This study aimed to define how the gut microbiota and microbiota‑derived metabolites shape alloimmune responses and early clinical outcomes after transplantation, with a particular focus on heart transplantation. At the individual bacterium level, oral administration of the commensal Alistipes onderdonkii to mice receiving allogeneic skin grafts was sufficient to prolong allograft survival, supporting the concept that specific gut taxa can be harnessed as probiotics to modulate alloimmunity. At the microbial metabolite level, targeted delivery of the short‑chain fatty acid (SCFA) butyrate reduced the number and inflammatory function of circulating and graft‑infiltrating myeloid cells, thereby attenuating the effector phase of rejection and extending graft survival. Finally, in a cohort of heart transplant recipients at the University of Chicago, post-transplant fecal metagenomic and metabolomic profiling revealed that while gut microbiota composition did not predict measures of graft damage or alloreactivity, reduced microbial diversity and loss of SCFA-producing taxa were strongly associated with subsequent postoperative infections. Together, these findings highlight that microbiota‑derived signals play a critical role, whether considering individual taxa, metabolites, or human gut communities, and suggest that peri‑transplant microbiome and metabolite profiling could inform personalized strategies to improve transplant outcomes and reduce complications.
