Self-assembling gardenia pectin gel for cholestatic liver injury: Dual mechanisms of hepatoprotection via PPARα activation and gut microbial modulation

Bioactive pectin is a considerable candidate for drug delivery to improve stability and bioavailability. Geniposide (GS) is a hepatoprotective compound with poor bioavailability, limiting its application. Herein, we first designed a self-assembled Gardenia Pectin Gel (GPG) from pectin-rich Gardenia jasminoides Ellis fruit extracts (GE), spontaneously encapsulating co-extracted GS. Compared with non-gelling GE, pectin gel delivery achieved enhanced stability and delayed release in vitro and increased half-time (2.6-fold, p  < 0.05) and bioavailability (2.35-fold, p  < 0.05) of GS in vivo. Moreover, GPG provided superior hepatoprotective effects over GS and GE, including reducing hepatic injury indicators (e.g. ALP level, p  < 0.01 vs GS; p  < 0.05 vs GE), inflammation and necrosis in α-naphthylisothiocyanate-induced cholestatic liver disease (CLD) mice. Mechanistically, GPG restored hepatic glycolipid metabolic homeostasis via GS-mediated PPARα activation. Meanwhile, GPG promoted gut microbes remodeling and hepatoprotective acetate and butyrate production ( p  < 0.001), producing synergistic effects. Notably, after 7-day administration, GPG outperformed ursodeoxycholic acid, a first-line CLD medicine, in the CLD mice model, demonstrating its clinical potential. Collectively, this study developed a promising self-assembled pectin-assisted formulation that enhanced the bioavailability of GS and CLD intervention, more importantly, established a theoretical foundation for clinical application of pectin-based drug delivery systems.