Spermidine Ameliorates Nonalcoholic Steatohepatitis through Thyroid Hormone-Responsive Protein Signaling and the Gut Microbiota-Mediated Metabolism of Bile Acids

Spermidine, a natural polyamine and physiological autophagy inducer, is involved in various physiological processes. However, the impact and mechanism of spermidine on nonalcoholic steatohepatitis (NASH) remains unclarified. We found that daily spermidine intake was significantly lower in volunteers with liver dysfunction than the healthy controls, and the serum and fecal spermidine levels were negatively correlated with the NASH phenotypes. Spermidine supplementation significantly attenuated hepatic lipid accumulation, insulin resistance, hepatic inflammation, and fibrosis in NASH mice induced by a western diet. The ameliorating effect of spermidine on lipid accumulation might be partly regulated by thyroid hormone-responsive protein (THRSP) signaling and autophagy. Moreover, spermidine altered the profile of hepatic bile acids (BAs) and microbial composition and function. Furthermore, spermidine reversed the progression of hepatic steatosis, inflammation, and fibrosis in mice with preexisting NASH. Therefore, spermidine ameliorates NASH partly through the THRSP signaling and the gut microbiota-mediated metabolism of BAs, suggesting that spermidine might be a viable therapy for NASH.