*Purpose: High tacrolimus variability (TV), low time in therapeutic range (TTR) and high percentage of donor derived cell-free DNA (dd-cfDNA) are associated with acute kidney rejection and graft loss. Due to the narrow therapeutic index of tacrolimus (TAC), African American patients usually require higher dose of TAC caused by expression of CYP3A5. The gut microbiota affects metabolization of TAC and plays a significant role in the function of T cells. This pilot study is the first to investigate the combined effect of gut microbiota and CYP3A5 on transplant outcomes.

*Methods: 10 kidney transplant recipients were enrolled from the George Washington University Hospital. Fecal samples were collected one week before and 1-3 months post transplantation. Whole bacterial DNA was sequenced using shotgun metagenomics. We analyzed the change in abundance of bacterial species. Blood samples were collected for sequencing of CYP3A5 and dd-cfDNA AlloSure testing. TAC levels were collected from electronic health records. Rosendaal method was used to calculate TTR. Coefficient of Variance was used to measure TV.

*Results: Change in Shannon diversity, change in relative abundance of species and Jaccard dissimilarity index were plotted against TV, TTR and dd-cfDNA. Pearson correlation coefficient was calculated for bivariate analysis. Association between TV and change in relative abundance of Bacteroides (r=0.56, p=0.08), Phocaeicola vulgatus (r=0.61, p=0.05), Prevotella (r=-0.57, p=0.08) and Ruminococcus (r=-0.51, p=0.10). dd-cfDNA was associated with change in relative abundance of Lachnospiraceae (r=-0.70, p=0.03). Jaccard dissimilarity index was positively associated with TV (r=0.52, p=0.10). All patients were high expressers of CYP3A5. TTR did not show any association with diversity indexes or bacterial species.

*Conclusions: Since all patients were high expressers of CYP3A5, the genetic effect of metabolization of TAC was controlled. If we attempt to reduce TV, we should focus on nutritional treatments which preserve the pre-transplant bacterial composition. Particularly, higher TV was associated with increase in the relative abundance of Bacteroides and Phocaeicola vulgatus and decrease in the relative abundance of Ruminococcus and Prevotella. Elevated abundance of Bacteroides is known to be associated with increased risk of IgA and membranous nephropathy. Thus, attempts to reduce TV could result in lowering the abundance of Bacteroides and risk of IgA. Patients with higher dd-cfDNA lost significant amount of Lachnospiraceae. Abundance of Lachnospiraceae is associated with decreased lethality from graft-versus-host disease in allogenic blood/marrow transplantation and higher survival rate by its anti-inflammatory effect through induction of regulatory T cells. We believe reduction in Lachnospiraceae could indicate a probability of active rejection.

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