Investigating gut microbiota and their metabolites as biomarkers for tacrolimus pharmacokinetic variability.

Tacrolimus (TAC), a cornerstone immunosuppressant in transplantation, presents a clinical challenge due to its narrow therapeutic index and substantial interindividual pharmacokinetic (PK) variability. This exploratory study investigated the association between gut microbiota composition, short-chain fatty acid (SCFA) metabolites, and TAC PK variability during the early post-kidney transplantation period. Based on prediction errors derived from a previously established population PK model, 36 transplant recipients were stratified into positive (n = 17) and negative (n = 19) deviation groups. Metagenomic sequencing and targeted SCFA metabolomic analysis of fecal samples revealed that the negative deviation group exhibited significantly reduced gut microbial diversity and altered community structure. Among 142 differentially abundant taxa, 10 microbial features, including Enterococcaceae - associated taxa, showed discriminative potential between the two PK phenotypes (AUC > 0.7), with three Enterococcus species (E. durans, E. faecium, and E. hirae) showing particularly robust signals (Cohen's d > 1.0 and power > 80%). Functional analysis suggested downregulation of butyrate biosynthesis pathways in the negative deviation group, which was consistent with significantly lower fecal butyrate and total SCFA concentrations. These hypothesis-generating findings suggest that gut microbiota and SCFAs are associated with TAC PK phenotypes, but independent validation in larger cohorts is required before clinical translation.