ALDH2 deficiency increases susceptibility to acetaminophen-induced liver injury through gut microbiota dysbiosis and altered bile acid metabolism.

Acetaminophen (APAP) overdose is a leading cause of acute liver injury (ALI), largely driven by mitochondrial dysfunction and oxidative stress. Mitochondrial aldehyde dehydrogenase-2 (ALDH2) detoxifies lipid peroxidation-derived reactive aldehydes; however, its role in APAP-induced hepatotoxicity, particularly in light of the high prevalence of ALDH2 deficiency in East Asian populations, remains incompletely understood. Fasted wild-type (WT) and ALDH2 knockout (KO) mice were challenged with APAP (500 mg/kg). Liver injury was evaluated by histopathological analysis, serum aminotransferase levels, and survival. Intestinal barrier integrity, gut microbiota composition (16S rRNA sequencing), fecal bile acid profiles (LC-MS/MS), and hepatic Nrf2 signaling were systematically examined. ALDH2 deficiency markedly exacerbated APAP-induced liver injury, as evidenced by extensive hepatic necrosis, elevated serum ALT and AST levels, and reduced survival. KO mice exhibited compromised intestinal barrier function, characterized by reduced expression of Claudin-1 and ZO-1 and increased accumulation of 4-hydroxynonenal. Gut microbiota analysis revealed pronounced microbial instability and a significant depletion of Lactobacillus, which was negatively correlated with the severity of liver injury. Consistently, fecal bile acid profiling demonstrated increased levels of tauro-β-muricholic acid in KO mice, which positively correlated with liver damage and inversely correlated with Lactobacillus abundance. Mechanistically, APAP robustly induced hepatic Nrf2-dependent antioxidant gene expression in WT mice, whereas this adaptive response was markedly blunted in ALDH2-deficient mice. Collectively, ALDH2 deficiency heightens susceptibility to APAP-induced ALI by impairing Nrf2-mediated antioxidant defenses and disrupting the gut-liver axis. These findings identify ALDH2 as a critical determinant of APAP sensitivity and a potential therapeutic target.