Gut microbial diversity, inflammation, and oxidative stress are associated with tacrolimus dosing requirements early after heart transplantation

INTRODUCTION: Effective tacrolimus (TAC) dosing is hampered by complex pharmacokinetics and significant patient variability. The gut microbiome, a key mediator of endotoxemia, inflammation and oxidative stress in advanced heart failure (HF) patients, is a possible contributor to interindividual variations in drug efficacy. The effect of alterations in the gut microbiome on TAC dosing requirements after heart transplant (HT) has not been explored. METHODS: We enrolled 24 patients (mean age = 55.8 ±2.3 years) within 3 months post-HT. Biomarkers of endotoxemia ((lipopolysaccharide (LPS)), inflammation (tumor necrosis factor-α (TNF-α)) and oxidative stress (8,12-iso-Isoprostane F-2alpha-VI) were measured in 16 blood samples. 22 stool samples were analyzed using 16S rRNA sequencing. TAC dose and serum trough level were measured at the time of stool and blood collection. TAC doses were reported in mg/kg/day and as level-to-dose (L/D) ratio, and categorized as ≤ vs. > median. RESULTS: The median TAC dose was 0.1 mg/kg/day and L/D ratio was 100.01. Above the median daily weight-based TAC dose was associated with higher gut microbial alpha diversity (p = 0.03); similarly, TNF-α and 8,12-iso-Isoprostane F-2alpha-VI levels were lower and LPS levels were higher in the above median TAC group, although these findings were only marginally statistically significant and dependent on BMI adjustment. We observed n = 37 taxa to be significantly enriched among patients with > median TAC dose (all FDR<0.05), several of which are potential short-chain fatty acid producers with anti-inflammatory properties, including taxa from the family Subdoligranulum. CONCLUSIONS: Our pilot study observed gut microbial alpha diversity to be increased while inflammation and oxidative stress were reduced among patients requiring higher TAC doses early after HT.