Integration strategies involving 16S rDNA sequencing combined with untargeted metabolomics revealed the mechanism of Selaginella tamariscina (Beauv.) Spring in db/db diabetic mice.

Selaginella tamariscina extracts (STS), total flavonoids of Selaginella tamariscina (TFST) and the main active component amentoflavone (AMT) have hypoglycaemic-mitigating effects, but their efficacy and mechanism of action in db/db mice are unknown. This study aimed to evaluate the hypoglycaemic effects of Selaginella tamariscina and its extracts in db/db diabetic mice and explore their mechanisms through gut microbiota modulation and metabolomics. Sixty male db/db mice were divided into model (db/db), STS (1.1 g/kg), TFST (140 mg/kg), AMT (60 mg/kg), mulberry twig alkaloid tablets (MTA, 24 mg/kg), and metformin (Met, 160 mg/kg) groups. Another 10 db/m mice served as controls. Treatments lasted 4 weeks. Blood glucose, body weight, diabetes symptoms, lipid levels, pathological changes, oxidative stress markers and liver damage levels were assessed. The gut microbiota composition was analyzed via 16S rDNA sequencing, and urinary metabolomics was conducted to understand metabolic changes. Selaginella tamariscina and its extracts significantly improved hyperglycaemia, insulin sensitivity, lipid metabolism, oxidative stress and liver injury in db/db mice, among which TFST was the most effective, with an effect comparable to that of Met and superior to that of MTA. TFST regulates gut microbiota disorders and metabolic profiles in db/db diabetic mice and modulates Alloprevotella levels, affecting butyric acid content and, thus, exerting a hypoglycaemic effect. These findings suggest that TFST modulates Alloprevotella, influencing butyric acid levels, which improves glycaemic control, enhances insulin sensitivity, and prevents oxidative stress and tissue damage. In conclusion, TFST has potential as a natural therapeutic agent for the control of T2DM.