*Purpose: The communities of microorganisms that colonize barrier surfaces, termed the microbiota, are environmental agents that can influence the maturation and function of the immune system and modulate immune responses in cancer immunology and autoimmunity. These environmental determinants also modulate solid organ transplant outcome and alloimmunity, but the mechanisms behind this regulation are not fully understood. We have previously reported that disturbing microbial composition by antibiotic pre-treatment in specific pathogen-free (SPF) mice or using germ-free (GF) mice both result in significantly prolonged skin graft survival in a minor mismatched skin graft model. Conventionalization of GF mice with fecal material from SPF mice resulted in accelerated rejection when compared to the kinetics in GF mice, confirming causality of the microbiota in modulating graft outcome. Moreover, mechanistic studies revealed that antibiotic-sensitive bacterial taxa were responsible for enhancing the ability of skin graft-draining lymph node dendritic cells to prime alloreactive T cell responses. However, oral antibiotic treatment impacted microbial diversity in both the intestinal and skin compartments, making it unclear which colonized barrier surface modulated alloimmunity. We have recently reported that the skin microbiota can modulate local immunity in the absence of intestinal microbiota, enhancing the effector phase of the alloresponse to a skin graft. In the current study, we addressed whether gut-tropic microbiota can have an impact on the distal alloresponse to a skin graft, independently from the skin microbiota.

*Methods: To address this question, we used segmented-filamentous bacterium (SFB), a gut-tropic microorganism that cannot colonize the skin. By using a combination of SFB-colonized GF and SPF mice, we determined the survival kinetics of a minor-mismatched skin graft model.

*Results: SFB mono-colonization of GF mice, as well as SFB mono-colonized fecal material transfer into SPF mice, resulted in a significant acceleration of skin graft rejection, compared to that in their respective control mice, confirming that an intestinal bacterium can have a distal impact on an uncolonized skin graft.

*Conclusions: Surprisingly, SFB-colonization did not increase the priming of alloreactive T cells, arguing that this microorganism might be accelerating graft rejection by other means. Understanding how the intestinal microbiota impacts graft outcome is critical to be able to design microbiota-manipulating therapies that can benefit transplant recipients.

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