Gut microbial-derived metabolites: key players in kidney disease and renal fibrosis

Kidney disease is a major global public health problem that affects 15-20% of adults globally. Increasing evidence shows that kidney injury results in intestinal barrier dysfunction, microbial dysbiosis, and microbial-derived metabolite disorder. Microbial-derived metabolites are recognized as multi-kingdom intermediates. The alterations of the gut microbiota lead to the reductions of short-chain fatty acids including acetate, butyrate, and propionate, while excessive accumulation of uremic toxins, including indoxyl sulfate, indole-3-acetic acid, trimethylamine-N-oxide, and p-cresyl sulphate that involved in renal disease. Various effects are moderated by regulating aryl hydrocarbon receptor, G-protein-coupled receptor 43, Toll-like receptor 4, domain-like receptor family protein 3, phosphatidylinositol-3 kinase, inhibitor of kappa B /nuclear factor kappa B and kelch-like ECH-associated protein 1/nuclear factor erythroid 2-related factor 2 pathways via gut microbiota-derived metabolites. Among them, tryptophan metabolites are considered pivotal in the communication between gut microbiota and kidneys. This review summarizes current understanding of the role of gut microbial-derived metabolites in acute kidney injury and chronic kidney disease including diabetic kidney disease, immunoglobulin A nephropathy and membranous nephropathy, explain the underlying pathophysiology of these associations and pinpoint potential targets for the future precision-based modulation of therapies. This review also explores therapeutic options, such as natural products, prebiotics, probiotics, and renal replacement therapy, for targeting gut microbiota dysbiosis and their metabolites in patients with kidney diseases to provide a more concept-driven and precise therapy strategy.