Gut microbiota-based metabolism contributes to the protection of pseudolaric acid B against MAFLD

Background: The pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) involves gut microbiota dysbiosis. This study investigated pseudolaric acid B (PAB), a diterpenoid from Pseudolarix kaempferi, for its potential to ameliorate MAFLD via microbiota-metabolite-host signaling pathways.

Method: We evaluated the effects of PAB on MAFLD in high-fat diet (HFD)-fed mice. 16S rRNA Sequencing and metabolomics analyzed the regulations of PAB on gut microbiota and metabolites. The fecal microbiota transplantation (FMT) experiment was conducted to validate the causal role of the gut microbiota in the efficacy of PAB. Mechanistic studies employed molecular docking, microscale thermal migration (MST), western blot, immunofluorescence, and PCR to elucidate how PAB alleviates hepatic lipid metabolism dysregulation in MAFLD via microbial metabolites. In vivo intervention with candidate metabolites assessed improvement of disease phenotypes.

Results: PAB effectively alleviatd the symptoms of HFD-induced MAFLD in mice, and repaired dysbiosis of intestinal microbiota, especially g_Faecalibaculum, g_Allobaculum, g_Ileibacterium, and g_Dubosiella, which were markedly down-regulated by PAB and showed a positive correlation with liver injury. FMT confirmed the relevance of PAB efficacy to the microbial community structure. Moreover, PAB intervention led to a dramatically enrichment of the tryptophan metabolism pathway, with cinnabarinic acid (CA), a microbial tryptophan metabolite, exhibiting a significat negative correlation with the abundance of the down-regulated bacteria. CA supplementation alleviated HFD-induced MAFLD in mice, indicating the hepatoprotective effect of CA. Molecular docking and MST revealed CA binds stablly to Aryl Hydrocarbon Receptor (AhR) with higher affinity/stability, indicating a direct interaction between them. Mechanistically, PAB increased CA level and then activited AhR, downregulated hepatic lipogenesis genes by AhR-mediated IL-22/JAK1/STAT3 pathway.

Conclusion: PAB exerts a protective effect against MAFLD via restructuring the gut microbiota ecosystem, and activating CA/AhR/IL-22 signaling axis to reduce lipogenesis. These findings reveal a novel microbiota-metabolite-host mechanism and highlight PAB as a promising prebiotic-based therapeutic candidate for MAFLD.

Aryl hydrocarbon receptor; Gut microbiota; Metabolic dysfunction-associated fatty liver disease; Pseudolaric acid B; Tryptophan metabolism.