Coordinated elimination of bacterial taxa optimally attenuates alloimmunity and prolongs allograft survival.

This study aimed to dissect the relationship between specific gut commensal bacterial subgroups, their functional metabolic pathways, and their impact on skin allograft outcome and alloimmunity. We previously showed that oral broad-spectrum antibiotic (Abx) pretreatment in mice delayed skin, heart, and lung allograft rejection and dampened alloimmune responses. Here, rationally designed Abx combinations targeting major bacterial groups were used to elucidate their individual contribution to modulating alloimmune responses. Abx cocktails targeting intestinal gram-negative, gram-positive, or anaerobic/gram-positive bacteria by oral gavage, all delayed skin allograft rejection, and reduced alloreactive T cell priming to different extents. Notably, the most pronounced extension of skin allograft survival and attenuation of alloimmunity were achieved when all gut bacterial groups were simultaneously targeted. These results suggest a model in which the strength of the alloimmune response is additively tuned up by gut microbial diversity. Shotgun metagenomic sequencing enabled strain-level resolution and identified a shared commensal, Parabacteroides distasonis, as the most enriched following all Abx treatments. Oral administration of P.distasonis to mice harboring a diverse microbiota significantly prolonged skin allograft survival, identifying a probiotic with therapeutic benefit in transplantation.