Dehydrolithocholic Acid Mitigates Diabetic Kidney Disease by Activating TGR5 and FXR

Background: Diabetic kidney disease (DKD) is a significant contributor to chronic kidney disease, with metabolic factors playing a crucial role in its development. Our study aimed to investigate the impact of bile acid (BA) metabolism on DKD progression and to explore the mechanisms through which BA metabolism influences DKD. Methods: Plasma BA levels in healthy control (HC), type 2 diabetes mellitus (T2DM), and DKD groups were measured using ultrahigh-performance liquid chromatography tandem-mass spectrometry (UPLC-MS/MS). Following the identification of potential biomarkers in the clinical study, further in vivo validation was performed. Dehydrolithocholic acid (DHLCA) intervention was administered to DKD mice, and samples of blood, urine, feces, and kidney tissues were collected at 20 weeks of age. Kidney injury was assessed using HE, PAS, and Masson staining. The expression of Takeda G protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR) in kidney tissues was analyzed using immunohistochemistry, immunofluorescence, real-time quantitative polymerase chain reaction (RT-qPCR), and western blot (WB). Gut microbiota (GM) metagenomic analysis and targeted BA metabolomics were conducted on fecal samples to assess changes in GM composition and BA levels following DHLCA intervention. Results: Variations in BA levels were noted among HC, T2DM, and DKD groups. The DHLCA levels in the DKD with macroalbuminuria group were significantly lower compared to the T2DM group, and univariate correlation analysis revealed that DHLCA had the strongest correlation with the urine albumin-to-creatinine ratio (UACR) (r = −0.329, P = 0.001). In the DKD+DHLCA group, UACR, fasting blood glucose (FBG), liver function, and total BA (TBA) levels were significantly reduced compared to the DKD group alone. Kidney tissue pathology showed that DHLCA intervention mitigated renal tubular injury in DKD. Compared to the DKD group, the expression of TGR5 and FXR in kidney tissues was restored following DHLCA intervention. Metagenomic analysis revealed a significant alteration in GM composition in mice post-DHLCA intervention, marked by an increased presence of Firmicutes, particularly Lachnospiraceae bacterium. Conclusion: BA metabolism is altered with the progression of DKD. DHLCA may enhance DKD renal tubular recovery by activating TGR5 and FXR. DHLCA could serve as a potential biomarker for DKD diagnosis and treatment. Funding: Government Support – Non-U.S.