Gut Microbiota in Kidney Transplantation: Mechanistic Insights and Implications for Precision Immunosuppression

Kidney transplantation represents the optimal treatment for eligible patients with end-stage renal disease (ESRD), yet long-term graft survival remains threatened by rejection, infection, and immunosuppressant-related toxicity. Increasing evidence identifies the gut microbiome as an important modulator of these outcomes through the bidirectional gut-kidney axis. After kidney transplantation, microbial dysbiosis is commonly characterized by reduced diversity, enrichment of pathobionts such as Escherichia-Shigella and Enterococcus, and depletion of short-chain fatty acid (SCFA)-producing bacteria, including Faecalibacterium prausnitzii and members of the Lachnospiraceae family. These alterations are driven by the combined effects of pre-existing uremia, surgical and ischemia-reperfusion stress, immunosuppressive therapy, and antimicrobial exposure. Mechanistically, impaired barrier integrity and reduced SCFA production promote systemic inflammation and disrupt the regulatory T-cell (Treg)/T helper 17-cell (Th17) balance, whereas tryptophan metabolites and aryl hydrocarbon receptor signaling further influence alloimmune responses. The microbiota also contributes to variability in immunosuppressant efficacy and toxicity. Bacterial metabolism of tacrolimus and microbiota-mediated regulation of intestinal ABCB1 expression may account for a clinically relevant proportion of tacrolimus pharmacokinetic variability, while bacterial beta-glucuronidase reactivates mycophenolic acid in the intestine and contributes to mycophenolate mofetil-associated gastrointestinal toxicity. Microbiota-derived uremic toxins may additionally reinforce oxidative stress and graft fibrosis. Although fecal microbiota transplantation, precision nutrition, probiotics, and postbiotics show therapeutic potential, current evidence remains largely observational or exploratory. Multicenter randomized controlled trials are therefore required before microbiome-based strategies can be incorporated into routine precision immunosuppression.