Indoxyl sulfate in the gut-kidney axis: from diet-microbiome interactions to renal injury and targeted therapies.

Indoxyl sulfate (IS) is a prototypical protein-bound uremic toxin, linking dietary tryptophan metabolism by gut microbiota to renal injury. Derived from dietary tryptophan metabolized by gut microbiota into indole, which is subsequently transported to the liver and sulfated to form IS. In circulation, IS binds serum albumin and is actively secreted into urine via renal tubular organic anion transporters. In chronic kidney disease (CKD), impaired renal clearance and altered albumin-binding capacity contribute to IS accumulation and an increased free fraction. IS exerts nephrotoxic effects through multiple mechanisms. As an endogenous ligand of the aryl hydrocarbon receptor (AHR), it activates AHR signaling and contributes to mitochondrial dysfunction, oxidative stress, inflammation, regulated cell death, and renal fibrosis through interconnected downstream pathways. Therapeutic strategies targeting IS include dietary and microbiota-based interventions, oral adsorbent AST-120, modified dialysis approaches, and traditional Chinese medicine interventions. Although these strategies may reduce IS exposure or its downstream effects, the current evidence is predominantly derived from preclinical studies and surrogate-endpoint assessment. Further well-designed clinical trials are needed to determine whether reducing IS exposure can translate into sustained improvements in renal and patient-centered outcomes.