Causal relationships between the gut microbiota, immune cells, and diabetic kidney disease: a Mendelian randomization and mediation analysis.

Observational studies have indicated that the gut microbiota is associated with diabetic kidney disease (DKD). However, it remains unclear whether disturbances in the gut microbiota causally contribute to DKD. This study aimed to investigate the causal relationships between the gut microbiota and DKD and explore peripheral immune cell traits as potential mediators. Summary statistics were extracted from genome-wide association studies of the Dutch Microbiome Project (N = 7,738), SUMMIT Consortium (N = 10,875), and GWAS summary statistics for immune cell traits (N = 3,757). We used a two-sample two-step mediation Mendelian randomization analysis to investigate genetic causality between immune cell traits and the phenotypes of DKD, causal effect of gut microbiota/microbiota metabolism pathways on DKD, and mediation effects of immune cell traits. In total, seven immune cell traits and five taxa were causally associated with the DKD phenotypes after multiple testing corrections. We performed mediation analysis on gut microbiota and immune cell traits that passed the Bonferroni correction, and identified five mediation relationships. For instance, mediation analysis indicated that Pseudoflavonifractor capillosus had adverse effects on chronic kidney disease in type 2 diabetes by downregulating CD25 expression in CD4+ regulatory T cells (proportion mediated = 19.8%, p = 0.035). These results indicate that the gut microbiota has causal effects on DKD and that immune cell traits exert a mediation effect to some extent.