Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice.

IF 12.2 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY

Gut Microbes Pub Date : 2024-09-21 DOI:10.1080/19490976.2024.2404138

Shenhai Gong,Yunong Zeng,Ze Wang,Yanru Li,Rong Wu,Lei Li,Hongbin Hu,Ping Qin,Zhichao Yu,Xintao Huang,Peiheng Guo,Hong Yang,Yi He,Zhibin Zhao,Weidong Xiao,Xiaoshan Zhao,Lei Gao,Shumin Cai,Zhenhua Zeng

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引用次数: 0

Abstract

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.

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雌性小鼠肠道 deguelin 对乙酰氨基酚诱导的肝毒性具有抗性。

对乙酰氨基酚（APAP）过量是药物性肝损伤（DILI）的主要病因，其易感性存在性别差异。然而，这一现象的机制仍不清楚。我们的研究发现，对 APAP 引起的肝毒性的易感性的性别差异是由肠道微生物群的差异造成的。通过微生物多组学和培养，我们观察到女性和雌性小鼠肠道微生物群衍生的脱氢甘油酯含量都有所增加。服用去瓜尔林能够减轻经 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。从机理上讲，deguelin 通过直接相互作用降低了经 APAP 处理的肝细胞中促甲状腺激素受体（TSHR）的表达。使用 ML224 对 TSHR 的表达进行药物抑制，可显著提高 APAP 处理的雄性小鼠肝脏谷胱甘肽（GSH）的含量。这些研究结果表明，肠道微生物群衍生的deguelin在降低APAP诱导的雌性小鼠肝毒性方面发挥着至关重要的作用，为DILI的治疗策略提供了新的思路。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Gut Microbes Medicine-Microbiology (medical)

CiteScore

18.20

自引率

3.30%

发文量

196

审稿时长

10 weeks

期刊介绍： The intestinal microbiota plays a crucial role in human physiology, influencing various aspects of health and disease such as nutrition, obesity, brain function, allergic responses, immunity, inflammatory bowel disease, irritable bowel syndrome, cancer development, cardiac disease, liver disease, and more. Gut Microbes serves as a platform for showcasing and discussing state-of-the-art research related to the microorganisms present in the intestine. The journal emphasizes mechanistic and cause-and-effect studies. Additionally, it has a counterpart, Gut Microbes Reports, which places a greater focus on emerging topics and comparative and incremental studies.