Multi-omics joint analysis: Pachymic acid ameliorated non-alcoholic fatty liver disease by regulating gut microbiota

Poria cocos a traditional Chinese medicinal material with both culinary and therapeutic applications, contains pachymic acid (Pac) as one of its main active compounds, which has demonstrated anti-lipid accumulation and hypoglycemic effects. However, its impact on the biochemical changes in the enterohepatic axis induced by a high-fat diet remains poorly understood. This study investigated the protective mechanism of Pac using a high-fat diet-induced non-alcoholic fatty liver disease (NAFLD) mouse model. 16S rRNA sequencing of gut microbiota revealed that Pac administration reduced the Firmicutes to Bacteroidetes ratio, restored Akkermansia abundance, decreased Desulfovibrio and Streptococcus population, and ameliorated gut dysbiosis. Concurrently, Pac treatment reduced the expression of hepatic inflammatory factors by mainly adjusted LPS/TLR4/MYD88/NFκB pathway. Liver transcriptome analysis indicated that Pac primarily affects genes involved in lipid metabolism, apoptosis, and inflammatory responses. Specifically, Pac inhibited FASN, SREBP1c, and SCD1 expression while upregulating PPARα and CPT1α, thereby improving high-fat diet-induced hepatic steatosis in mice. Additionally, Pac treatment reduced hepatocellular apoptosis. Non-targeted liver metabolomics analysis following Pac intervention revealed increased levels of acylcarnitine and oleic acid. Collectively, these findings suggest that Pac alleviates high-fat diet-induced hepatic lipid accumulation and damage by modulating gut microbiota, lipid metabolism, inflammation, and apoptosis. This comprehensive study provides valuable insights into the therapeutic potential of Pac and offers a reference for the development and utilization of Poria cocos resources in addressing NAFLD.