Dehydrolithocholic Acid (DHLCA) Ameliorates Diabetic Kidney Disease by Activating TGR5/FXR Signaling and Remodeling the Gut Microbiota

Diabetic kidney disease (DKD) is one of the primary causes of long-term loss of renal function internationally. In recent years, bile acids (BAs) have emerged as important metabolic signals influencing glucose control and kidney physiology. This project explored how disturbances in BA pathways contribute to DKD advancement. Plasma BA concentrations were quantified in healthy individuals (HC), subjects with type 2 diabetes mellitus (T2DM), and patients diagnosed with DKD using ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). After potential BA markers were identified in the clinical cohort, mechanistic validation was carried out in a DKD mouse model treated with dehydrolithocholic acid (DHLCA). Kidney injury indicators and the expression of Takeda G protein-coupled receptor 5 (TGR5) and farnesoid X receptor (FXR) were assessed. Metagenomic sequencing was also performed to characterize gut microbiota (GM) after DHLCA exposure.
DHLCA levels in plasma were markedly decreased in DKD patients with macroalbuminuria compared with both the T2DM group and the DKD cohort with microalbuminuria (P < 0.01). Partial Spearman analysis controlling for age and diabetes duration indicated a negative correlation between DHLCA and urinary albumin (ρ = –0.347; 95% CI, –0.531 to –0.135; q = 0.008), as well as with urine albumin-to-creatinine ratio (UACR) (ρ = –0.332; 95% CI, –0.499 to –0.155; q = 0.010). In vivo, DHLCA administration significantly reduced UACR and fasting blood glucose (FBG) levels (P < 0.01) and improved liver enzyme status (ALT, P < 0.05). DHLCA lowered renal tubular damage, restored normal TGR5 and FXR expression patterns, and decreased kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Metagenomic analysis showed an increase in Lachnospiraceae bacterium after treatment. DHLCA may represent a useful DKD therapeutic candidate by engaging the FXR/TGR5 pathways and altering gut microbial composition. Its renal and metabolic improvements, together with enhanced liver safety and absence of hepatotoxicity, justify continued translational development.