Gut‑liver‑kidney axis: A systems biology framework for understanding and treating chronic kidney disease (Review)

Chronic kidney disease (CKD) is traditionally studied through an organ‑centric paradigm, despite its frequent coexistence with intestinal dysbiosis and metabolic dysfunction‑associated steatotic liver disease, which confers a 38% increased CKD risk. Multi‑organ crosstalk along the gut‑liver‑kidney axis remains inadequately addressed in current guidelines. The present study aimed to establish the gut‑liver‑kidney axis as an integrated systems biology framework for understanding CKD progression and to translate this framework into diagnostic, therapeutic and clinical trial strategies. The present review aimed to combine mechanistic summaries with systems biology perspectives, including weighted gene co‑expression network analysis, Bayesian causal inference and ordinary differential equation‑based dynamic modeling, to map bidirectional signaling across microbial, metabolic, inflammatory and hemodynamic dimensions, with diabetic kidney disease (DKD) as the principal exemplar. The axis operates through anatomically and molecularly defined positive feedback loops in which gut dysbiosis drives barrier failure and endotoxemia, amplifying hepatic lipotoxicity and bile acid dysregulation, precipitating renal tubular injury and fibrosis. This self‑perpetuating cycle, sustained by uremic toxin signaling, dysregulated peroxisome proliferator‑activated receptor/farnesoid X receptor (FXR)/Takeda G protein‑coupled receptor 5 (TGR5) pathways and trained immunity (a persistent hyperinflammatory state of innate immune cells driven by epigenetic and metabolic reprogramming), is most pronounced in DKD. Microbiome‑targeted interventions and FXR/TGR5 modulators are as the most clinically advanced axis‑directed strategies, though most remain at preclinical or early‑phase stages. Reframing CKD as gut‑liver‑kidney axis dysfunction enables systems‑level mechanistic integration, precision diagnostics through composite microbiome‑metabolomic signatures, and adaptive trial designs targeting upstream pathology, providing a foundation for incorporating axis‑based approaches into future CKD management.