Current data indicates that between 10-20% of patients that receive renal transplants experience acute rejection. Acute rejection is an important predictor of future complications that can lead to complete graft loss. Serine Protease Inhibitor proteins (Serpins) have shown incredible promise in working to lessen or inhibit the onset and effects of acute rejection in multiple solid organ transplant studies. However, it has been proposed that the mechanisms of Serp-1 immunomodulation can be affected by the native gut microbiome of recipient animals. This study utilizes murine renal allograft transplant from C57BL/6 to BALB/c and microbiome depletion to model the acute rejection response and to determine if there are interactions between the gut microbiome and Serp- 1 during the acute renal allograft rejection response. After antibiotic administration, expected decreases in richness and diversity in the designated group were observed. After renal subcapsular allograft transplant, histological and microbiome analyses revealed neither significant microbiome changes persistent after surgery based on pre-treatment nor changes associated with the administration of the isolated Serp-1 protein. Additionally, it was found that Serp-1 improves the histological presentation of acute renal allograft rejection regardless of the status of the microbiome.