Gut microbiome alterations precede graft rejection in kidney transplantation patients Original paper

What was studied?

Gut microbiome alterations preceding kidney transplant rejection form the focus of this original research article, which uses 16S rRNA gene sequencing to evaluate how microbial composition and function shift before, during, and after graft rejection. The study examines a multicenter cohort and emphasizes the role of short-chain fatty acid (SCFA)–producing taxa as a central microbiome signature. This research reveals that the gut microbiome in kidney transplant recipients shows a recovery trajectory over time, yet this trajectory is disrupted in patients who progress to rejection. Prior to rejection, patients develop a microbiome signature characterized by reduced diversity, reduced SCFA production potential, and increased enrichment of disease-associated genera. This prerejection microbiome resembles a prolonged chronic kidney disease (CKD) gut signature, suggesting that residual CKD-related dysbiosis may play a mechanistic role in immune dysregulation leading to rejection.

Who was studied?

The study analyzes 562 fecal samples collected from 245 individuals participating in the DZIF transplant cohort in Germany, of whom 217 were kidney transplant recipients and 28 were kidney donors. After applying inclusion and exclusion criteria, 76 patients experiencing biopsy-confirmed rejection events were compared with 141 non-rejection patients. A propensity-matched subcohort of 92 individuals (32 rejection, 60 non-rejection) was also analyzed to control for confounders such as age, sex, donor type, HLA mismatch, and time from transplant. Samples were drawn longitudinally before transplant, at predefined intervals post-transplant, at the time of rejection, and in the later post-rejection period, enabling assessment of temporal microbiome dynamics relative to transplant status and graft rejection.

Most important findings

Patients who later rejected their graft exhibited reduced Shannon diversity, lower Simpson evenness, and distinct beta-diversity clustering compared to non-rejection recipients. Key SCFA-producing genera—including Blautia, Faecalibacterium, Roseburia, Coprococcus, and the Ruminococcus torques group—were depleted prior to rejection. Conversely, Streptococcus and Fusobacterium, taxa associated with inflammation and CKD dysbiosis, were enriched. qPCR confirmed functional loss of SCFA-producing pathways, revealing decreased abundance of butyryl-CoA:acetate CoA-transferase (but) and methylmalonyl-CoA decarboxylase (mmdA), with trends toward reduction of bcd and acK enzymes. Pathway analysis (GOmixer) showed increased proteolytic fermentation, reactive nitrogen and oxygen species pathways, and ammonia metabolism in the prerejection state, while healthy controls demonstrated higher mucin degradation and carbohydrate fermentation capacity. Post-rejection, the microbiome began normalizing, with increasing SCFA-producing taxa and reduced inflammatory genera. Comparisons with a published CKD cohort confirmed strong overlap, suggesting rejection-associated dysbiosis represents a persistent CKD-like microbiome state.

Key implications

These findings position the gut microbiome as a predictive and modifiable factor in kidney transplant rejection. Depletion of SCFA-producing taxa and reduced microbial metabolic capacity may impair regulatory T cell modulation, weakening immune tolerance and facilitating rejection. Identifying a pre-rejection microbial signature offers potential for early-detection biomarkers, microbiome-targeted therapeutics, and dietary or microbial interventions aimed at restoring SCFA production, improving immune homeostasis, and enhancing long-term graft survival. Post-rejection normalization suggests that intervention windows may exist both before and after rejection episodes, further underscoring the microbiome’s relevance in clinical transplant management.

Citation

Holle J, Reitmeir R, Behrens F, et al. Gut microbiome alterations precede graft rejection in kidney transplantation patients.American Journal of Transplantation. 2025;25:1643-1656. doi:10.1016/j.ajt.2025.02.010