Microbiota-derived deoxycholic and lithocholic acids attenuate diabetic kidney disease through suppression of podocyte ferroptosis via TGR5-SLC7A11 interaction

Objectives Diabetic kidney disease (DKD) is related to gut dysbiosis, yet the specific causative microbes remain unclear. This study integrated multi-omics, including 16S rRNA sequencing, metagenomics, and bile acid metabolomics on fecal samples from DKD patients and mice. Methods Parabacteroides goldsteinii ( P. goldsteinii ) was orally administered to DKD mice, with assessment of podocyte injury, glomerular function, renal inflammation, and gut barrier integrity. Results In this study, we found a significant depletion of the gut commensal P. goldsteinii in both murine models and patients with DKD. Oral administration of P. goldsteinii ameliorated podocyte injury, glomerular dysfunction, renal inflammation, and gut barrier disruption in diabetic mice. The protective effects were mediated by microbially derived bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), which activate Takeda G protein-coupled receptor 5 (TGR5), with the combined treatment producing greater protective effects than either bile acid alone. Furthermore, inhibition of bile acid hydrolysis (BSH) activity blocked the production of DCA/LCA and eliminated the renal benefits of P. goldsteinii . Mechanistically, DCA and LCA inhibited ferroptosis by promoting the interaction between TGR5 and SLC7A11 in podocytes. This interaction may contribute to the preservation of SLC7A11 function and enhancement of cellular antioxidant capacity, thereby attenuating iron-dependent lipid peroxidation. Podocyte-specific knockdown of TGR5 abolished the renoprotection conferred by P. goldsteinii and DCA/LCA. Conclusion Collectively, our work identified a gut–kidney axis in which P. goldsteinii –derived bile acids regulated the TGR5-SLC7A11 macromolecular interaction to suppress podocyte ferroptosis, thereby attenuating DKD progression. These findings revealed a functional interaction between TGR5 and SLC7A11 and highlighted its regulation by microbial metabolites as a potential therapeutic mechanism for DKD.