Effect of Atractylodis Macrocephalae Rhizoma-Atractylodis Rhizoma couplet medicines and its processed products on improving hyperlipidemia via promoting bile acid metabolism

Background: Atractylodis Macrocephalae Rhizoma (AMR) and Atractylodis Rhizoma (AR) medicinal-edible herbs traditionally used to regulate gastrointestinal function and metabolic homeostasis. Their products, fried AMR with bran (FAMR) and fried AR with bran (FAR) are applied to improve lipid metabolism. Increasing evidence highlights bile acid metabolism and the gut-liver axis as central regulators of lipid homeostasis. However, whether the lipid-lowering effects of AMR-AR and FAMR-FAR are mediated through bile acid remains unclear. Objectives: This study aimed to elucidate the characteristic effects of AMR-AR and FAMR-FAR in the treatment of hyperlipidemia and to explore their potential mechanisms of action. Methods: The composition changes of AMR-AR and FAMR-FAR were detected by HPLC. Hyperlipidemia was induced in mice by a high-fat diet for six weeks. Serum TC, TG, LDL-C and HDL-C levels were measured on days 11, 27, and 44. On day 44, total bile acids in serum and liver were quantified, and hepatic bile acid profiles were analyzed by UPLC-MS/MS. Hepatic histopathology and lipid accumulation were assessed by HE and Oil Red O staining. Immunohistochemistry for hepatic lipid metabolism-related proteins and RT-qPCR for ileal cholesterol metabolism-related mRNA. Intestinal TPH1 as well as colonic FXR and TGR5 expression were evaluated by immunofluorescence. Results: AMR-AR significantly reduced serum TC and LDL-C levels, while both AMR-AR and FAMR-FAR markedly alleviated hepatic steatosis and inflammatory infiltration, remodeled hepatic bile acid profiles. AMR-AR enhanced hepatic LDLR, SR-BI, CYP7A1, and PPARγ expression, whereas FAMR-FAR predominantly increased LXRα expression. AMR-AR and FAMR-FAR suppressed TPH1 and HTR4 expression in intestine, activated FXR-FGF15, upregulated bile acid transporters, and reduced colonic FXR and TGR5 expression. Conclusions: AMR-AR and FAMR-AR ameliorate hyperlipidemia primarily by restoring bile acid homeostasis and coordinating gut-liver axis signaling.