Integrated analysis of metabolomics, network pharmacology, and intestinal microbiota reveals Tibetan herb E’se ameliorate disorders of glycolipid metabolism in db/db mice

Abstract

Background

E’se (Malus toringoides (Rehd.) Hughes or Malus transitoria (Batal.) Schneid) is widely used as a drug for the treatment of diabetes mellitus in China, but the mechanism by which E 'se regulates disorders of glucose-lipid metabolism has lacked in-depth study. The intestinal microbiota also plays a crucial role in lipid metabolism, but whether E 'se regulates this process by modulating the intestinal microbiota needs to be further investigated.

Objective

Effects of aqueous extract of E'se decoction lyophilized powder (EMT) on metabolic disorders of glucose and lipid, and its mechanism of glucose regulation mediated through intestinal microbiota in db/db mice.

Methods

UPLC-Q-TOF-MS was used to analyze the chemical composition of EMT and predict potential therapeutic targets in combination with network pharmacology and molecular docking. The pharmacological effects of EMT were evaluated in six groups of db/db mice (db/db group, rosiglitazone group, low, medium, and high dose EMT of 0.75 g, 1.5 g, 3.0 g/kg/d) and db/m (WT) for 4 weeks’ treatment. ELISA was performed to determine serum concentrations of glycated hemoglobin (HbA1C), glycated serum protein (GSP), free fatty acids (FFA), fasting insulin (FINS), lipopolysaccharide (LPS), and glucagon-like peptide-1 (GLP-1), feces was used for microbial 16S rRNA sequencing and short-chain fatty acid (SCFA) quantification, and organs were used for pathologic assessment and subsequent mechanistic studies.

Results

Based on network pharmacology and molecular docking predictions, the role of EMT in regulating glycolipid metabolism mainly involves pathways such as G protein-coupled receptor(GPR) activity and GLP-1 secretion. Subsequently, it was demonstrated in animal experiments that EMT significantly ameliorated the abnormalities of glycolipid metabolism in db/db mice. Further microbial 16S r RNA sequencing analysis revealed significant changes in the composition of the intestinal microbiota, with increased abundance of Muribaculacea, Alloprevotella, Rikenella, and Parabacteroides, associated with enhanced SCFA secretion. Increased SCFA activated hepatic GPR, promoted GLP-1 secretion, modulated secretion of inflammatory factors and oxidative factors in the intestine, and down-regulated the NF-κB pathway in db/db mice.

Conclusion

Studies have demonstrated that E'se can effectively alleviate abnormalities of glucose-lipid metabolism and intestinal barrier inflammation, making it a novel drug with great therapeutic potential.