Decoding the Gut‐Renal Crosstalk: Mechanistic Insights Into Microbial Dysbiosis, Metabolomic Signaling and Kidney Transplantation Outcomes

Abstract

The gut microbiome has emerged as a major regulator of host metabolic, immune and barrier functions, with growing implications for renal physiology and kidney transplantation. In this review, we synthesize current evidence supporting a bidirectional gut‐renal axis in which microbial dysbiosis contributes to kidney injury through four interconnected mechanisms: intestinal barrier disruption with systemic translocation of microbial products, accumulation of nephrotoxic microbial metabolites, immune reprogramming toward pro‐inflammatory pathways, and reciprocal remodeling of the gut ecosystem by uremia. We further extend this framework to kidney transplantation, where dysbiosis is increasingly linked to perioperative injury, alloimmune activation, acute and chronic rejection, infectious complications, and variability in immunosuppressant pharmacokinetics. Particular emphasis is placed on the mechanistic roles of short‐chain fatty acids, indole and phenolic uremic toxins, trimethylamine‐N‐oxide, bile acid signaling, and microbiome‐driven modulation of host immunity and drug handling. We also examine emerging concepts including donor‐recipient microbiome compatibility, pharmacomicrobiomics and the potential contributions of the virome and mycobiome to graft outcomes. Finally, we critically assess current methodological limitations, unresolved controversies and the translational landscape of microbiome‐targeted interventions, including diet, prebiotics, probiotics, postbiotics, microbial enzyme inhibitors and fecal microbiota transplantation. Collectively, this review proposes an integrated gut‐renal‐transplant model in which the intestinal microbiome functions not merely as a biomarker, but as a potentially modifiable determinant of transplant outcomes. Defining causal mechanisms and developing standardized, multi‐omic mechanism‐driven clinical studies will be essential to advance microbiome‐informed precision medicine in kidney transplantation.