Pien Tze Huang Protects Against Non-Alcoholic Steatohepatitis by Modulating the Gut Microbiota and Metabolites in Mice

Abstract

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease without effective treatment. The traditional Chinese medicine formulation Pien Tze Huang (PTH) can suppress inflammatory diseases. Here, we evaluate the effects of PTH on the evolution of NASH and its underlying mechanisms. We found that PTH prevented the development of steatohepatitis induced by various dietary models, including a high-fat high-cholesterol (HFHC) diet, choline-deficient high-fat diet (CD-HFD), and methionine- and choline-deficient (MCD) diet, along with significant suppression of liver injury, hepatic triglyceride, and lipid peroxidation. Moreover, ten days of PTH treatment after the onset of NASH significantly ameliorated MCD diet-induced steatosis and liver injury in mice. Through the metagenomic sequencing of stool samples, we found that PTH administration restored the gut microbiota with enrichment of probiotics including Lactobacillus acidophilus (L. acidophilus), Lactobacillus plantarum, Lactococcus lactis, and Bacillus subtilis. The enriched L. acidophilus prevented MCD diet-induced steatohepatitis. In addition, PTH restored the gut barrier function in mice with steatohepatitis, as evidenced by reduced intestinal permeability, decreased serum lipopolysaccharides (LPS) level, and increased epithelial tight-junction protein E-cadherin expression. Our metabolomic analysis via liquid chromatography-mass spectrometry profiling identified the alteration in the metabolism of bile acids in the portal vein of PTH-treated mice. We further confirmed that an intact gut microbiota is necessary for PTH to exhibit anti-steatohepatitis effects. In conclusion, PTH protects against steatohepatitis development by modulating the gut microbiota and metabolites. PTH is a potential promising prophylactic and therapeutic option for patients with NASH.