Gut microbiome and metabolite signatures for predicting acute kidney transplant rejection

Acute rejection (AR) remains a significant challenge in kidney transplantation (KT), despite advances in immunotherapy. Recognizing the gut microbiome's critical influence on host immunity, our study aimed to define the association between gut dysbiosis and AR in KT. We prospectively enrolled 97 KT patients from two institutions (33 with AR and 64 without AR) and analyzed their stool samples at multiple time points: 97 pre-transplant, 66 at three months, and 36 at twelve months post-transplant. 16S rRNA sequencing for metagenomics and nuclear magnetic resonance spectroscopy for fecal metabolomics were used to analyze samples from patients with 1-year biopsy-confirmed AR, revealing reduced bacterial richness and diversity in AR patients. Before and after KT, the AR group showed increased Escherichia-Shigella and decreased Phascolarctobacterium levels. Pathway analysis identified 47 enriched pathways in AR patients, including those involved in lipopolysaccharide biosynthesis and short-chain fatty acid metabolism. Consistent results were obtained from stool metabolomics, showing reduced propionate and lactate concentrations in AR patients' stools. Finally, combining pre-KT bacterial and metabolite features with clinical parameters significantly improved AR status prediction accuracy. Our results suggest that integrating clinical, microbial, and metabolomic data may provide a more holistically tailored patient care regimen at both pre- and post-transplant points.