Gut microbiome modulates tacrolimus pharmacokinetics through the transcriptional regulation of ABCB1

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...
Ausführliche Beschreibung

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. 5nEvj3aohpq9uU8QResbYsVideo Abstract Ausführliche Beschreibung

Autor*in:	Degraeve, Alexandra L. [verfasserIn] Haufroid, Vincent Loriot, Axelle Gatto, Laurent Andries, Vanessa Vereecke, Lars Elens, Laure Bindels, Laure B.

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Inter-individual pharmacokinetic variability Intra-individual pharmacokinetic variability Cytochrome P-450 CYP3A Narrow therapeutic index Therapeutic drug monitoring Immunosuppressive therapy

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Microbiome - London : Biomed Central, 2013, 11(2023), 1 vom: 06. Juli
Übergeordnetes Werk:	volume:11 ; year:2023 ; number:1 ; day:06 ; month:07

Links:	Volltext

DOI / URN:	10.1186/s40168-023-01578-y

Katalog-ID:	SPR052162877