*Purpose: Mycophenolate mofetil (MMF) is an important immunosuppressant used after allogeneic hematopoietic cell transplant (HCT). Blood concentrations of mycophenolic acid (MPA) are highly variable and low concentrations are associated with greater risk of graft vs host disease. Variability may be due to the greater presence of beta-glucuronidase producing bacteria in the GI tract which enhance MPA enterohepatic recirculation (EHR) which transforms MPA metabolites back to active MPA. We hypothesized that MPA EHR and higher MPA concentrations are associated with a greater abundance of Bacteroides, a beta-glucuronidase producing bacteria.

*Methods: We conducted a pharmacomicrobiomics study in 20 adult HCT recipients receiving a myeloablative or reduced intensity preparative regimen. Participants received MMF 1g IV every 8 hours with tacrolimus. Pharmacokinetic (PK) sampling of mycophenolate was conducted before hospital discharge. Stool sample collected at time of PK. Total MPA, MPA glucuronide (MPAG) and acylMPAG PK were determined. EHR was defined as a ratio of MPA AUC_4-8 to MPA AUC_0-8. Differences in microbiome diversity and composition were compared above and below the median EHR (0.22, range 0.05-0.44). Median EHR was 0.12 and 0.29 in the low and high EHR groups, respectively.

*Results: MPA troughs, MPA AUC_4-8 and acylMPAG AUC_4-8/AUC_0-8 were significantly higher in the high EHR group than the low EHR group [1.53 vs 0.28 mcg/mL,p<0.01], [7.33 vs 1.79 hr*mcg/mL, p<0.01] and [0.33 vs 0.24 hr*mcg/mL, p<0.01], respectively. MPA AUC_0-8 was more than 30% greater in the high EHR than the low EHR group and trended towards significance [22.8 Vs. 15.3, p=0.06]. B. vulgatus, B. stercoris and B. thetaiotaomicron were 1.2-2.4×more abundant (p=0.039, 0.024, 0.046) in the high EHR group. MPA AUC_4-8/AUC_0-8 ratio was positively correlated with B.vulgatus (⍴=0.58, p=0.01) and B.thetaiotaomicron (⍴=0.46, p=0.04). 80% of the high EHR group achieved MPA troughs within the therapeutic range and 0% in the low EHR.

*Conclusions: EHR varied from 5-44%. Patients with high MPA EHR had greater abundance of the beta-glucuronidase-producing Bacteroides species in the stool and higher MPA exposure. No patients with low EHR achieved therapeutic MPA troughs. Individuals with low Bacteroides species may be at greater risk of insufficient immunosuppression. These data need to be confirmed and studied after oral MMF where EHR may be even more profoundly influenced.

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