Glycyrrhiza flavonoids improves hyperglycemia inT2DM mice by microbial-gut-liver axis

Licorice ( Glycyrrhiza uralensis Fisch) is commonly used as a natural flavoring agent in candies, beverages, and herbal teas. Its active compounds, such as glycyrrhizin and flavonoids, exhibit antioxidant and anti-inflammatory effects. However, its potential effects on type 2 diabetes remain unclear. The present study aimed to investigate the protective effects of glycyrrhiza flavonoids against type 2 diabetes mellitus (T2DM) in mice and explore the underlying molecular mechanisms. STZ injection and high-fat diet (HFD) combined to establish T2DM mouse model. T2DM mice were treated with different concentrations of glycyrrhiza flavonoids for 5 weeks. We observe that Glycyrrhiza flavonoids significantly ameliorated hyperglycemia, hyperlipidemia, insulin resistance, and pathological damage in liver and colonic tissues, activated the PI3K/AKT pathway. Glycyrrhiza flavonoids also increase the level of short chain fatty acids (SCFAs) such as Valeric acid, 4-Methylvaleric acid, Caproic acid in liver. Glycyrrhiza flavonoids also reduced the abundance of Ileibacterium in the gut at the genus level. In addition, glycyrrhiza flavonoids modulates the metabolisms of tryptophan and arginine in gut. In conclude, Glycyrrhiza flavonoids improve metabolic outcomes in T2DM by modulating PI3K/AKT signaling pathway, gut microbiota composition and SCFAs production in liver. These findings amplified the mechanisms of Glycyrrhiza flavonoids and its potential to attenuate insulin resistance. • Glycyrrhiza flavonoids reduce blood glucose, lipids, and insulin resistance by activating the PI3K/AKT pathway in T2DM mice. • Glycyrrhiza flavonoids upregulate gut microbiota-derived SCFAs. • These flavonoids boost beneficial bacteria (e.g., norank_f__Muribaculaceae, Allobaculum) and suppress harmful Ileibacterium, enhancing microbial metabolism.