Extract from Eucommia ulmoides Oliv. Leaves alleviates APAP-induced acute liver injury via reshaping gut microbiota and attenuating microbial bile acids metabolism disorder

BACKGROUND: Increasing studies suggest that supplementing flavonoids from Eucommia ulmoides Oliv. Leaves (EUL) exerts liver protective effects via reshaping gut microbiota and regulating bile acids (BAs) metabolism. However, the relationship between EUL, gut microbiota and BAs metabolism remains unclear and the potential mechanisms of action has not been expounded clearly. PURPOSE: To demonstrate the important role of gut microbiota and microbial BAs metabolism in alleviation acetaminophen-induced liver injury (AILI) by EUL. METHODS: AILI mice model was employed to evaluate the therapeutic efficacy of EUL. The hepatic function was assessed, and biological samples were collected for histopathological examination, bacterial 16S rRNA sequencing analysis, BAs-targeted metabolomics, and the evaluation of the intestinal barrier function. Additionally, antibiotic cocktail-triggered gut microbiota deficiency and fecal microbiome transplantation were investigated to the relationship of molecular mechanistic between the protective efficiency of EUL in AILI, gut microbiota, and the metabolism of microbial BAs. RESULTS: EUL alleviate liver damage, involving reduction of liver function index, down-regulation of inflammatory cytokines and oxidative stress index, and restoration of pathological changes of liver tissue. EUL also improved intestinal barrier dysfunction and reshaped gut microflora dysbiosis in AILI mice. Moreover, antibiotic cocktail-triggered intestinal microbiota deficiency and fecal microbiome transplantation (FMT) evidenced that the liver protection of EUL was tightly related with gut microbiota. BAs-targeted metabolomics assay demonstrated that EUL mitigated the altered metabolism of microbial BAs during the development of AILI. EUL promoted the abundance of Firmicutes phylum, and elevating the beneficial microbes in Ruminococcaceae and Lachnospiraceae family, which were associated with up-regulated proportion of secondary bile acids (including DCA, NorDCA and 7-ketoLCA), leading to the reduction intestinal inflammation and preservation intestinal integrity. In particular, EUL enriched the beneficial microbes in Lachnoclostridium, Lachnospiraceae_UCG-006, [Eubacterium]_xylanophilum_group, Oscillibacter, Ruminiclostridium, and Desulfovibrio genera. Furthermore, EUL administration increased levels of CDCA, which could activate FXR-FGF15, enabling to decreased synthesis of BAs in the liver and promoting excretion. CONCLUSIONS: EUL supplementation alleviate AILI by reshaping the dysfunctional gut microbiota and attenuating disordered BAs metabolism, resulting to improvements in BAs enterohepatic circulation and gut barrier function. The mechanism may be closely related to the gut microbiome-BAs-FXR signaling in gut-liver axis.