Pueraria flavones attenuate DSS-induced colitis by regulating the microbiota-bile acid-FXR/TGR5 axis and suppressing mtDNA-cGAS-STING signaling.

Ulcerative colitis (UC) is characterized by inflammation and impaired barrier function. Pueraria flavones (PFs) possess anti-inflammatory properties, though their underlying mechanisms remain poorly understood. This study assessed PFs in a dextran sulfate sodium (DSS)-induced colitis mouse model. PFs alleviated colitis symptoms, including weight loss and colon shortening, in a dose-dependent manner, while restoring barrier integrity and reducing pro-inflammatory cytokines. Mechanistically, PFs inhibited cGAS-STING activation by decreasing mitochondrial DNA (mtDNA) release, thereby limiting cytokine production. Furthermore, fecal microbiota transplantation (FMT) confirmed that PFs exert protective effects through the modulation of the gut microbiota. Metabolomic analysis revealed that PFs increased bile acids, such as tauroursodeoxycholic acid (TUDCA) and ursodeoxycholic acid (UDCA), which activated the farnesoid X receptor (FXR)/TGR5 signaling pathway to enhance barrier function. Collectively, these findings suggest that PFs mitigate colitis by remodeling the microbiota-bile acid-FXR axis and suppressing mtDNA-cGAS-STING signaling, presenting a promising therapeutic approach for UC.