Gut Microbiota and Metabolite Changes Induced by Tacrolimus: Implications for Skin Transplant Immunology in Mice

Tacrolimus is the most widely used immunosuppressive therapy in solid organ transplantation. However, whether it can inhibit transplant graft rejection by altering the composition and metabolism of gut microbiota remains unclear.

In this study, a skin transplantation mouse model was established to explore the effects of tacrolimus on gut microbiota and its metabolites. Additionally, we investigated the protective effect and potential mechanism of feces from mice treated with tacrolimus on skin allografts.

Tacrolimus did not significantly affect gut microbiota α-diversity but altered β-diversity, with specific changes in microbial composition. LEfSe analysis identified 19 microbial taxa with reduced and 12 with elevated relative abundance in the Tac group (mice treated with tacrolimus) compared to the Ctrl group (mice with no treatment). Metabolomic analysis identified 33 differential fecal metabolites (17 upregulated and 16 downregulated) in the Tac group compared to the Ctrl group. FMT from tacrolimus-treated mice significantly prolonged skin allograft survival, reduced inflammatory cell infiltration, and improved graft histopathology. This protective effect was associated with increased Treg cell proportions and decreased Th17 cell proportions in draining lymph nodes and mesenteric lymph node.

Overall, our data may provide a basis for establishing gut microbiota-based therapies for allograft rejection.