The oral administration of Lacticaseibacillus casei Shirota alleviates acetaminophen-induced liver injury through accelerated acetaminophen metabolism via the liver-gut axis in mice

Acetaminophen is a widely used antipyretic and analgesic drug, and its overdose is the leading cause of drug-induced acute liver failure. This study aimed to investigate the effect and mechanism of Lacticaseibacillus casei Shirota (LcS), an extensively used and highly studied probiotic, on acetaminophen-induced acute liver injury. C57BL/6 mice were gavaged with LcS suspension or saline once daily for 7 days before acute liver injury was induced via intraperitoneal injection of 300 mg/kg acetaminophen. The results showed that LcS significantly decreased acetaminophen-induced liver and ileum injury, as demonstrated by reductions in the increases in aspartate aminotransferase, total bile acids, total bilirubin, indirect bilirubin, and hepatic cell necrosis. Moreover, LcS alleviated acetaminophen-induced intestinal mucosal permeability, decreased serum IL-1 alpha and lipopolysaccharide levels, and elevated serum eosinophil chemokine (eotaxin) and hepatic glutathione levels. Furthermore, analysis of the gut microbiota and metabolome showed that LcS reduced the acetaminophen-enriched levels of Cyanobacteria, Oxyphotobacteria, long-chain fatty acids, cholesterol, and sugars in the gut. Additionally, the transcriptomic and proteomic results showed that LcS mitigated the decrease in metabolic and immune pathways as well as glutathione formation during acetaminophen-induced acute liver injury. This is the first study showing that pretreatment with LcS alleviates acetaminophen-enriched acute liver injury, and it provides a reference for the application of LcS.IMPORTANCE Acetaminophen is the most frequently used antipyretic analgesic worldwide. As a result, overdoses easily occur and lead to drug-induced acute liver injury, which quickly progresses to liver failure with a mortality of 60%-80% if not corrected in time. The current emergency treatment for overused acetaminophen needs to be administered within 8 hours to avoid liver injury or even liver failure. Therefore, developing preventive strategies for liver injury during planned acetaminophen medication is particularly important, preferably nonpharmacological methods. Lacticaseibacillus casei Shirota (LcS) is a famous probiotic that has been used for many years. Our study found that LcS significantly alleviated acetaminophen-induced acute liver injury, especially acetaminophen-induced liver injury toward fulminant hepatic failure. Here, we elucidated the function and potential mechanisms of LcS in alleviating acetaminophen-induced acute liver injury, hoping it will provide preventive strategies to people during acetaminophen treatment.