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甲状腺激素受体βagonist HSK31679通过调节肠道微生物脂蛋白来缓解MASLD

Yu-Hang Zhang¹, Ran Xie¹, Chen-Shu Dai²

¹Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, 100191, China; Department of Pharmacy, Peking University First Hospital, Beijing, 100034, China.

Journal of hepatology

|August 24, 2024

概括

甲状腺激素受体βagonist HSK31679通过向微生物葡萄糖胺合成酶 (GCS) 有效地治疗与代谢功能障碍相关的脂肪肝炎 (MASH). 微生物GCS活动预测治疗反应,并为MASH提供了一个新的治疗点.

科学领域:

肝病学肝病学是一种肝病学.
微生物组研究微生物组研究
药理学药理学是指药理学的学科.

背景情况:

代谢功能障碍相关的脂肪肝炎 (MASH) 是一个日益严重的健康问题,甲状腺激素受体-β (THR-β) 激动剂,如MGL-3196显示出承诺.
对MGL-3196的个体反应各不相同,其与肠道微生物群的相互作用尚未完全理解.

研究的目的:

调查肠道微生物群在MASH治疗的有效性中的作用.
为了阐明HSK31679的作用机制,一种MGL-3196的衍生物,与肠道微生物群相关.

主要方法:

在无细菌和无特定病原体的小鼠中,MGL-3196和HSK31679疗效的比较.
在接受HSK31679.9的人群中进行交叉奥米克分析 (元基因组,代谢组,单细胞RNA测序).
评估微生物葡萄糖胺合成酶 (GCS) 活性及其对MASH分辨率的影响.

主要成果:

与无细菌小鼠相比,HSK31679在没有特定病原体的小鼠中显示出优异的MASH改善,这表明肠道微生物群的作用.
在接受HSK31679治疗的个体中*Bacteroides thetaiotaomicron*的丰富导致微生物GCS活动受损.
在无菌小鼠中,HSK31679的有效性取决于功能性微生物GCS的存在,并观察到特定的硬质障碍.
在具有高便GCS活性的参与者中,HSK31679治疗将免疫特征转移到免疫抑制状态.

结论:

微生物葡萄糖胺合成酶 (GCS) 是HSK31679对MASH的疗效的关键调解剂.
微生物GCS活动可以作为预测HSK31679治疗反应的生物标志物.
准微生物GCS为基于微生物群的MASH疗法提供了一个新的策略.

关键词:

跨学科分析的分析.我们的肠道微生物组.代谢功能障碍相关的脂肪肝炎 (MASH)斯芬戈脂类的新陈代谢甲状腺激素受体β (THR-β) 激动剂

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