Trilobatin, a Novel Naturally Occurring Food Additive, Ameliorates Alcoholic Liver Disease in Mice: Involvement of Microbiota–Gut–Liver Axis and Yap/Nrf2 Signaling Pathway

Trilobatin, a novel natural food additive, exerts a protective effect on acute liver injury. However, whether Trilobatin can protect against alcoholic liver disease (ALD) has not been elucidated. This research is intended to ascertain the impact of Trilobatin on ALD in mice and decipher the potential underlying mechanisms. Lieber–DeCarli liquid alcohol diet was used to induce ALD in mice, followed by administration of Trilobatin (10, 20, 40 mg·kg–1·d–1) for 15 days. The results suggested that Trilobatin significantly alleviated ethanol-induced hepatic injury in mice. Furthermore, RNA-Seq analysis revealed that yes-associated protein (YAP) downregulation occurred in the liver after Trilobatin treatment. Mechanistically, Trilobatin directly bound to YAP and hindered its nuclear translocation, which activated the Nrf2 pathway to reduce pro-inflammatory cytokines and oxidative stress. Intriguingly, 16S rDNA analysis results revealed that Trilobatin reshaped the gut microbiota, reducing harmful bacteria and increasing beneficial bacteria. It also enhanced tight junction proteins, defending against damage to the intestinal barrier. These findings not only highlight the microbiota–gut–liver axis and YAP/Nrf2 pathway as crucial potential targets to treat ALD but also reveal that Trilobatin effectively protects against ALD, at least partly, through modulating the microbiota–gut–liver axis and YAP/Nrf2 pathway.