Metabolic dysfunction-associated kidney disease (MDAKD) is increasingly recognised as a major clinical consequence of the global rise in obesity, type 2 diabetes, hypertension, and cardiovascular disease. Accumulating evidence suggests that the gut microbiota may contribute to the development and progression of metabolic and renal disorders through complex mechanisms involving microbial metabolites, immune activation, and disruption of the intestinal barrier. This review provides an overview of current knowledge regarding the role of the gut microbiota and gut-derived metabolites in the pathogenesis of chronic kidney disease (CKD) associated with metabolic disorders. Special attention is given to short-chain fatty acids, bile acids, N-trimethylamine oxide, branched-chain amino acids, indoxyl sulfate, p-cresol sulfate, and lipopolysaccharides. Accumulating experimental and clinical evidence suggests that dysbiosis may contribute to chronic low-grade inflammation, insulin resistance, endothelial dysfunction, lipotoxicity, and profibrotic signaling pathways associated with kidney injury and cardiovascular complications. The review also identifies significant limitations in current microbiome research, such as the predominance of animal studies, methodological challenges in metabolite quantification, and difficulties in establishing causality in humans. Emerging therapeutic strategies targeting the gut microbiota, including dietary interventions, prebiotics, probiotics, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and faecal microbiota transplantation, may offer novel approaches to slowing CKD progression and improving metabolic health. However, further mechanistic and clinical studies are required to determine the efficacy of microbiota-targeted therapies in MDAKD.
