Functional gut microbiome dysbiosis is associated with overall survival after solid organ transplantation

Background Long-term survival after solid organ transplantation remains limited by infection, graft dysfunction, and systemic complications. Recent evidence suggests that gut dysbiosis, marked by loss of beneficial commensals and expansion of opportunistic pathogens, is associated with increased mortality in solid organ transplant recipients (SOTRs). While specific species have been associated with higher mortality risk or improved survival, the functional mechanisms on the strain level underlying these associations remain unclear. Here, we integrated gene-centric functional profiling with strain-level resolved metagenome-assembled genomes (MAGs) across 1231 gut metagenomes from 1008 SOTRs (580 kidney, 245 liver, 133 lung and 50 heart transplant recipients) and 233 healthy controls from the TransplantLines Biobank and Cohort Study to link gut microbial functions and metabolic modules to their originating MAGs and assess their association with post-transplant overall survival. Results Functional profiling of the gut microbiome revealed pronounced functional dysbiosis in SOTRs compared with healthy controls, with higher dysbiosis scores significantly associated with increased post-transplant mortality. We identified 97 microbial functions (KEGG Orthologs, KOs) positively associated with impaired survival (hazard ratio >1; FDR < 0.10) and 661 KOs associated with improved survival (hazard ratio <1; FDR < 0.10) after transplantation. KOs associated with excess mortality predominantly encoded functions related to bacterial adhesion, virulence, and stress adaptation. In contrast, protective KOs mapped to 12 highly complete metabolic modules, including shikimate and pyridoxal phosphate biosynthesis. Genome-resolved analysis of 10,397 MAGs revealed that KOs associated with excess mortality were concentrated in members of the Proteobacteria phylum, particularly the Enterobacteriaceae family, whereas protective KOs were enriched in members of the Firmicutes A lineage. Conclusion The functional capacity of the post-transplant gut microbiome differed significantly from that of healthy controls, consistent with a state of post-transplant gut dysbiosis. Notably, functional dysbiosis of the gut microbiome was associated with post-transplant survival. These findings highlight microbial functional potential as a determinant of post-transplant survival and a promising target for microbiome-informed risk prediction and therapeutic intervention.