Enhancement of ursolic acid (UA), an active ingredient in hawthorn, on the uptake and metabolism of 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG) derived from Polygonum multiflorum.

Hawthorn (Crataegus pinnatifida Bge.) and Polygonum multiflorum are medicinal and edible plants, with their major constituents being ursolic acid (UA) and 2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (THSG), respectively. Prolonged or high-dose intake of THSG may induce hepatotoxicity. While these plants are commonly combined in dietary formulations, the mechanism behind their compatibility is unclear. This study investigated how UA influences the absorption and disposition of THSG to clarify this compatibility. In vitro intestinal perfusion experiments demonstrated that the hawthorn-processed Polygonum multiflorum decoction (HPDC) significantly enhanced THSG absorption. In vivo pharmacokinetic analysis showed that UA increased the Cmax of THSG while decreasing Tmax and t₁/₂β. Mechanistically, UA facilitated intestinal absorption by downregulating the intestinal efflux transporter Multidrug resistance-associated protein 2 (MRP2), while concurrently upregulating hepatic UGT1A1 expression, consistent with altered glucuronidation-related handling of THSG, suggesting differential regulation in intestinal and hepatic tissues. qRT-PCR analysis indicated that UA significantly reduced serum exosomal miR-150-5p levels. Combined miRDB and TargetScanRat databases and dual-luciferase reporter validation supported that miR-150-5p directly inhibits UGT1A1 mRNA. UA upregulated UGT1A1 expression and altered THSG disposition, potentially involving miR-150-5p-mediated post-transcriptional regulation. In addition, UA enriched Clostridium-related taxa; extracellular vesicles from Clostridium butyricum (Cb-EVs) were internalized by hepatocytes and upregulated UGT1A1 in vitro, supporting microbiota-derived EV signaling. Overall, these findings suggest that UA modulates THSG absorption and disposition through coordinated intestinal, hepatic, and microbiota-related pathways, providing pharmacokinetic and mechanistic evidence for understanding the combination of these two medicinal and edible foods.