Causal effects of gut microbiota on diabetic kidney disease: insights from 16S rRNA sequencing and bidirectional Mendelian randomization

Dysbiosis of the gut microbiome plays a critical role in diabetic kidney disease (DKD) development and progression. We stratified 46 type 2 DKD patients from Ruijin Hospital into early or advanced DKD groups in this cross-sectional study. Fecal samples underwent 16S rRNA sequencing. Statistical analyses (t-tests, Chi-square, GLMs) and MR were performed using SPSS and R. We found that advanced DKD patients exhibited distinct gut microbiota profiles, with LEfSe analysis showing higher Butyricimonas, Fusicatenibacter, and Barnesiella and lower Allisonella compared to early DKD, while DKD-susceptible individuals had elevated Fusobacterium and reduced Allisonella and Eubacterium. GLMs linked Barnesiella, Streptococcus, Fusobacterium to DKD susceptibility (p < 0.05), and Slackia and Eubacterium to early/resistant DKD. MR analysis demonstrated causality: Barnesiella (OR: 2.382), Butyricimonas (OR: 1.278), Desulfovibrio (OR: 2.518), and Hemophilus (OR: 1.622) worsened DKD, whereas Slackia and Allisonella protected against eGFR decline (p < 0.05). Reverse MR revealed the bidirectional effects-severe DKD increased Ruminococcus2 but suppressed Allisonella and Akkermansia (p < 0.05), underscoring microbiota-DKD interplay. Sensitivity analyses (MR-Egger, weighted median, leave-one-out) confirmed the robustness and directionality of these causal effects. In conclusion, 10 key bacterial genera were causally linked to DKD progression and susceptibility, including harmful (Barnesiella, Butyricimonas, Desulfovibrio, Hemophilus, Bacteroides, Streptococcus, Ruminococcus2) and protective taxa (Slackia, Allisonella, Akkermansia). These genera serve as novel biomarkers for early detection and risk stratification, and as potential therapeutic targets for microbiota-modulating interventions to mitigate DKD progression. The bidirectional microbiota-DKD interplay further underscores the promise of targeting gut dysbiosis in DKD precision management.