Abstract
Pre-diabetes (PD) represents a critical stage in the progression toward type 2 diabetes, with significant alterations observed in the human microbial community among pre-diabetic individuals in observational studies. However, understanding the interaction between human microbiota and the host during pre-diabetes remains limited. Therefore, this study aims to understand the alterations in the human microbial community during pre-diabetes, a critical stage toward type 2 diabetes. Using an integrated analysis of human microbiota and metabolomics data, we seek to identify the functional signature associated with PD and gain insights into potential mechanisms driving its progression to type 2 diabetes. These findings could inform the development of early intervention strategies for those at high risk. Samples were collected from pre-diabetes, diabetes, and healthy control groups. Through metagenome and 16S rRNA sequencing, we analyzed the gut microbial and tongue coating compositions, respectively. Untargeted metabolomics techniques were also applied for comprehensive plasma data. Using integrated multi-omics analysis, we aim to understand the metabolic potentials of the human microbiome, its molecular links with host targets, and their effects on pre-diabetes, thereby deepening our understanding of microbiome-host interactions in this context. The pre-diabetes group exhibited distinct clinical characteristics, particularly in blood glucose levels and a higher average level of γ-glutamyl transferase. We identified 509 intestinal bacterial species, with Megamonas funiformis and Parabacteroides merdae showing higher abundance in the PD group. In tongue coating samples, we found 1,122 bacterial genera, with the PD group showing altered levels of Corynebacterium and Johnsonella. Furthermore, we detected 795 metabolites, primarily involved in carbohydrate and lipid metabolism. Importantly, our integrated multi-omics analysis suggested Flavonifractor plautii's role in modulating blood glucose through influencing carbohydrate metabolism. Our integrated multi-omics analysis revealed significant alterations in several regulatory pathways associated with pre-diabetes, particularly emphasizing the impact of gut bacterium Flavonifractor plautii on blood glucose levels through its influence on carbohydrate metabolism. These intricate relationships among gut microbiota, metabolites, and blood glucose levels underscore the significance of personalized treatment approaches and preventive strategies for pre-diabetes. The insights gained from this research hold considerable promise for advancing our understanding and management of pre-diabetes.IMPORTANCEThis study investigates alterations in the human microbial community during PD, a critical stage leading to type 2 diabetes. Through integrated analysis of metagenomic and metabolomics data from pre-diabetes, diabetes, and healthy control groups, we identified distinct clinical characteristics in the PD group, including elevated blood glucose levels and γ-glutamyl transferase. A total of 509 intestinal bacterial species were identified, with Flavonifractor plautii playing a key role in modulating blood glucose levels via its influence on carbohydrate metabolism. Our findings underscore the complex interactions among gut microbiota, metabolites, and blood glucose levels, highlighting the potential for personalized treatment approaches and early intervention strategies for individuals at high risk of developing type 2 diabetes.