School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China.
Department of Critical Care Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Gut Microbes. 2024 Jan-Dec;16(1):2404138. doi: 10.1080/19490976.2024.2404138. Epub 2024 Sep 21.
Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.
对乙酰氨基酚（APAP）过量是药物性肝损伤（DILI）的主要原因，其易感性存在性别差异。然而，这种现象的机制尚不清楚。我们的研究表明，APAP 诱导的肝毒性易感性的性别差异是由于肠道微生物组的差异所致。通过微生物多组学和培养，我们观察到女性和雌性小鼠的肠道微生物组衍生的滇黄芩素含量增加。给予滇黄芩素可缓解 APAP 处理的雄性小鼠的肝毒性，这种保护作用与抑制肝细胞氧化应激有关。在机制上，滇黄芩素通过直接相互作用降低了 APAP 处理的肝细胞中促甲状腺素受体（TSHR）的表达。使用 ML224 抑制 TSHR 表达可显著增加 APAP 处理的雄性小鼠的肝内谷胱甘肽（GSH）。这些发现表明，肠道微生物组衍生的滇黄芩素在降低雌性小鼠的 APAP 诱导的肝毒性中起关键作用，为 DILI 的治疗策略提供了新的见解。
