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https://doi.org/10.1002/hep.29327
Title: | The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat | Authors: | 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 |
Keywords: | Science & Technology Life Sciences & Biomedicine Gastroenterology & Hepatology CHAIN FATTY-ACIDS BETA-GLUCURONIDASE DRUG HEPATOTOXICITY ALZHEIMERS-DISEASE LITHOCHOLIC ACID RUMEN BACTERIA METABOLITES MICROFLORA PROTEIN MICROORGANISMS |
Issue Date: | 1-Jan-2018 | Publisher: | WILEY | Citation: | 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 (2018-01-01). The liver-gut microbiota axis modulates hepatotoxicity of tacrine in the rat. HEPATOLOGY 67 (1) : 282-295. ScholarBank@NUS Repository. https://doi.org/10.1002/hep.29327 | Abstract: | © 2017 by the American Association for the Study of Liver Diseases. 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). | Source Title: | HEPATOLOGY | URI: | https://scholarbank.nus.edu.sg/handle/10635/173622 | ISSN: | 02709139 15273350 |
DOI: | 10.1002/hep.29327 |
Appears in Collections: | Staff Publications Elements |
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