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Dysbiosis of the Female Murine Gut Microbiome Exacerbates Neutrophil-mediated Vascular Allograft Injury by Affecting Immunoregulation by Acetate

Background. The gut microbiota affects immune responses that cause organ transplant rejection, but the mechanisms by which this occurs remain poorly understood. Methods. We have examined, in a murine model, how disruption of the gut microbiota with antibiotics early in life alters this microbial community later in life to affect immune responses that injure vascular allografts. Results. Analysis of 16S rRNA and whole genome sequencing of the gut microbiota demonstrated that early life disruption of this microbial community with antibiotics caused a reduction in taxa and enzymatic genes involved in the synthesis of acetate, an immunoregulatory metabolite in mice and humans. When allograft vascular injury was examined, early life disruption of the gut microbiota increased neutrophil accumulation and related medial injury of transplanted arteries. Normalizing the gut microbiota by co-housing and oral administration of acetate prevented neutrophil-mediated vascular allograft injury. Conclusions. Dysbiosis of the gut microbiome that reduces its production of the immunoregulatory metabolite acetate exacerbates neutrophil-mediated allograft vascular injury.