Radix Rehmanniae polysaccharides enhanced hypoglycaemic effect of metformin by stimulating glucagon-like peptide-1 secretion via gut microbiota-SCFA-GPCR43 axis

Radix Rehmanniae is a commonly used traditional Chinese medicinal herb and polysaccharides were among its major hypoglycaemic constituents. Although Radix Rehmanniae is often in combined use with metformin (MET) for treating Type-II diabetes in clinical practice, the effect of Radix Rehmanniae polysaccharides (RRP) on the pharmacokinetic and pharmacodynamic properties of MET still remained unclear. To investigate the effect, db/db mice were orally treated with high (250 mg/kg) or low (125 mg/kg) dose of MET 2 h after dosing RRP (300 mg/kg) once daily for consecutive 37 days. In comparison to the MET monotherapy, Co-administration with RRP (300 mg/kg) could only further significantly improve the hypoglycaemic effect of MET at low dose (125 mg/kg). Although the microbial biodiversity was not further improved, gut microbiota analysis demonstrated that combined use with RRP could further significantly increase the relative abundance of Bifidobacterium and decrease the relative abundance of Desulfovibrio in comparison with that of MET monotherapy. In addition, the steady state concentration of MET was not affected by the co-administration of RRP. Mechanistic studies revealed that combined use with RRP significantly enhanced short chain fatty acids (SCFA) formation and further promoted glucagon-like peptide-1 (GLP-1) secretion via the gut microbiota-SCFA-GPCR43 axis. This study for the first time demonstrated that combined use of RRP could further enhance the hypoglycaemic effect of low-dose MET by promoting GLP-1 secretion rather than altering its steady state concentration.