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. (Hepatology 2018;67:282‐295).

中文翻译：

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肝肠菌群轴调节他克林对大鼠的肝毒性

肠道微生物群具有多种代谢活动，但其对异质毒理学反应的贡献知之甚少。在这项研究中，我们研究了肝 - 肠道微生物群轴在支持他克林肝毒性中的作用。我们采用结合药代动力学、毒理学、代谢组学、基因组学和宏基因组学的综合策略来阐明和验证他克林诱导的李斯特头罩大鼠肝毒性的机制。在大鼠中的药代动力学研究表明，在经历转氨炎的强反应者中，他克林的全身暴露量高出 3.3 倍，这表明该亚组中脱葡萄糖醛酸化他克林的肠肝循环增强，这与肝脏处置基因表达的变化无关。代谢组学研究涉及映射到他克林引起的转氨酶的肠道微生物活动的变化。宏基因组学根据不同的肠道微生物组成（例如，乳杆菌、拟杆菌和肠杆菌科）以及与无反应者相比高约 9% 的 β-葡萄糖醛酸酶基因丰度，描绘了强反应者具有更强的脱葡萄糖醛酸化能力。在验证研究中，与来自大肠杆菌的口服β-葡萄糖醛酸酶共同给药以及用万古霉素和亚胺培南预处理显着调节了体内他克林诱导的转氨酶的易感性。结论：本研究确定了肠道微生物对改变他克林肝毒性的相关影响，为个性化医疗计划提供了见解。（肝病学 2018 年；67：282-295）。