Li_2026_Front.Microbiol_17_1838289

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease worldwide. The latest research shows that its pathogenesis is closely related to the imbalance of gut microbiota. Prunella vulgaris L. is an edible-medicinal plant containing bioactive compounds such as polyphenols that can lower cholesterol and protect the liver. However, whether it has anti MASLD effects has not been reported. The present study aimed to investigate the effect of Prunella vulgaris polyphenols (PVP) on alleviating MASLD from the perspective of the gut-liver axis. METHODS: PVP composition was characterized via UPLC-MS/MS and HPLC. Enzymatic kinetics, fluorescence quenching, and molecular docking were used to study the inhibition of PVP and rosmarinic acid (RA) on cholesterol esterase (CEase). Effects on liver lipid accumulation and intestinal cholesterol transport were assessed using HepG2 and Caco-2 cell models. A MASLD mouse model was evaluated through ELISA, tissue staining, and 16S rRNA sequencing to determine the efficacy and mechanisms. RESULTS: PVP and RA exhibited anti-competitive inhibition of CEase, with IC(50) values of 1.63 +/- 0.06 and 0.39 +/- 0.17 mg/mL, respectively. RA showed strong binding to CEase. PVP and RA significantly alleviated hepatic lipid accumulation in HepG2 cells, inhibited intestinal cholesterol absorption, and promoted cholesterol efflux in Caco-2 monolayers. In MASLD mice, PVP significantly reduced serum ALT, TBA, and TG, lowered hepatic TC and fecal TBA (P < 0.05), and ameliorated liver pathological damage. In addition, both PVP and RA modified the composition of gut microbiota in the cecum, which characterized by a reduction in bile acid (BA)-related bacteria such as g_UBA7173, g_Bacteroides_H, f_Burkholderiaceae_A, g_Phocaeicola_A, and g_Turicimonas, while increasing f_Lachnospiraceae and f_Oscillospiraceae. CONCLUSION: PVP ameliorates MASLD by inhibiting CEase and intestinal cholesterol absorption, promoting cholesterol efflux, and regulating TBA levels along with intestinal microbiota homeostasis. Our findings suggest that PVP and RA deserve further investigation as potential modulators of cholesterol metabolism in MASLD.