Cell惊人发现!肠道微生物影响大脑关键免疫细胞,不同性别有差异
2018/01/07
肠道微生物是人类的“第二基因组”。除了与肥胖、饮食等有关,越来越多的证明表明,它们还对大脑有重要影响。近日,发表在顶级期刊Cell上的一项研究发现,肠道微生物影响着大脑中关键的免疫细胞——小胶质细胞(microglia),且这种影响在雄性和雌性小鼠中显著不同。


图片来源:网络

小胶质细胞是一种免疫细胞,能够对创伤性损伤或炎症信号做出反应,以保护大脑,充当了各种环境信号的传感器。除了扮演“免疫哨兵”(immune sentinels),小胶质细胞还被证明能够调节大脑布线和功能(brain wiring and functioning)的多个步骤。

先前的研究表明,小胶质细胞功能障碍与多种神经退行性疾病和神经发育障碍(包括精神分裂症或自闭症谱系障碍)的病因学有关。因此,这类细胞还代表一种新的、重要的细胞靶点(cellular target),有望用于缓解和治疗大脑疾病。


图片来源:Cell

在这项新研究中,来自法国和新加坡的一个科学家小组利用无菌小鼠(缺乏所有的微生物组)和被抗生素处理的成年小鼠(严重破坏了肠道菌群),结合基因组分析和组织学研究发现,小胶质细胞受到了微生物群破坏(microbiota disruption)的严重影响,这种影响甚至从产前阶段(prenatal stages)就已经开始了。


图片来源:Cell

此外,令人惊讶的是,微生物组对小胶质细胞的影响具有性别和年龄依赖性:雄性小鼠的小胶质细胞在胎儿期就被影响了,而雌性小鼠的小胶质细胞要到成年期才会受到影响。这种性别差异正好与“许多神经发育障碍在男性中发病率较高,而自身免疫性疾病在女性中更为普遍”这一事实相呼应。

尽管还需要对潜在的机制和后果进行进一步的调查,但这一研究揭示了小胶质细胞在大脑/环境交界面(brain/environment interface)中的关键作用,表明了雄性和雌性小鼠对微生物组的改变有着不同的敏感性时间窗口(susceptibilities time windows)。作者们认为,这些因素应该在临床前和临床水平被系统性地考虑进去。

参考资料:

Microbiome Influences Brain’s Immune Cells in a Sex and Age-dependent manner

Of sex and germs: Microglia sexual identity matters!

Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner

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  • Microbiome Influences Prenatal and Adult Microglia in a Sex-Specific Manner

    Microglia are embryonically seeded macrophages that contribute to brain development, homeostasis, and pathologies. It is thus essential to decipher how microglial properties are temporally regulated by intrinsic and extrinsic factors, such as sexual identity and the microbiome. Here, we found that microglia undergo differentiation phases, discernable by transcriptomic signatures and chromatin accessibility landscapes, which can diverge in adult males and females. Remarkably, the absence of microbiome in germ-free mice had a time and sexually dimorphic impact both prenatally and postnatally: microglia were more profoundly perturbed in male embryos and female adults. Antibiotic treatment of adult mice triggered sexually biased microglial responses revealing both acute and long-term effects of microbiota depletion. Finally, human fetal microglia exhibited significant overlap with the murine transcriptomic signature. Our study shows that microglia respond to environmental challenges in a sex- and time-dependent manner from prenatal stages, with major implications for our understanding of microglial contributions to health and disease.

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