Rhizoma Coptidis alkaloids alleviate hyperlipidemia in B6 mice by modulating gut microbiota and bile acid pathways

It is hypothesized that Rhizoma Coptidis (RC) alkaloids exert their hypolipidemic effects primarily by targeting the gastrointestinal tract and liver. Thus, this study was conducted to evaluate the antihyperlipidemic mechanisms of RC alkaloids (at a daily dose of 140mg/kg for 35days) in high-fat and high-cholesterol induced hyperlipidemic B6 mice. After treatment, serum lipid parameters were determined, the expression of lipid metabolism related genes and pathways such as the sterol regulatory element binding proteins (SREBPs) and bile acid signaling in mice were also investigated. Meanwhile, Illumina sequencing was used to investigate the differences in gut microbiota of B6 mice. The results indicated that RC alkaloids reduced the body weight gain and serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), total bile acids (TBA) and lipopolysaccharide of B6 mice. Liver fat deposition and epididymal adipose cell size were also deceased in therapy group. RC alkaloids feeding significantly promoted the abundance of Sporobacter termitidis, Alcaligenes faecalis, Akkermansia muciniphila in the gut of mice, whereas, the abundance of Escherichia coli, Desulfovibrio C21_c20, Parabacteroides distasonis was suppressed. The observed antihyperlipidemic effects of RC alkaloids can also be attributed to their action as agonists of FXR and TGR5, activators for SREBP2, LDLR, UCP2 and CYP7A1, inhibitors of HMGCR, TXNIP, TLR4 and JNK. Therefore, this study expands current knowledge on hypolipidemic mechanisms of RC alkaloids and presents new evidence supporting a key role for RC alkaloids as regulators of lipid homeostasis by modulation gut microbiota and hepatic lipid metabolism.