The Bacterial Metabolite Lndole-3-Propionic Acid Alleviates Acetaminophen-Induced Acute Liver Injury Partly through the Aryl Hydrocarbon Receptor Pathway.

Acetaminophen (APAP)-induced liver injury is a major cause of acute liver injury (ALI). Indole-3-propionic acid (IPA), a gut microbiota-derived tryptophan metabolite with potent anti-inflammatory and antioxidant properties, has not been fully explored for its therapeutic potential in APAP-induced ALI. APAP-induced liver injury is often accompanied by dysregulation of both the gut microbiota and the intrahepatic immune system. In our study, IPA levels were markedly reduced in the ALI model, reflecting impaired gut tryptophan metabolism. In vitro and in vivo experiments demonstrated that IPA mitigates cytotoxicity, reduces hepatocyte apoptosis, and alleviates liver inflammation, thereby conferring significant hepatoprotective effects. The aryl hydrocarbon receptor (AhR), a key mediator of IPA's effects, was substantially downregulated in APAP-induced ALI and negatively correlated with serum AST and ALT levels, suggesting that AhR may serve as a potential early biomarker for APAP-induced hepatotoxicity. Notably, IPA treatment restored hepatic and serum AhR expression and attenuated liver injury. Collectively, these findings underscore the critical role of IPA in modulating AhR signaling and highlight its therapeutic potential in APAP-induced ALI.