Gut Microbiota-Derived β-Glucuronidase Governs the Anticolitic Efficacy of Daidzein via the ERβ-PI3K/Akt/mTOR-Autophagy Axis

Abstract

Precision nutritional interventions targeting the gut microenvironment have emerged as a pivotal strategy for managing inflammatory bowel disease (IBD). However, the specific microbial mechanisms governing the therapeutic efficacy of dietary flavonoids, such as daidzein (DA), remain largely unexplored. In this study, it was observed that administration of 40 mg/kg DA significantly attenuated DSS-induced colitis, preserving mucosal barrier integrity and suppressing inflammation. Multiomics analysis revealed that DA reprogrammed the gut microbiota composition, specifically enriching β-glucuronidase (GUS)-producing bacteria, especially Bacteroides thetaiotaomicron. Mechanistically, the effects of microbially bioactivated DA were associated with host estrogen receptor beta (ERβ) signaling. Pharmacological blockade further supported the involvement of ERβ signaling in the suppression of PI3K/Akt/mTOR signaling and restoration of autophagy, thereby contributing to intestinal epithelial repair. Collectively, these findings unveil a potential Microbiota-GUS-ERβ-PI3K/Akt/mTOR-autophagy mechanistic axis, establishing a robust theoretical foundation for precision nutritional strategies targeting specific gut microbiota.