Simiao Decoction alleviates hyperuricemia-induced renal injury through regulating gut dysbiosis and decreasing gut-derived uremic toxins.

Simiao decoction (SMD) effectively alleviated hyperuricemia-induced renal injury in a spontaneous HUA rat model.

• A spontaneous hyperuricemia (HUA) rat model was used to assess SMD's therapeutic effects.
• SMD treatment reduced markers of renal injury associated with hyperuricemia.
• Hyperuricemia was recognized as an independent risk factor for chronic kidney disease (CKD) in the study context.
• SMD is a traditional Chinese medicine formula used as the intervention.

SMD modulated gut microbiota composition and reduced gut dysbiosis in hyperuricemic rats.

• SMD treatment altered the gut microbiota composition in the spontaneous HUA rat model.
• Fecal microbiota transplantation (FMT) confirmed that the therapeutic effect of SMD was mediated by gut microbiota.
• FMT experiments demonstrated that transferring SMD-treated microbiota was sufficient to recapitulate the therapeutic effects.
• The gut-kidney axis theory was invoked to explain the mechanism of SMD's action on renal injury.

SMD reduced gut-derived uremic toxins indoxyl sulfate (IS) and p-Cresol (PC) by modulating bacterial metabolism of tryptophan and tyrosine.

• SMD decreased levels of indoxyl sulfate (IS), a tryptophan-derived uremic toxin.
• SMD decreased levels of p-Cresol (PC), a tyrosine-derived uremic toxin.
• The reduction in uremic toxins was attributed to SMD's modulation of bacterial metabolic pathways for tryptophan and tyrosine.
• IS and PC are classified as gut-derived uremic toxins in this study.

Indoxyl sulfate (IS) promotes epithelial-mesenchymal transition (EMT) in tubular cells in vitro.

• In vitro studies were conducted to assess the effects of IS on tubular cells.
• IS treatment induced epithelial-mesenchymal transition (EMT) in tubular cells.
• EMT in tubular cells is associated with renal fibrosis and progression of kidney disease.
• These findings were identified using in vitro cell studies.

p-Cresol (PC) induces cellular senescence in tubular cells in vitro.

• In vitro studies demonstrated that PC induced cellular senescence in tubular cells.
• Cellular senescence induced by PC represents a distinct mechanism of renal tubular injury from that caused by IS.
• These findings were identified using in vitro cell studies.
• Both IS and PC were identified as contributors to HUA-induced renal injury through separate cellular mechanisms.

The therapeutic effects of SMD on hyperuricemia-induced renal injury were confirmed to be mediated through the gut microbiota via fecal microbiota transplantation.

• Fecal microbiota transplantation (FMT) was performed to verify the gut microbiota-mediated mechanism.
• FMT using microbiota from SMD-treated rats reproduced the renoprotective effects observed with direct SMD treatment.
• This finding directly implicates gut microbiota as the mediator of SMD's therapeutic effect rather than direct systemic action of SMD compounds.
• The gut-kidney axis was identified as the key mechanistic pathway for SMD's action.