Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1

Abstract

Background Following solid organ transplantation, tacrolimus (TAC) is an essential drug in the immunosuppressive strategy. Its use constitutes a challenge due to its narrow therapeutic index and its high inter- and intra-pharmacokinetic (PK) variability. As the contribution of the gut microbiota to drug metabolism is now emerging, it might be explored as one of the factors explaining TAC PK variability. Herein, we explored the consequences of TAC administration on the gut microbiota composition. Reciprocally, we studied the contribution of the gut microbiota to TAC PK, using a combination of in vivo and in vitro models. Results TAC oral administration in mice resulted in compositional alterations of the gut microbiota, namely lower evenness and disturbance in the relative abundance of specific bacterial taxa. Compared to controls, mice with a lower intestinal microbial load due to antibiotics administration exhibit a 33% reduction in TAC whole blood exposure and a lower inter-individual variability. This reduction in TAC levels was strongly correlated with higher expression of the efflux transporter ABCB1 (also known as the p-glycoprotein (P-gp) or the multidrug resistance protein 1 (MDR1)) in the small intestine. Conventionalization of germ-free mice confirmed the ability of the gut microbiota to downregulate ABCB1 expression in a site-specific fashion. The functional inhibition of ABCB1 in vivo by zosuquidar formally established the implication of this efflux transporter in the modulation of TAC PK by the gut microbiota. Furthermore, we showed that polar bacterial metabolites could recapitulate the transcriptional regulation of ABCB1 by the gut microbiota, without affecting its functionality. Finally, whole transcriptome analyses pinpointed, among others, the Constitutive Androstane Receptor (CAR) as a transcription factor likely to mediate the impact of the gut microbiota on ABCB1 transcriptional regulation. Conclusions We highlight for the first time how the modulation of ABCB1 expression by bacterial metabolites results in changes in TAC PK, affecting not only blood levels but also the inter-individual variability. More broadly, considering the high number of drugs with unexplained PK variability transported by ABCB1, our work is of clinical importance and paves the way for incorporating the gut microbiota in prediction algorithms for dosage of such drugs.

Human gut Actinobacteria boost drug absorption by secreting P-glycoprotein ATPase inhibitors

“… 10 Abcb1a can be differentially expressed between germ-free (GF) and conventionally raised (CONV-R) mice 11 , 12 ; however, a recent study failed to detect a significant difference in Abcb1a transcript levels. 13 Variation in the specific gut microbiota found between facilities could provide one potential reason for these discrepant results, consistent with experiments administering single pathogenic, probiotic, and commensal bacteria that can tune Abcb1a expression in either direction, 11 , 14 , 15 , 16 experiments with broad-spectrum antibiotics, 17 and a study implicating butyrate-producing bacteria in colonic P-gp protein levels. 18 More importantly, the functional consequences of microbiota-driven changes in Abcb1a expression and the mechanisms responsible remain largely unexplored, with the exception of a recent paper implicating microbiota-dependent induction of Abcb1a expression in tacrolimus pharmacokinetics.…”

“… 18 More importantly, the functional consequences of microbiota-driven changes in Abcb1a expression and the mechanisms responsible remain largely unexplored, with the exception of a recent paper implicating microbiota-dependent induction of Abcb1a expression in tacrolimus pharmacokinetics. 17 …”

Unraveling interindividual differences and functional consequences of gut microbial metabolism of immunosuppressants

“…Building on prior research that highlighted the influence of microbial metabolism on the efficacy and toxicity of immunosuppressive drugs (20,21), our study further elucidates how gut microbiota can modify drug responses both locally and systemically. We demonstrated that bacteria can activate the prodrug MMF into its active form, mirroring the host's prodrug activation.…”

Pharmacomicrobiomics of Classical Immunosuppressant Drugs: A Systematic Review

“…In fact, upon antibiotic treatment, TAC exposure increased in a manner totally reversible with the ABC1B1 blocker zosuquidar. While the study by Guo et al [ 25 ] seem to suggest that fecal microbiota reduces TAC bioavailability, the data reported by Degraeve et al (2023) [ 124 ] seem to propend for the opposite scenario of intestinal bacteria enhancing TAC absorption. The inconsistent findings of these two studies (one performed in man and the other in mice) leave open the question of how the intestinal microbiota affects TAC pharmacokinetics and whether species-specific factors are involved.…”