Yellow tea polysaccharides protect against non-alcoholic fatty liver disease via regulation of gut microbiota and bile acid metabolism in mice

Background: Nonalcoholic fatty liver disease (NAFLD) is a major clinical and global public health issue, with no specific pharmacological treatment available. Currently, there is a lack of approved drugs for the clinical treatment of NAFLD. Large-leaf yellow tea polysaccharides (YTP) is a natural biomacromolecule with excellent prebiotic properties and significant therapeutic effects on multiple metabolic diseases. However, the specific mechanisms by which YTP regulates NAFLD remain unclear. Purpose: This study aims to explore the prebiotic effects of YTP and the potential mechanisms by which it inhibits hepatic cholesterol accumulation in NAFLD mice. Methods: The effects of YTP on lipid accumulation were evaluated in NAFLD mice through obesity trait analysis and bile acids (BAs) metabolism assessment. Additionally, fecal microbiota transplantation (FMT) was performed, and high-throughput sequencing was employed to investigate the mechanisms underlying YTP's regulatory effects on gut microbiota and BA metabolism. Results: Our study demonstrated that YTP altered the constitution of colonic BA, particularly increasing the levels of conjugated BA and non-12OH BA, which suppressed ileum FXR receptors and hepatic BA reabsorption, facilitated BA synthesis, and fecal BA excretion. The modifications were characterized by a decrease in the levels of FXR, FGF15, FGFR4, and ASBT proteins, and an increase in the levels of Cyp7a1 and Cyp27a1 proteins. YTP might affect enterohepatic circulation and by the activated the hepatic FXR-SHP pathway. Meanwhile, YTP reshaped the intestinal microbiome structure by decreasing BSH-producing genera and increasing taurine metabolism genera. The correlation analysis implied that Muribaculaceae, Pseudomonas, acterium_coprostanoligenes_group, Clostridiales, Lachnospiraceae_NK4A136_group, Delftia, Dubosiella, and Romboutsia were strongly correlated with specific BA monomers. Conclusions: YTP modulates bile salt hydrolase-related microbial genera to activate alternative bile acid synthesis pathways, thereby inhibiting NAFLD progression. These results suggest that YTP may serve as a potential pro- biotic formulation, offering a feasible dietary intervention for NAFLD.