Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 160, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2023.114400
Keywords
Isoniazid; Liver injury; Gut microbiota; Immune response; Adaptation
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Isoniazid (INH) is an effective anti-tuberculosis drug, but its clinical application is limited due to hepatotoxicity. INH-induced liver injury (INH-DILI) is an immune-mediated idiosyncratic drug-induced liver injury. This study found that gut microbiota plays a role in the development and severity of INH-DILI. Depletion of gut microbiota improved INH-DILI, and fecal microbiota transplantation from INH-treated mice alleviated hepatoxicity. The abundance of Bifidobacterium was associated with transaminase levels. These findings suggest that gut microbiota and probiotics like Bifidobacterium may impact INH-DILI and its adaptation phenomenon.
Isoniazid (INH) is a highly effective single and/or combined first-line anti-tuberculosis (anti-TB) therapy drug, and the hepatotoxicity greatly limits its clinical application. INH-induced liver injury (INH-DILI) is a typical immune-mediated idiosyncratic drug-induced liver injury. Existing mechanisms including genetic variations in drug metabolism and immune responses cannot fully explain the differences in susceptibility and sensitivity to INH-DILI, suggesting that other factors may be involved. Accumulating evidence indicates that the development and severity of immune-mediated liver injury is related to gut microbiota. In this study, INH exposure caused liver damage, immune disregulation and microbiota profile alteration. Depletion of gut microbiota ameliorated INH-DILI, and improved INH-DILI-associated immune disorder and inflammatory response. Moreover, hepato-toxicity of INH was ameliorated by fecal microbiota transplantation (FMT) from INH-treated mice. Notably, Bifidobacterium abundance was significantly associated with transaminase levels. In conclusion, our results suggested that the effect of gut microbiota on INH-DILI was related to immunity, and the difference in INH-DILI sensitivity was related to the structure of gut microbiota. Changes in the structure of gut microbiota by continuous exposure of INH resulted in the tolerance to liver injury, and probiotics such as Bifidobacterium might play an important role in INH-DILI and its adaptation phenomenon. This work provides novel evidence for elucidating the underlying mechanism of difference in individual's response to INH-DILI and potential approach for intervening anti-TB drug liver injury by modulating gut microbiota.
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