Ethanol extract of propolis regulates type 2 diabetes in mice via metabolism and gut microbiota

Ethnopharmacological relevance: Propolis is a traditional natural medicine with various activities such as anti-oxidant and anti-inflammatory, immunomodulatory, anti-tumour, gastroenteritis treatment and prevention, anti-microbial and parasitic, as well as glucose regulation and anti-diabetes, and is expected to be an anti-diabetic candidate with few side effects, but the mechanism of action of propolis on type 2 diabetes mellitus (T2DM) has not been fully elucidated.Aim of the study: The purpose of this study was to investigate the mechanism of the effect of ethanol extract of propolis (EEP) on the regulation of blood glucose in T2DM mice. Materials and methods: We studied the possible mechanism of EEP on T2DM using an animal model of T2DM induced by a combination of a high-fat diet and intraperitoneal injection of streptozotocin (STZ). The experiment was divided into four groups, namely, the normal group (HC), model group (T2DM), EEP and metformin group (MET). Biochemical indexes and cytokines were measured, and the differences of metabolites in the serum were compared by 1H-NMR. In addition, the diversity of intestinal flora in feces was studied by 16S rDNA amplicon sequencing.Results: The results showed that following treatment with EEP and MET, the weight-loss trend of mice was alleviated, and the fasting blood glucose, insulin secretion level, insulin resistance index, C peptide level and oral glucose tolerance level decreased, whereas the insulin sensitivity index increased, thereby EEP effectively alle-viated the occurrence of T2DM and insulin resistance. Compared with the T2DM group, the concentrations of pro-inflammatory cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) decreased significantly in EEP and MET groups, whereas the concentrations of anti-inflammatory cytokine interleukin-10 (IL-10) increased significantly. Metabolomics results revealed that EEP and MET regulate car-bohydrate metabolism and restore amino acid and lipid metabolism. Correlation analysis of intestinal flora in mouse feces showed that compared with the HC group, harmful bacteria such as Bilophila, Eubacterium_ven-triosum_group, Mucispirillum and Desulfovibrio were found in the T2DM group, whereas the abundance of bene-ficial bacteria such as Lactobacillus was significantly reduced. Parabacteroides, Akkermansia, Leuconostoc, and Alloprevotella were abundantly present in the EEP group; however, the MET group showed an increase in the genus Parasutterella, which could regulate energy metabolism and insulin sensitivity.Conclusions: The results showed that EEP and MET reduce fasting blood glucose in T2DM mice, followed by alleviating insulin resistance, improving the inflammatory reaction of mice, regulating the metabolism of mice, and affecting the steady state of gut microbiota. However, the overall therapeutic effect of EEP is better than that of MET.