The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat

What is it about?

Pharmacokinetic studiesin rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealingenhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposi-tion gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-inducedtransaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gutmicrobial composition (e.g., Lactobacillus, Bacteroides,andEnterobacteriaceae) and approximately 9% higher b-glucuronidase geneabundance compared with nonresponders. In the validation study, coadministration with oral b-glucuronidase derived fromEscherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-inducedtransaminitis in vivo.

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Why is it important?

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses ispoorly understood. In this study, we investigated the role of the liver–gut microbiota axis in underpinning the hepatotoxicity oftacrine.

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