*Purpose: The gut microbiota influences immune responses in many ways but its involvement in transplant rejection is poorly understood. We have examined how changes in the gut microbiota affect acute vascular rejection.

*Methods: The gut microbiota was disrupted by treating mice with broad-spectrum antibiotics for only the first 3 weeks of life. Mice were subsequently maintained without antibiotics into adulthood to allow the bacterial community to establish prior to transplantation at ~ 10 weeks of life. The taxonomic composition of the intestinal bacteria in adults was determined by 16S sequencing, the metagenome inferred using Picrust2, and rejection evaluated by aortic interposition grafting.

*Results: Disruption of the gut microbiota with broad-spectrum antibiotics early in life (for only the first three weeks of life) exacerbated acute rejection in adult graft recipients that was characterized by excessive neutrophil accumulation. 16S rRNA sequencing of fecal samples obtained from adult mice immediately prior to transplantation identified several differences in the abundance of bacterial taxa that were associated with treatment with antibiotics early in life. Analysis of the inferred bacterial metagenome using Picrust2, which provides information on the functional potential of this microbial community, suggested that early disruption of the gut microbiota with antibiotics substantially affects the gene content of this bacterial community in adults. Notably, treatment with antibiotics was associated with a significant reduction in genes related to certain fermentation pathways that produce the immunoregulatory short chain fatty acid acetate. The potential role of the composition of the gut microbiota and of acetate in transplant rejection was then examined by co-housing untreated mice with those that were treated with antibiotics early in life or by treating mice with acetate in their drinking water prior to transplantation of allogeneic aortic segments. Co-housing and administration of acetate prevented the exacerbation of neutrophil accumulation in allograft artery segments that was caused by early disruption of the gut microbiota.

*Conclusions: Our findings suggest that dysbiosis of the gut microbiota exacerbates neutrophil responses that are related to acute rejection, that this may be caused by defects in the production of acetate, and that dietary modifications may be able to influence immunological responses in this setting.

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