Gut Microbial Diversity, Inflammation and Oxidative Stress is Associated with Tacrolimus Dosing Requirements Early after Heart Transplant

Purpose Effective tacrolimus (TAC) dosing is hampered by complex pharmacokinetics and significant intra- and interpatient variability. One prior report suggests that TAC dosing is influenced by gut microbiota, while the effects of systemic inflammation and oxidative stress are unknown. We evaluated these relationships in adult heart transplant (HT) pts. Methods We prospectively enrolled 24 HT pts (age=56±2 years, 88% male, 25% AA). Stool samples were analyzed using 16S rRNA sequencing. Alpha diversity metrics (number and evenness of bacterial taxa within samples) were estimated using Shannon index. TAC dose and serum trough level were measured at the time of gut and blood analysis. TAC doses were reported in mg/kg/day and as level-to-dose (L/D) ratio; pts were categorized as above vs. below the median. Biomarkers of inflammation (tumor necrosis factor-α (TNF-α)) and oxidative stress (Isoprostane) were measured in blood. Gut diversity and blood biomarkers were compared by TAC dose using ANOVA. DESeq regression analyses explored differences in individual taxa by weight-based TAC dose - false discovery rate (FDR) adjusted for multiple comparisons. Results The average time from HT to sample collection was 63±6 days. The median TAC dose was 0.1 mg/kg/day, while the median L/D ratio was 1.15. Above the median daily weight-based TAC dose was associated with higher Shannon index (p=0.03), lower TNF-α (p=0.05) and lower isoprostane levels (p=0.02) (Figure). These findings were similar when analyzed using the L/D ratio. We observed n=38 taxa to be significantly enriched among pts with >median TAC dose (all FDR Conclusion Our pilot study observed gut microbial diversity to be increased while inflammation and oxidative stress were reduced among pts requiring higher TAC dosing.