PuRenDan alleviates type 2 diabetes mellitus symptoms by modulating the gut microbiota and its metabolites

Ethnopharmacological relevance: PuRenDan (PRD) is a traditional Chinese medicine formula comprising five herbs that have been traditionally used to treat type 2 diabetes mellitus (T2DM). While PRD has been shown to be effective in treating T2DM in clinical and animal studies, the mechanisms by which it works on the gut microbiome and metabolites related to T2DM are not well understood. Aim of the study: The objective of this study was to partially elucidate the mechanism of PRD in treating T2DM through analyses of the gut microbiota metagenome and metabolome. Materials and methods: Sprague-Dawley rats were fed high-fat diets (HFDs) and injected with low-dose streptozotocin (STZ) to replicate T2DM models. Then the therapeutic effects of PRD were evaluated by measuring clinical markers such as blood glucose, insulin resistance (IR), lipid metabolism biomarkers (total cholesterol, low-density lipoprotein, non-esterified fatty acids, and triglycerides), and inflammatory factors (tumor necrosis factor alpha, interleukin-6 [IL-6], interferon gamma, and IL-1 beta). Colon contents were collected, and metagenomics, combined with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry metabolic profiling, was performed to evaluate the effects of T2DM and PRD on gut microbiota and its metabolites in rats. Spearman analysis was used to calculate the correlation coefficient among different microbiota, clinical indices, and metabolites. Results: PRD exhibited significant improvement in blood glucose and IR, and reduced serum levels of lipid metabolism biomarkers and inflammatory factors. Moreover, the diversity and abundance of gut microbiota undergo significant changes in rats with T2DM that PRD was able to reverse. The gut microbiota associated with T2DM including Rickettsiaceae bacterium 4572_127, Psychrobacter pasteurii, Parabacteroides sp. CAG409, and Paludibacter propionicigenes were identified. The gut microbiota most closely related to PRD were Prevotella sp. 10 (H), Parabacteroides sp. SN4, Flavobacteriales bacterium, Bacteroides massiliensis, Alistipes indistinctus, and Ruminococcus flavefaciens. Additionally, PRD regulated the levels of gut microbiota metabolites including pantothenic acid, 1-Methylhistamine, and 1-Methylhistidine; these affected metabolites were involved in pantothenate and coenzyme A biosynthesis, histidine metabolism, and secondary bile acid biosynthesis. Correlation analysis illustrated a close relationship among gut microbiota, its metabolites, and T2DM-related indexes. Conclusion: Our study provides insights into the gut microbiota and its metabolites of PRD therapy for T2DM. It clarifies the role of gut microbiota and the metabolites in the pathogenesis of T2DM, highlighting the potential of PRD for the treatment of this disease.