Abstract

Ethnopharmacological relevance Gynostemma pentaphyllum , a traditional Chinese medicine with a history of use dating back over 500 years, was described for treating conditions such as heat-clearing and detoxification. Contemporary pharmacopoeias confirm its therapeutic value, including anti-inflammatory, immunomodulatory, and antioxidant effects. Gynostemma pentaphyllum polysaccharides (GPP) are its primary bioactive macromolecules, however, its underlying pharmacological mechanisms in ulcerative colitis (UC) remain unclear. Aim of the study This study aimed to elucidate the protective role and mechanisms of GPP in UC. Materials and methods The comprehensive structural characterization of GPP was achieved through integrated chromatography coupled with NMR, FT-IR, and SEM analyses. The efficacy and mechanisms of GPP were investigated in a DSS-induced UC mouse model and an LPS-stimulated Caco-2 cell inflammatory model, employing transcriptomic analysis, GeneCards Human Gene Database, 16S rRNA sequencing, and validation in Nrf2 -/- mice. Results GPP alleviated UC symptoms by suppressing inflammation, reducing oxidative stress, and improving gut barrier dysfunction. RNAseq and GeneCards identified Nrf2 as a key target, with GPP exerting anti-inflammatory and antioxidant effects via the Nrf2/HO-1 pathway; this efficacy was attenuated in Nrf2 -/- mice. Furthermore, 16S rRNA sequencing revealed that GPP modulated the gut microbiota, increasing the abundance of Firmicutes while decreasing Proteobacteria , thereby helping to re-establish microbial homeostasis. Conclusions Collectively, our findings demonstrate that GPP alleviates UC symptoms by activating the Nrf2/HO-1 pathway, reducing ROS levels, subsequently inhibiting NLRP3 inflammasome activation, mitigating oxidative stress, and improving intestinal barrier dysfunction. These findings identify GPP as a promising macromolecule with translational potential for UC.