Diosgenin alleviates nonalcoholic steatohepatitis through affecting liver-gut circulation

Nonalcoholic steatohepatitis (NASH), as the aggressive form of nonalcoholic fatty liver disease (NAFLD), rapidly becomes the leading cause of end-stage liver disease or liver transplantation. Nowadays, there has no approved drug for NASH treatment. Diosgenin possesses multiple beneficial effects towards inhibition of lipid accumulation, cholesterol metabolism, fibrotic progression and inflammatory response. However, there has been no report concerning its effects on NASH so far. Using methionine and choline-deficient (MCD) feeding mice, we evaluated the anti-NASH effects of diosgenin. 16 S rDNA was used to investigate gut microbiota composition. Transcriptome sequencing, LC/MS and GC/MS analysis were used to evaluate bile acids (BAs) metabolism and their related pathway. Compared with the MCD group, diosgenin treatment improved the hepatic dysfunction, especially decreased the serum and hepatic TC, TG, ALT, AST and TBA to nearly 50%. Content of BAs, especially CA and TCA, were decreased from 59.30 and 26.00-39.71 and 11.48 ng/mg in liver and from 0.96 and 2.1-0.47 and 1.13 μg/mL in serum, and increased from 7.01 and 11.08-3.278 and 5.11 ng/mg in feces, respectively. Antibiotic and fecal microbiota transplantation (FMT) treatment further confirmed the therapeutic effect of diosgenin on gut microbiota, especially Clostridia (LDA score of 4.94), which regulated BAs metabolism through the hepatic FXR-SHP and intestinal FXR-FGF15 pathways. These data indicate that diosgenin prevents NASH by altering Clostridia and BAs metabolism. Our results shed light on the mechanisms of diosgenin in treating NASH, which pave way for the design of novel clinical therapeutic strategies.