No abstract

The gut microbiota possesses diverse metabolic activities, but its contribution toward heterogeneous toxicological responses is poorly understood. In this study, we investigated the role of the liver-gut microbiota axis in underpinning the hepatotoxicity of tacrine. We employed an integrated strategy combining pharmacokinetics, toxicology, metabonomics, genomics, and metagenomics to elucidate and validate the mechanism of tacrine-induced hepatotoxicity in Lister hooded rats. Pharmacokinetic studies in rats demonstrated 3.3-fold higher systemic exposure to tacrine in strong responders that experienced transaminitis, revealing enhanced enterohepatic recycling of deglucuronidated tacrine in this subgroup, not attributable to variation in hepatic disposition gene expression. Metabonomic studies implicated variations in gut microbial activities that mapped onto tacrine-induced transaminitis. Metagenomics delineated greater deglucuronidation capabilities in strong responders, based on differential gut microbial composition (e.g., Lactobacillus, Bacteroides, and Enterobacteriaceae) and approximately 9% higher b-glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral b-glucuronidase derived from Escherichia coli and pretreatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. Conclusion: This study establishes pertinent gut microbial influences in modifying the hepatotoxicity of tacrine, providing insights for personalized medicine initiatives. (HEPATOLOGY 2018;67:282-295). SEE EDITORIAL ON PAGE 18E lucidating the mechanisms underlying interindividual responses to pharmacotherapy is paramount in personalized medicine research. The superorganismic nature of the human host means that not all variations in therapeutic outcome can be attributed to host genetics. (1)(2)(3) Indeed, the gut microbiota possesses vast metabolic activities that can either complement or oppose the host's enzymatic actions, thereby modulating drug disposition and therapeutic outcomes. (3)(4)(5) To date, only a small fraction of marketed drugs are known to be metabolically influenced by the microbiota, (3) and the contribution of gut microbiota toward interindividual variation in pharmacology remains poorly understood.