Nontargeted metabolomics combining with intestinal microbiota and hypolipidemia targets elucidates anti-hyperlipidemia effect of Sangju yinzha tea in hyperlipidemia rats

Hyperlipidemia is characterized by disrupted lipid homeostasis and excessive lipid accumulation in the body. Non-targeted metabolomics is an important tool to elucidate nutrient composition, metabolites and micro-ecology. In the current study, untargeted metabolomics combining with intestinal microbiota and metabolites, and hypolipidemia's targets were employed to investigate lipid-lowering effect and mechanism of Sangju yinzha tea (SYT). In vitro, network pharmacological analysis indicated that TNF , IL6, FOS, RELA , VEGFA, CTNNB1, ESR1, PIK3R1 , PIK3CA may be potential targets of 72 active ingredients identified by SYT's untargeted metabolomics for alleviating hyperlipidemia. In vivo, serum untargeted metabolomics showed that TNF , MMP9 , IFNG, PTGS2, PPARG, MMP2 , AKT1 , INS, ESR1 may be the potential targets of SYT's 14 blood-entering components for lowering blood lipids . In addition, SYT decreased the blood lipid (TG, TC , LDL-C and NEFA), liver organ index, hepatic lipid accumulation, and MDA , increased HDL-C, T-AOC, GSH-Px and SOD in serum of hyperlipidemic rats. SYT may regulate AMPK , FoxO, arachidonic acid and tyrosine pathway owing to the change of colic acid, dehydrocholic acid , gentian acid, etc. In cecum to enhance cholesterol excretion and relieve hyperlipidemia, according to cecal untargeted metabolomics. SYT up-regulated the abundance of Bacteroides , Prevotella , etc ., down-regulated the abundance of Coprococcus, etc., and promoted SCFAs production, further regulating lipid metabolism. All data show that SYT alleviated hyperlipidemia probably owing to its entered-blood compounds through regulating TNF and ESR1, modulating gut microbiota, thereby reversing gut and blood metabolites, further reducing blood lipid and hepatic fat accumulation via a compounds-target-gut microbiota-faeces network. • ESR1 is a SYT's potential target for treating hyperlipidemia. • SYT's 14 compounds can enter blood of rats to regulate blood lipid. • SYT alleviate hyperlipidemic through regulating gut microbiota, intretinal and blood metabolites.