Metronidazole-mediated gut anaerobe remodeling is associated with transplant rejection.

Background: The gut microbiome has emerged as a potential modulator of transplant rejection. However, the relevance of anaerobe-associated gut microbial communities to transplant rejection responses remains unclear. Methods: In a murine islet transplantation model, we assessed the effects of metronidazole pretreatment on allograft survival and function. 16S rRNA sequencing was performed to characterize treatment-associated changes in gut microbial composition. Separately, an exploratory two-sample MR analysis using human GWAS data was performed to prioritize gut microbial taxa associated with a composite outcome of transplant failure or rejection. Biological annotation was subsequently used to prioritize candidate host pathways. Immunohistochemistry and flow cytometry were used to evaluate post-transplant immune responses after metronidazole pretreatment. Results: Metronidazole treatment remodeled gut microbiota composition and significantly delayed islet allograft rejection. MR analyses identified several anaerobe-associated gut microbial taxa potentially relevant to transplant rejection risk, including the family Conclusion: Altogether, our findings document gut microbial remodeling and delayed allograft rejection following metronidazole pretreatment. These findings are hypothesis-generating and warrant further mechanistic investigation.