Microbiota-associated metabolic networks in gut-kidney communication and renal immune regulation: mechanisms and therapeutic potential
TL;DR
Current evidence linking microbiota-associated metabolic networks to renal immune remodeling across different kidney diseases is summarized, highlighting metabolite origin, shared target-cell responses, disease-specific and context-dependent mechanisms, and current evidence limitations.
Abstract
Kidney disease development and progression involve not only local inflammation, immune dysregulation, and fibrosis but also alterations in gut microbiota composition and metabolic function. Microbiota-associated metabolic signals connect the intestinal ecosystem, host metabolism, and the renal immune microenvironment through their associations with intestinal barrier integrity, renal tubular epithelial homeostasis, immune cell function, and inflammatory-fibrotic responses. Depending on their biological origin, receptor engagement, target-cell specificity, and disease context, these signals may either support immune homeostasis and tissue repair or contribute to persistent inflammation and tissue remodeling. Representative mediators include short-chain fatty acids, tryptophan-derived metabolites, bile acid-related signaling molecules, indoxyl sulfate, p-cresyl sulfate, trimethylamine N-oxide, succinate, and other host-microbiota-associated metabolites. Their biological effects, however, cannot be interpreted independently of renal function because circulating metabolite levels are also influenced by impaired renal clearance, systemic inflammation, dietary factors, and host metabolism. Conversely, kidney dysfunction reshapes intestinal barrier integrity, microbial ecology, and metabolic output, establishing a dynamic gut-kidney metabolic-immune feedback network. In this Review, we summarize current evidence linking microbiota-associated metabolic networks to renal immune remodeling across different kidney diseases, highlighting metabolite origin, shared target-cell responses, disease-specific and context-dependent mechanisms, and current evidence limitations. We further discuss therapeutic strategies targeting this axis and emphasize key translational challenges, including distinguishing causal metabolic drivers from secondary metabolic alterations and developing precision interventions based on metabolic and immune phenotypes.