Gut microbiota-liver-kidney axis in diabetic kidney disease: mechanistic insights into amino acid metabolism and nutritional intervention strategies targeting natural bioactive compounds

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease globally. Emerging research highlights the gut microbiota-gut-liver-kidney axis as a critical metabolic nexus linking dietary intake to DKD pathogenesis and progression. The gut microbiota, acting as a vast metabolic organ, transforms dietary components into key metabolites. Beneficial fermentation of fiber produces short-chain fatty acids (SCFAs) like butyrate, which exert anti-inflammatory and renal protective effects. Conversely, microbial metabolism of aromatic amino acids generates protein-bound uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, which promote oxidative stress, inflammation, and fibrosis upon renal accumulation. DKD is characterized by intestinal barrier dysfunction (“leaky gut”) and metabolic endotoxemia, creating a vicious cycle that sustains systemic inflammation and kidney injury. Nutritional interventions targeting this axis show therapeutic promise. Dietary patterns (e.g., Mediterranean diet, increased plant protein) and specific prebiotics can modulate microbial composition, enhance SCFA production, and reduce uremic toxins. Natural bioactive compounds (e.g., berberine, quercetin, astragalus polysaccharides) and “medicine food homology” substances demonstrate multi-target renoprotective effects by restoring microbiota balance, improving intestinal barrier integrity, and mitigating metabolic dysregulation. Future management strategies will leverage precision nutrition, utilizing multi-omics and artificial intelligence to design personalized dietary interventions based on individual microbiota profiles, offering a novel paradigm for comprehensive DKD care alongside conventional therapies.