Abstract

Licorice flavonoids have shown therapeutic potential in ulcerative colitis (UC), but their efficacy is often limited by low extraction efficiency and poor bioavailability due to their predominant glycosylated forms in plants. To address this issue, a synthetic microbial consortium (SMC) composed of a Phanerochaete chrysosporium , Aspergillus niger , and Bacillus subtilis was constructed to ferment licorice residues, aiming to enhance flavonoid yield and bioactivity. The results demonstrated that SMC fermentation resulted in an approximately 6.83-fold relative increase in total flavonoid content compared with the unfermented control, as estimated by the aluminum chloride colorimetric method using rutin as the reference standard. LC-MS/MS analysis revealed that SMC fermentation markedly remodeled the flavonoid profile, in which multiple flavonoid glycosides (e.g., liquiritin and naringin) were likely converted into their corresponding bioactive aglycones (e.g., liquiritigenin, naringenin, and quercetin) through deglycosylation. In a dextran sulfate sodium (DSS)-induced murine UC model, high-dose SMC-fermented licorice flavonoid extract significantly alleviated clinical symptoms, preserved colon length, and reduced histopathological damage. Furthermore, network pharmacology analysis combined with molecular docking identified isogemichalcone B and amentoflavone as key bioactive constituents, which may exert anti-colitic effects by targeting critical inflammation- and survival-related hubs, including TNF, AKT1, and EGFR. Collectively, these findings suggest that SMC-based fermentation represents an effective biotransformation strategy to enhance the bioactivity of licorice flavonoids, providing a scientific basis for the high-value utilization of licorice processing residues and for further investigation into fermented plant-derived extracts as potential interventions for inflammatory bowel diseases.