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 Defluviitaleaceae and the genera Intestinibacter, Bilophila, Ruminococcus and Eubacterium fissicatena. Integrative biological annotation highlighted glycosylation-related pathways and prioritized ST3GAL4 for subsequent expression assessment in the murine transplant model. Furthermore, metronidazole treatment reduced CD4+ T-cell infiltration around the allograft and Th17-related inflammatory responses.

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.