Investigating the role of gut microbiota in diabetic nephropathy through plasma proteome mediated analysis

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and poses significant threats to individuals with diabetes. The concept of gut-kidney axis has gained increasing attention in recent years and the in the occurrence and development of DN, alterations in the gut microbiota also plays a crucial and indispensable role. However, the specific causal relationships between various gut microbial communities and DN, as well as the underlying molecular mechanisms, remains unclear. This study utilized data from genome-wide association studies. After screening for qualified instrumental variables, mendelian randomization causal analyses were performed by inverse variance weighting, MR-Egger, weighted median, weighted mode and MR-RAPS methods. Additionally, sensitivity analyses such as heterogeneity, multiplicity, and the direction of the causal effect were carried out to ensure that the results were robust. After identifying significant gut microbiota, protein-proteomics mediation analysis was conducted on potential 3282 plasma proteins to determine those with mediating effects. Finally, Reactome enrichment analysis was performed to ascertain metabolic or signaling pathways with mediating effects. Mendelian randomization analysis indicated associations between 21 gut microbiota and DN. After adjusting significance levels, Catenibacterium and Parasutterella were found to have causal effects on the onset of DN. Subsequently, we identified 22 plasma proteins with mediating effects, along with 27 metabolic or signaling pathways including activated propionic acid metabolism. Increased in the abundance of Catenibacterium and Parasutterella intestinal bacteria are causative factors for DN. More importantly, the underlying mechanism by which the increased abundance of Catenibacterium and Parasutterella intestinal bacteria lead to DN were revealed, providing a blueprint for the involvement of gut-kidney axis in the pathogenesis of DN and paving the way for future studies.