The Liver-Gut Microbiota Axis Modulates Hepatotoxicity of Tacrine in the Rat

Abstract

The gut microbiota possesses diverse metabolic activities but its contribution towards heterogeneous toxicological responses is poorly understood. Here, we elucidate 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 variation 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 ∼9% higher β-glucuronidase gene abundance compared to non-responders. In the validation study, co-administration with oral β-glucuronidase derived from Escherichia coli and pre-treatment with vancomycin and imipenem significantly modulated the susceptibility to tacrine-induced transaminitis in vivo. Conclusion: Our study establishes the pertinent gut microbial influences in defining the hepatotoxicity of tacrine, providing crucial insights for personalized medicine initiatives. This article is protected by copyright. All rights reserved.

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