Blood metabolites mediate causal inference studies on the effect of gut microbiota on the risk of vascular calcification

Abstract

Background

Emerging evidence indicates a notable connection between gut microbiota and Vascular Calcification (VC). Gut microbiota influences various disease processes through host metabolic pathways; however, the causative link between gut microbiota and VC, along with the potential mediating role of metabolites, is still not well understood.

Methods

We leveraged data from the largest Genome-Wide Association Studies (GWAS) concerning gut microbiota, blood metabolites, and VC. To explore the causal relationships among these variables, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses. Furthermore, mediation analyses were conducted to determine if metabolites act as an intermediary in the impact of gut microbiota on VC. In addition, we recruited CKD patients for mass spectrometry and CT examination, and performed a correlation analysis between the expression of blood metabolites and VC score. Finally, we experimentally validated the effects of intermediate metabolites on VC.

Results

We identified 19 positive gut microbiota species and 52 positive blood metabolites with causal effects on VC. Additionally, the onset of VC was found to induce changes in the abundance of 24 gut microbiota species and 56 metabolites. Further analyses revealed that up to 13 positive gut microbiota species regulate the expression of 20 positive metabolites. Mediation analysis suggests that the gut microbiota g_KLE1615 promotes VC by downregulating the methionine-to-phosphate ratio. Mass spectrometry results indicate that over half of the metabolites identified through MR analysis show altered expression during CKD progression. Among them, 7 metabolites were significantly associated with the progression of VC. Further in vitro experiments confirmed the inhibitory effect of the intermediate metabolite methionine on VC.

Conclusion

Gut microbiota and blood metabolites are causally linked to VC. These findings provide a theoretical basis for microbiome- and metabolome-based therapeutic strategies for targeting VC and enhances our comprehension of the gut-vascular axis.