Bifidobacterium longum R0175 protects mice against APAP-induced liver injury by modulating the Nrf2 pathway

Acetaminophen (APAP) overdose is the most common driver of drug-induced liver injury (DILI) worldwide, and the gut microbiome plays a crucial role in this process. In this study, we estimated the effect of Bifidobacterium longum R0175 on APAP-induced liver injury in mice and discovered that B. longum R0175 alleviated liver injury by diminishing inflammation, reducing oxidative stress levels, inhibiting hepatocyte death and improving APAPinduced microbiome dysbiosis. Further studies revealed that the antioxidative effects of B. longum R0175 were primarily due to activation of the Nrf2 pathway, which was supported by the Nrf2 pathway inhibitor ML385 counteracting these ameliorative effects. B. longum R0175 modified intestinal metabolites, especially the key metabolite sedanolide, which could activate the Nrf2 pathway and contribute to the protective effects against APAP-induced liver injury. Moreover, we found that sedanolide exhibited close interrelationships with specific microbial taxa, indicating that this factor may be derived from gut microbes. In conclusion, our work demonstrated that B. longum R0175 could reduce oxidative damage, inflammation and hepatocyte death by activating the Nrf2 pathway. Importantly, we identified the microbiota-derived metabolite sedanolide, which was first discovered in the mouse intestine, as a key agonist of the Nrf2 pathway and primary effector of B. longum R0175 in APAP challenge. These findings provide new perspectives for APAP overdose therapy and demonstrate the enormous potential of B. longum R0175 in alleviating acute liver injury.