Jianhua Zhen Yunan Zhang Yini Li Yali Zhou ^* Yanan Cai ^* Guangrui Huang ^* Anlong Xu ^*

• Beijing University of Chinese Medicine, Beijing, China

Objective: This study aims to investigate the pathogenesis of hyperglycemia and its associated vasculopathy by using multiomics analyses in diabetes and impaired glucose tolerance. Methods: In this study, we conducted a comprehensive analysis of the metagenomic sequencing data of diabetes. Subsequently, participants diagnosed with impaired glucose tolerance (IGT), and healthy subjects, were recruited for fecal and blood sample collection. The dysbiosis of the gut microbiota (GM) and its associated metabolites were analyzed using 16S rDNA sequencing and liquid chromatograph mass spectrometry, respectively. The regulation of gene and protein expression was evaluated through RNA sequencing and data-independent acquisition technology, respectively. The specific mechanism by which GM dysbiosis affects hyperglycemia and its related vasculopathy was investigated using real-time qPCR, Western blotting, and enzyme-linked immunosorbent assay techniques in HepG2 cells and neutrophils. Results: Based on the published data, the key alterable genera in the GM associated with diabetes were identified. The GM metabolites taurodeoxycholate (TUDCA) and carnosine were both found to be decreased, which in turn regulated the expression of proteins in plasma and mRNAs in neutrophils. Insulin-like growth factor-binding protein 3 and interleukin-6 proteins were found to be suppressed by TUDCA and carnosine (CARN) in HepG2 cells and neutrophils. Conclusion: Dysbiosis of the GM occurred throughout the entire progression from IGT to diabetes, characterized by an increase in Blautia and a decrease in Faecalibacterium, leading to reduced levels of TUDCA and CARN, which promoted the expression of insulin-like growth factor-binding protein 3 and interleukin-6, contributing to the development of hyperglycemia and associated vasculopathy.