Nat Biotech:定向改造肠道微生物群,可抑制动脉粥样硬化的发生

2020-06-23 生物探索 生物探索

肠道微生物组是具有延展性的微生物群落,对人类和动物的生理健康有着基本影响。肠道微生物组的调节可以促进慢性疾病的发作和发展,例如动脉粥样硬化,心血管疾病,肥胖症,糖尿病和中枢神经系统疾病。而包括饮食在内

肠道微生物组是具有延展性的微生物群落,对人类和动物的生理健康有着基本影响。肠道微生物组的调节可以促进慢性疾病的发作和发展,例如动脉粥样硬化,血管疾病,肥胖症,糖尿病和中枢神经系统疾病。而包括饮食在内的各种因素可以通过重塑微生物组以及对宿主的直接作用在疾病中发挥重要作用。

6月15日,来自美国斯克里普斯研究院的研究人员在《Nature biotechnology》上发表了关于肠道微生物影响人体健康的最新研究成果,发现口服可选择性修饰细菌生长的分子环状D,L-α-肽,以定向改造小鼠肠道微生物群,可降低血浆总胆固醇水平和动脉粥样硬化斑块,抑制动脉粥样硬化的发生。

https://doi.org/10.1038/s41587-020-0549-5

低密度脂蛋白受体无效(LDLr-/-)小鼠被广泛用作饮食诱导的动脉粥样硬化的动物模型,研究人员发现,LDLr-/-小鼠在饲喂日粮(CHD)时表现为健康,而饲喂西方饮食(WD)时表现为高脂血症和动脉粥样硬化,且两者的肠道微生物组状态不同。因此,研究人员猜测,将体内微生物群的组成(即使在WD的影响下)重塑为CHD状态或许可以改善其疾病进展。

研究人员基于序列多样性和缺乏哺乳动物细胞毒性从抗菌肽库中选择了29种环状D,L-α-肽,根据其对WD喂养的小鼠中大量生长细菌种类的抑制程度,选择阳离子肽1和两性离子肽11,进行下一步体内验证和功效研究。

对WD和CHD饲喂的LDLr-/-小鼠使用环肽1和11处理10周,发现WD喂养对照组中肠道微生物丰富度显著降低,而肽1和11处理可逆转这种降低,且小鼠的拟杆菌/厚壁菌门比率出现增加。

环肽在体外调节肠道菌群

对肽处理2周后的小鼠粪便中细菌进行转录组测序,发现肽可引起微生物群转录组的广泛重编程,肽11处理降低了厚壁菌门基因表达,而增加了拟杆菌的总体基因表达。靶向代谢组学分析表明,肽可恢复受损肠道菌群的重要功能。功能宏基因组学分析表明,肽可诱导酶表达水平发生变化,丁酸酯生物合成及乙酰乙酸-CoA转移酶水平增加,色氨酸和苯丙氨酸的分解代谢降低。

用肽处理饲料喂养的小鼠引起肠道微生物群的代谢变化和转录重编程

除此之外,研究者发现,肽处理后,WD小鼠的血浆胆固醇水平和动脉粥样硬化病变显著降低。与对照相比,口服肽1和11分别降低了小鼠血浆总胆固醇37%和36%。而在CHD喂养的小鼠中,没有类似的肽介导的胆固醇降低。主动脉病变区域的分析表明,肽1和11分别使动脉粥样硬化病变显著减少了37%和48%,同时,主动脉窦病变体积分别减少了44%和37%。

肽治疗减少了wd喂养的LDLr?/?小鼠动脉粥样硬化的发展

微生物群组成分析表明,肽会降低与血浆胆固醇水平呈正相关的微生物群,而增加负相关的分类单元丰度。使用广谱抗生素混合物处理小鼠以消耗微生物组,然后进行肽处理,可发现肽11完全丧失了降低血浆胆固醇水平(动脉粥样硬化的关键标记)的能力,这也表明其通过肽直接靶向和重构肠道菌群以实现调控。

炎症在动脉粥样硬化的发展中起关键作用。研究人员还发现,肽处理可重新编程微生物组转录组,抑制促炎细胞因子的产生,短链脂肪酸和胆汁酸水平的重新平衡,改善肠屏障的完整性并增加肠道T调节细胞。

简而言之,研究人员从体外选择的肽可在体内选择性地将WD诱导的肠道微生物组重塑为低脂饮食下的状态,进而可以防止动脉粥样硬化的发展。定向化学操作为解密肠道微生物组的化学生物学特性也提供了额外的工具。

原始出处:

Poshen B. Chen, Audrey S. Black, Adam L. Sobel, et.al. Directed remodeling of the mouse gut microbiome inhibits the development of atherosclerosis. Nature Biotechnology 15 June 2020

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    2020-10-01 sunylz
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    2020-07-30 liao1632
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    2020-10-05 cathymary
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    2021-04-26 shock_melon
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    2021-04-26 liye789132251
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