两篇PNAS共同揭示:肠道微生物与多发性硬化症有关!
2017/09/14
肠道微生物与多发性硬化症有关联?这是真的,近期《PNAS》期刊同时发表两篇文章揭示这一事实。而且,科学家们不仅仅找到关联性,还发现了肠道微生物调控免疫系统攻击神经细胞的机制。


肠道微生物的热门程度毋庸置疑,数以万亿计的细菌生活在肠道中,它们被称为一个“隐形器官”,与多种疾病有关。9月11日,《PNAS》期刊同时发表两篇文章,揭示了又一种与肠道细菌有关联的疾病——多发性硬化症(MS)!

更重要的是,他们不仅仅找到关联性,还发现了肠道微生物调控免疫系统攻击神经细胞的机制。这有助于我们开发对应的治疗手段,例如基于微生物产物的药品,从而改善病症。

MS是一种最常见的中枢神经脱髓鞘疾病,易导致肌无力、失明甚至于死亡,影响着全球250万人的健康和生命。但是,对于MS的致病原因以及逐步损伤神经系统的机制,我们了解相对有限。大多数研究人员认为,当携带易感基因的人遇到某些特定(未知)的环境因素就会生病。之前的研究已经发现,MS患者肠道中存在大量的特定细菌。

MS患者的肠道菌影响免疫系统,引发大脑炎症

《Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models》

加州大学旧金山分校的人类遗传学家Sergio Baranzini带领团队分析了71名MS患者和71名健康人的肠道菌群。他们发现,在MS患者肠道中,有2个肠道细菌群——Acinetobacter和Akkermansia数量是正常人的4倍多!此外,Parabacteroides菌在健康人体内的数量是MS患者的4倍!

随后,他们从健康个体血液中分离出免疫细胞,将其暴露于MS患者的肠道菌群中。当Acinetobacter和Akkermansia存在时,天然免疫细胞会分化成辅助T细胞,引发炎症、协助免系统防御入侵者或者感染细胞。而且,Acinetobacter细菌会抑制调节T细胞,从而影响它们阻止自身免疫性疾病的功能。

将MS患者的肠道菌群移植至无菌小鼠体内后,其免疫系统也会发生类似的变化。在移植20天左右,小鼠表现出严重的大脑炎症。“将健康人的肠道菌移植给同一批小鼠,这些小鼠并没有生病。” Baranzini教授表示。

MS患者的肠道菌群抑制抗炎分子

《Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice》

来自于德国Max Planck神经生物学研究所的免疫学家Gurumoorthy Krishnamoorthy和Hartmut Wekerle进行了更为巧妙的研究。他们招募了34对同卵双胞胎(年龄在21-63岁),有意思的点在于这些双胞胎有且仅有一位患有多发性硬化症

研究人员通过分析他们的肠道微生物发现:相比于健康个体,MS患者肠道中的Akkermansia菌群水平显著较高。当将双胞胎的肠道菌群分别移植给小鼠12周后,移植有MS菌群的小鼠表现出类似于MS的病症。来自于MS患者的肠道细菌相对更容易抑制细胞因子IL-10等负责减轻炎症的分子的分泌。

这两篇研究虽然分析的样本量相对较少,但是它们给出了“让人激动的新证据”——一些特定的肠道微生物会抑制关键抗炎分子,从而会与其他遗传、环境因素一起引发多发性硬化症。

研究人员相信,了解多发性硬化症发生过程中肠道菌群改变免疫系统的机制,有助于我们开发对应的治疗手段,例如抗炎细菌或者药物“鸡尾酒”。

参考资料:

Gut microbes could help trigger multiple sclerosis

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  • Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models

    The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10–expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice “humanized” with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.

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  • Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice

    There is emerging evidence that the commensal microbiota has a role in the pathogenesis of multiple sclerosis (MS), a putative autoimmune disease of the CNS. Here, we compared the gut microbial composition of 34 monozygotic twin pairs discordant for MS. While there were no major differences in the overall microbial profiles, we found a significant increase in some taxa such as Akkermansia in untreated MS twins. Furthermore, most notably, when transplanted to a transgenic mouse model of spontaneous brain autoimmunity, MS twin-derived microbiota induced a significantly higher incidence of autoimmunity than the healthy twin-derived microbiota. The microbial profiles of the colonized mice showed a high intraindividual and remarkable temporal stability with several differences, including Sutterella, an organism shown to induce a protective immunoregulatory profile in vitro. Immune cells from mouse recipients of MS-twin samples produced less IL-10 than immune cells from mice colonized with healthy-twin samples. IL-10 may have a regulatory role in spontaneous CNS autoimmunity, as neutralization of the cytokine in mice colonized with healthy-twin fecal samples increased disease incidence. These findings provide evidence that MS-derived microbiota contain factors that precipitate an MS-like autoimmune disease in a transgenic mouse model. They hence encourage the detailed search for protective and pathogenic microbial components in human MS.

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