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. 2015 Aug;39(8):1465-75.
doi: 10.1111/acer.12777. Epub 2015 Jul 14.

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

Kamaljit K Chaudhry  1 , Geetha Samak  1 , Pradeep K Shukla  1 , Hina Mir  1 , Ruchika Gangwar  1 , Bhargavi Manda  1 , Toyohi Isse  2 , Toshihiro Kawamoto  2 , Mikko Salaspuro  3 , Pertti Kaihovaara  3 , Paula Dietrich  1 , Ioannis Dragatsis  1 , Laura E Nagy  4 , Radha Krishna Rao  1
Affiliations

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

Kamaljit K Chaudhry et al. Alcohol Clin Exp Res. 2015 Aug.

Abstract

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.

Keywords: Acetaldehyde; Adherens Junction; Alcohol; Gut Permeability; Tight Junction.

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Figures

Fig. 1
Fig. 1. ALDH2 deficient mice accumulate higher level of acetaldehyde in colonic mucosa
Wild type (WT), ALDH2+/− (HT) and ALDH2−/− (KO) mice were fed Lieber-DeCarli liquid diet with (black bars) or without (gray bars) 4% ethanol as described in the Methods section. After 3 days with 4% ethanol feeding, animals were fasted overnight followed by ad libitum feeding of 5% ethanol diet for two hours. Diet intake (A) and plasma ethanol concentration (B) were measured during the last 2 hours of feeding immediately after overnight fasting. Acetaldehyde levels in colonic mucosal extract (C) and colonic luminal contents (D) were estimated. Values are mean ± SE (n = 6). Asterisks indicate the values that are significantly (p<0.05) different from corresponding control values, and hash tags indicate values that are significantly (p<0.05) different from corresponding WT values.
Fig. 2
Fig. 2. ALDH2 deficiency promotes ethanol-induced increase in intestinal permeability in mice
A–E: Wild type and ALDH2+/− mice were fed with Lieber-DeCarli liquid diet with (black bars) or without (gray bars) ethanol (up to 6% as described in the Methods section). Intestinal mucosal barrier function was evaluated by measuring plasma-to-lumen flux of FITC-inulin in distal colon (A), proximal colon (B), ileum (C), jejunum (D) and duodenum (E) as described in Methods section. Values are mean ± SE (n = 8). Asterisks indicate the values that are significantly (p<0.05) different from corresponding values for non-ethanol group, and hash tags indicate the values that are significantly (p<0.05) different from corresponding values for wild type group. F: Inulin permeability in duodenum (D), jejunum (J), ileum (I), proximal colon (PC) and distal colon (DC) was calculated as fold change by dividing values for ethanol group by corresponding values for non-ethanol groups.
Fig. 3
Fig. 3. Ethanol-induced disruption of tight junctions in distal colon is more severe in ALDH2 deficient mice
Wild type and ALDH2+/− mice were fed Lieber-DeCarli liquid diet with or without ethanol (up to 6% as described in the Methods section). Cryosections of distal colon were stained for occludin (green) and ZO-1 (red) by immunofluorescence method. Images collected by confocal microscopy. These are the representative images from at least 4 different mice.
Fig. 4
Fig. 4. Ethanol-induced disruption of adherens junctions in distal colon is more severe in ALDH2 deficient mice
Wild type and ALDH2+/− mice were fed Lieber-DeCarli liquid diet with or without ethanol (up to 6% as described in the Methods section). Cryosections of distal colon were stained for E-cadherin (green) and β-catenin (red) by immunofluorescence method. Images collected by confocal microscopy. These are the representative images from at least 4 different mice.
Fig. 5
Fig. 5. ALDH2 deficiency promotes ethanol-induced disruption of tight junctions in mouse ileum in vivo
Wild type and ALDH2+/− mice were fed Lieber-DeCarli liquid diet with or without ethanol (up to 6% as described in the Methods section). Cryosections of ileum were stained for occludin (green) and ZO-1 (red) by immunofluorescence method. Images collected by confocal microscopy. These are the representative images from at least 4 different mice.
Fig. 6
Fig. 6. ALDH2 deficiency promotes ethanol-induced disruption of adherens junctions in mouse ileum in vivo
Wild type and ALDH2+/− mice were fed Lieber-DeCarli liquid diet with or without ethanol (up to 6% as described in the Methods section). Cryosections of ileum were stained for E-cadherin (green) and β-catenin (red) by immunofluorescence method. Images collected by confocal microscopy. These are the representative images from at least 4 different mice.
Fig. 7
Fig. 7. Chronic ethanol-induced liver injury is more severe in ALDH2 deficient mice
Wild type (WT) and ALDH2+/− mice were fed Lieber-DeCarli liquid diet with (black bars) or without (gray bars) ethanol (up to 6% as described in the Methods section). Liver weights (A) were recorded and H&E stained paraffin sections of liver were imaged by light microscopy (B). Plasma was analyzed for ALT (C) and AST (D) activities. Values are mean ± SE (n = 7). Asterisks indicate the values that are significantly (p<0.05) different from corresponding values for non-ethanol pair fed group, and hash tags indicate the values that are significantly (p<0.05) different from corresponding values for wild type group. E: Cryosections of liver were stained with Oil Red-O and imaged by light microscopy. These are the representative images from at least 3 different mice. F: Liver extracts were assayed for triglyceride content. Values are mean ± SE (n = 6). Asterisks indicate the values that are significantly (p<0.05) different from corresponding values for non-ethanol pair fed group, and the hash tag indicates that the value is significantly (p<0.05) different from corresponding value for wild type group.
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