Gut microbiome alterations precede graft rejection in kidney transplantation patients

Background Kidney transplantation (KT) is the optimal treatment for end-stage kidney disease, with graft survival critically affected by the recipient’s immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might associate with allograft rejection. Methods We analyzed existing biomaterials of a multicenter prospective study involving 217 KT recipients and 28 kidney donors from the German Center for Infection Research. Changes in the gut microbiome were analyzed using 16S rRNA gene amplicon sequencing and functional predictions (PICRUSt2) and quantitative PCRs for the production potential of propionate and butyrate. Propensity score matching was utilized to compare patients who experienced graft rejection with those who did not. Results The gut microbiome showed gradual recovery post-KT, marked by an increase of Shannon diversity and SCFA-producing bacterial taxa. However, prior to graft rejection, significant alterations were noted in microbiome composition, characterized by a decrease in microbial diversity and SCFA-producing taxa. Post-rejection analysis revealed normalization of these microbiome features. Functional analysis highlighted a decreased potential for SCFA production in patients prior to rejection. Comparison to published microbiome signatures from chronic kidney disease (CKD) patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD. Conclusions Our findings suggest that alterations in the gut microbiome composition and function may precede and influence KT rejection, suggesting potential for use as biomarker and early therapeutic microbiome-targeting interventions to improve transplant outcomes. Key points – CKD-related microbiome alterations recover over time after transplantation mirroring CKD-to-health transition – Microbiome alterations with lowered production potential of short-chain fatty acids precede graft rejection, likely influencing graft immunity – The persistence of CKD-associated microbiome characteristics in rejection patients opens avenues for innovative treatment strategies.