*Purpose: The gut microbiota alters expression of drug-metabolizing enzymes and transporters, and consequently affects therapeutic dose and response of medicines. We aimed to investigate the effect of the gut microbiome on the variation of blood tacrolimus concentration, one of the most important immunosuppressant in kidney transplant (KT) recipients.

*Methods: We prospectively enrolled KT recipients at two centers. Pretransplant stool samples were collected and stored at -80’C immediate after collection. From DNA extracted from the feces, the composition of the microbiota was analyzed using metagenomic sequencing with the Illumina MiSeq system. All of the tacrolimus trough levels from every recipients were obtained for 1 year after KT and their standard deviation (SD)s were calculated from each recipients, which used to determine intrapatient variability (IPV) of tacrolimus. We divided patients into high, middle, and low IPV groups according to their tacrolimus SD tertiles.

*Results: A total of 66 fecal samples were analyzed from KT recipients. The mean age of the patients was 49.3 ± 12.2 years, and 51.5% was male. The mean tacrolimus trough level was 9.9 ± 1.0 ng/mL and the mean SD value was 4.7 ± 1.4 ng/mL, ranging from 2.7 to 8.3 ng/mL. There was no difference in age, sex, composition of ABO incompatibility, the number of HLA mismatch between the groups according to tacrolimus tertiles. Among the total microbiota, the only taxon that was significantly associated with the tacrolimus SD was the genus Eubacterium. The relative abundance of Eubacterium significantly differed between the three IPV groups (P for trend = 0.001), and the multiple comparison showed a significantly lower Eubacterium level than low IPV group in high IPV group (P = 0.001). Linear regression analysis also showed that the Eubacterium level was significantly inversely related to the tacrolimus SDs (beta = -0.323, P = 0.008). In addition, there was no difference in either the tacrolimus SDs or abundance of Eubacterium between the group of four recipients that developed calcineurin inhibitor nephrotoxicity within 1 year and the other recipients.

*Conclusions: A decrease in the abundance of the genus Eubacterium among the gut microbiome in kidney recipients is associated with increased fluctuation of the tacrolimus level after transplantation. Further studies on the mechanism of the effect of genus Eubacterium on tacrolimus levels are needed.

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