ACT001 alleviates MASLD through gut microbiota-bile acid-FXR axis in mice.

BACKGROUND AND OBJECTIVE: ACT001 is a novel sesquiterpene lactone derivative with noteworthy antineoplastic and anti-inflammatory properties. This study aimed to investigate the efficacy of ACT001 against metabolic dysfunction associated steatotic liver disease (MASLD) pathogenesis in two established murine models, and to elucidate its regulatory role in the gut microbiota-bile acid-FXR axis. MATERIALS AND METHODS: A high-fat diet (HFD) and a methionine-choline-deficient (MCD) diet induced two MASLD models in C57BL/6J mice. Histological analysis was performed, biochemical indices were measured, and the expression of tight junctions and farnesoid X receptor (FXR)-related pathways was detected. Gut microbiota was assessed by 16S rDNA sequencing, while bile acids (BAs) in fecal samples were analyzed using UPLC/MS-MS. RESULTS: ACT001 decreased liver injury, alleviated hepatic lipid accumulation, and restored intestinal barrier integrity. Furthermore, 16S rDNA illustrated that ACT001 could partially rebalance intestinal dysbacteriosis and upregulate the relative abundance of various bacteria, especially Clostridium and Erysipelotrichaceae_Clostridium. Moreover, ACT001 facilitated the generation of uncombined BAs and accumulated specific BAs within the ileum, such as 23-Nor-deoxycholic acid (23-DCA) and lithocholic acid-3-sulfate (LCA-3S), which had a downregulation effect on the expression of the enteral FXR-fibroblast growth factor 15 (FGF15) pathway. CONCLUSION: ACT001 exerted a multifactorial therapeutic effect on MASLD, potentially linked to the regulation of the gut microbiota-BAs-FXR axis. Thus, it has the potential to be an effective treatment for MASLD.