Tripterygium glycosides tablet ameliorates chronic kidney disease via gut-derived uremic toxins reduction in rats: alkaloids as major toxic ingredients.

OBJECTIVE: Tripterygium glycosides tablet (TGT), the major preparation of Tripterygium wilfordii Hook. f (TWHF), is widely used in treating chronic kidney disease (CKD). However, its complex composition and overlap between active and toxic constituents often lead to adverse effects, limiting precise clinical use. This study aimed to clarify the therapeutic mechanisms of TGT in CKD and identify its potential toxic ingredients.

METHODS: Using constituent knock-out/knock-in technology and HPLC fingerprinting, Tripterygium glycosides tablet was divided into an alkaloid-enriched fraction and a non-alkaloid-enriched fraction An adenine-induced CKD rat model was used to evaluate efficacy and toxicity. Non-targeted metabolomics and 16S rRNA sequencing identified key metabolites and gut microbiota, while a UPLC-MS/MS method quantified gut-derived uremic toxins.

RESULTS: TGT reduced serum creatinine, urea nitrogen, and uric acid levels, improved renal filtration, and restored kidney morphology. Metabolomic and microbiota analyses revealed decreased indole and amino acid derivatives and regulation of g_Bacteroides and g_Rodentibacter. UPLC-MS/MS confirmed reductions in indoxyl sulfate (IS) and p-cresyl sulfate (pCS), mainly via inhibition of the tryptophan-indole-IS pathway. Conversely, AEF increased creatinine, urea nitrogen, cystatin C, and trimethylamine N-oxide (TMAO), exacerbating glomerular dysfunction.

CONCLUSION: TGT exerts renoprotective effects partly by modulating the gut-liver-kidney axis and reducing gut-derived uremic toxins, while alkaloids likely contribute to its toxicity. These findings offer new insights into the safe and effective use of TGT in CKD therapy.