Role of GU174097 on type-2 diabetes pathogenesis: A longitudinal study of urine microbiome and metabolites

Recent investigations have identified the essential role of the human microbiome in Type 2 diabetes (T2D). However, despite the importance of understanding the microbiota throughout the body in the pathogenesis of T2D, most studies have been done on stool samples. Recently, extracellular vesicles have provided important clues in understanding pathogenetic mechanisms in Type 2 diabetes as extracellular vesicles play as key communication messenger between intestinal microorganisms and hosts. By tracking the changes in vesicle-based microorganisms in urine samples collected three times over six years, we investigated how microbes and their metabolites interact with the human body and affect the development of T2D. In addition, Mendelian randomization analysis was conducted to confirm the causal relationship among the microbial organisms, metabolites, and clinical measures to present a complete picture of how microorganism can affect T2D. We analyzed a prospective and longitudinal Korean community-based cohort (KARE) with EV-derived metagenomic (N = 393), clinical (N = 5032), genomic (N = 8842), and metabolite (N = 574) data. We identified GU174097_g, an unclassified Lachnospiraceae, to be associated with T2D and ketone bodies and demonstrated the causal relationship between acetoacetate, one of a ketone bodies, and HbA1c level. GU174097_g reduced ketone bodies, subsequently decreasing HbA1c level and the risk of T2D. Our findings indicate that GU174097_g may lower the risk of T2D by reducing ketone bodies. This result can facilitate large-scale longitudinal studies and in vivo and in vitro experiments in the future that explain biological mechanisms.