Gut microbiota and gut-kidney axis in kidney diseases: therapeutic potential and perspectives of natural products.

Gut microbiota exert core regulatory effects on systemic metabolic homeostasis and immune balance under physiological and pathological conditions. Marked gut dysbiosis occurs during the progression of chronic kidney disease (CKD), characterized by abnormal enrichment of opportunistic pathogens and depletion of beneficial commensal bacteria. This pathological alteration leads to excessive accumulation of uremic toxins including indoxyl sulfate, p-cresyl sulfate and trimethylamine N-oxide (TMAO), as well as sharp reductions in the synthesis of intestinal protective metabolites such as short-chain fatty acids (SCFAs) and indole-3-aldehyde. The imbalance between harmful and protective metabolites persistently triggers renal inflammatory activation and interstitial fibrosis via activating multiple signaling pathways, including the renin-angiotensin system, oxidative stress, Toll-like receptor 4, aryl hydrocarbon receptor, IκB/NF-κB, Keap1/Nrf2, NLRP3 inflammasome and ferroptosis. This review systematically summarizes the pathological correlations between gut microbiota disturbance and various renal disorders, namely diabetic kidney disease, membranous nephropathy, lupus nephritis, IgA nephropathy, hypertension-associated nephropathy and dialysis-related renal injury, and clarifies the universal mechanisms and disease-specific characteristics underlying gut-kidney axis-mediated progression of different subtypes of kidney diseases. Natural products represented by natural polysaccharides, traditional Chinese medicine formulas and plant polyphenols are capable of remodeling gut microbiota composition, repairing intestinal mucosal barrier function, balancing microbial metabolic profiles and regulating gut-kidney axis homeostasis, thereby exerting renal and multi-organ protective effects in patients with CKD and dialysis-dependent individuals. Targeted modulation of intestinal microecology and intervention against gut-kidney axis dysfunction using natural products provide novel strategies for early prevention and control of CKD, disease progression retardation and prognosis improvement in dialysis patients, and also lay a theoretical foundation for the development and clinical translational application of novel therapeutic targets for kidney diseases.