Fecal microbiota transplant improves hepatic fibro-inflammation via regulating oxidative stress in experimental NASH

Nonalcoholic steatohepatitis (NASH) is associated with imbalance of gut microbiome, indicating participation of gut environment in hepatic health status. Therefore, modulating gut environment via fecal microbiota transplant (FMT) has emerged as a promising therapeutic procedure for patients with NASH. However, the effect and mechanism of the FMT remains largely unexplored. Here, we aimed to investigate the gut and liver axis to understand the FMT-mediated hepatic improvement in NASH. Fecal contents from specific pathogen free mice were infused allogeneically into gastrointestinal tract of mice fed with high fat, high cholesterol and fructose (HFHCF) to induce NASH, resulting in suppressing hepatic pathogenic events, featured by decrease of inflammatory and fibrotic mediators. The FMT-mediated hepatic improvement was in parallel with elevated oxidative stress regulator, nuclear factor erythroid 2-related factor 2 and its downstream detoxicants in livers. The HFHCF-induced NASH increased intestinal permeability with abundant Facklamia and Aerococcus, an imbalanced gut environment that was significantly improved by the FMT, characterized with restoration of intestinal barrier function and an enrichment of Clostridium. Notably, the gut environment created by the FMT was inferred to produce metabolites from aromatic biogenic amine degradation pathway in which 4-hydroxyphenylacetic acid (4-HPA) was known to ameliorate hepatic injury. We suggest that gut-derived molecules, associated with hepatic improvement such as 4-HPA are the potential therapeutic agents for the prevention and treatment of NASH.