Gypensapogenin I reduces inflammation and modulates gut microbiota in ulcerative colitis by targeting AKT1

Gynostemma pentaphyllum (GP) is a traditional Chinese herbal medicine that has a regulatory effect on intestinal diseases. Gypensapogenin I (GI), a biologically active saponin compound extracted from GP, has shown therapeutic potential. However, its exact mechanism of action and molecular targets in the in vivo and in vitro treatment of ulcerative colitis (UC) remain to be fully elucidated.

This study systematically investigated GI's therapeutic mechanisms in UC, identifying molecular targets and elucidating its protective effects.

This study established both dextran sulfate sodium (DSS)-induced murine models and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage models. Transcriptional analysis identified potential molecular targets, which were subsequently verified. Additionally, 16S rRNA sequencing was used to detect the regulatory ability of GI on the intestinal microbiota induced by DSS. Molecular docking, SPR, CETSA, AKT1 inhibitor and siAKT1 experiments were conducted to verify whether GI exerts its regulatory effect through the AKT1-mediated PI3K/AKT pathway.

GI treatment significantly delayed the progression of ulcerative colitis (UC) and restored the integrity of the intestinal barrier. It reduces inflammatory responses and oxidative stress through the PI3K/AKT pathway. Furthermore, this study elucidated the therapeutic role of GI in modulating the microbiota-gut-inflammation axis. Notably, we demonstrated that GI exerts its effects primarily through the AKT1-mediated PI3K/AKT pathway modulation.

These findings strongly suggest that GI improves UC by targeting AKT1 to modulate the PI3K/AKT pathway and intestinal microbiota. This provides a theoretical basis for exploring GI as a novel drug for UC.