ALDH2 DEFICIENCY INCREASES SUSCEPTIBILITY TO BINGE ALCOHOL-INDUCED GUT LEAKINESS, ENDOTOXEMIA, AND ACUTE LIVER INJURY IN MICE THROUGH THE GUT-LIVER AXIS

Abstract

AbstractMitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol used disorder (AUD), including alcoholic liver disease (ALD), and elevated oxidative stress. We hypothesized that Aldh2-knockout (KO) mice are susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposing Aldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency in Aldh2-KO mice increases their sensitivity to alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia in Aldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and/or bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury, indicating the disruption in the gut-liver axis. Furthermore, treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colonic cells. These changes were reversed by Alda-1, an ALDH2 activator, indicating a crucial role of ALDH2 in protecting against alcohol-induced epithelial barrier dysfunction. All these findings suggest that ALDH2 deficiency or gene mutation in humans is a risk factor to alcohol-mediated gut and liver injury, and ALDH2 could be an important therapeutic target against alcohol-associated tissue/organ damage.HighlightsBinge alcohol increases oxidative and nitrative stress in the intestine and liver.Binge alcohol causes gut leakiness, endotoxemia, and acute liver injury.Leaky gut is caused by elevated degradation of nitrated intestinal TJ/AJ proteins.Aldh2-KO mice are susceptible to binge-alcohol-induced leaky gut and liver injury.ALDH2 inhibition increases alcohol-induced T84 colonic epithelial cell permeability.