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The liver–gut microbiota axis modulates hepatotoxicity of tacrine in the rat
Author(s) -
Yip Lian Yee,
Aw Chiu Cheong,
Lee Sze Han,
Hong Yi Shuen,
Ku Han Chen,
Xu Winston Hecheng,
Chan Jessalyn Mei Xuan,
Cheong Eleanor Jing Yi,
Chng Kern Rei,
Ng Amanda Hui Qi,
Nagarajan Niranjan,
Mahendran Ratha,
Lee Yuan Kun,
Browne Edward R.,
Chan Eric Chun Yong
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29327
Subject(s) - tacrine , pharmacology , gut flora , physiologically based pharmacokinetic modelling , pharmacokinetics , bacteroides , biology , medicine , biochemistry , enzyme , bacteria , acetylcholinesterase , genetics
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 β‐glucuronidase gene abundance compared with nonresponders. In the validation study, coadministration with oral β‐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. (H epatology 2018;67:282‐295).