Human gut microbiota and plasma metabolomics in Mn-glucose metabolism correlation

Previous epidemiological and laboratorial studies have demonstrated a close relationship between plasma manganese (Mn) levels and type 2 diabetes (T2D), however, the underlying mechanism remains undisclosed. In this study, we employed a comprehensive approach that integrated fecal 16S rRNA sequencing, plasma untargeted metabolomics as well as Mendelian randomization (MR) analysis in a community-based population to identify the key gut microbiota taxa and plasma metabolites involved in the correlation between Mn and glucose metabolism. We observed a significant negative correlation between plasma Mn concentrations and fasting plasma glucose (FPG) levels. The relative abundance of Prevotella genus showed a stepwise increase from the lowest to the highest Mn tertiles. Moreover, the plasma hypoxanthine levels were positively associated with the abundance of Prevotella while inversely linked to FPG levels. MR analysis further confirmed a negative causal relationship between Prevotella_7 and diabetes (OR = −0.312, 95% CI: −0.575 to −0.050, PIVW = 0.02), which aligned with the associations among Prevotella, hypoxanthine and FPG. Collectively, our findings suggested a novel “Mn-Prevotella-hypoxanthine” axis linking plasma Mn levels to glucose metabolism, offering promising mechanism insights into trace element-glucose metabolism and potential strategies for glycemic control.