH2+/− mice compared to wild type mice. Conclusion These data demonstrate that ALDH2 deficiency enhances ethanol-induced disruption of intestinal epithelial tight junctions, barrier dysfunction and liver damage.

Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice

“…Chronic ethanol feeding did not significantly affect body weight gain during the experimental period in wild type mice, which is different from previous studies showing a decline in body weight gain by ethanol feeding in mice [25]. Previous studies were performed in mice of C57BL/6 background.…”

“…These findings suggest that occludin deficiency elevates susceptibility of mice for alcohol-induced gut barrier dysfunction. Consistent with our recent studies [25, 26] colon is the primary target of ethanol-induced barrier dysfunction, while ileum is resistant to ethanol. However, studies by other laboratories have shown that chronic ethanol feeding increases permeability in the ileum [21, 33].…”

“…Inulin is a non-toxic, extracellular marker that is extensively used in the clinic due to its metabolically inert nature. It is also evident from our past studies that inulin permeability and TJ disruption, as assessed by confocal microscopy, corroborate well with each another [3, 6, 25, 26, 29]. …”

“…In all experiments animals were maintained in pairs to facilitate body temperature maintenance. The ethanol-feeding model used in this study is the same as the one previously used by others [21] and us [25, 26]. Ethanol concentration at 6% corresponds to 32% dietary calorie, which is in the range of ethanol-derived calorie consumption by alcoholics.…”

Targeting the gut barrier for the treatment of alcoholic liver disease

“…97 Our previous work showed that orally administered LPS can be detected in the plasma of alcohol-intoxicated mice but not in the control mice, 76 which provides direct evidence indicating that alcohol increases gut permeability to endotoxin. Gut permeability assays have shown that alcohol intoxication increases permeability of the duodenum, 99 ileum, 70 proximal colon 100,101 and distal colon 101 to macromolecules.…”