从开始的微生物群代谢物中产生的二因多尔作为内源性CAR/Nr1i3连接体起作用
Jiabao Liu1, Ainaz Malekoltojari1,2, Anjana Asokakumar3
1Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, M5S 3E1, Canada.
Nature communications
|March 23, 2024
概括
科学家们从肠道细菌中发现了激活构成性安德罗斯坦受体 (CAR) 的二醇. 这些分子通过调节宿主生理学而提供潜在的新疗法,没有副作用.
科学领域:
- 微生物学和分子生物学
- 肠道微生物组和宿主生理学
- 核接收器信号传输 核接收器信号传输
背景情况:
- 肠道细菌的代谢物影响宿主生理,主要是通过核受体 (NR).
- 识别微生物衍生的NR配体是具有挑战性的.
- 构成性安德罗斯坦受体 (CAR) 是一个关键的NR受体,参与异生物代谢和恒温.
研究的目的:
- 系统地识别和描述调节NRs的微生物衍生联体.
- 发现孤儿构成性安德罗斯坦受体 (CAR) 的新型激动剂.
- 调查这些新型化合物的治疗潜力.
主要方法:
- 从共生细菌代谢物中鉴定二醇分子.
- 生物物理分析以确定结合亲和关系和激活CAR的ortologues.
- 在初级人类肝细胞和小鼠肝脏模型中的基因表达分析.
主要成果:
- 发现二醇分子 (DIM和DIE) 作为特定的CAR激动剂.
- 纳米分子亲和力与合成CAR激动剂相当.
- 在人类和小鼠肝脏模型中选择性上调CAR目标基因,没有显著的副作用.
结论:
- 来自肠道细菌的二醇是动物和人类CAR的强有力的激活剂.
- 这些发现揭示了肠道微生物群与宿主相互作用的新机制.
- 迪因多尔为涉及CAR调节的疾病提供了有前途的治疗工具.
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