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Cell Res:我分泌胰岛素还得肠道菌说了算?中国科学家首次发现,肠道菌的溶解物竟然是胰岛素的通行证

2019-06-30 奇点糕 奇点网

对于分泌胰岛素这么重要的事,竟然要听命于肠道微生物。没有它们,我们可能连胰岛素都分泌不出来……

对于分泌胰岛素这么重要的事,竟然要听命于肠道微生物。没有它们,我们可能连胰岛素都分泌不出来……

最近,中科院生物物理所的刘志华组与中山大学附属第一医院的魏泓组合作,发现肠道细胞分泌的溶菌酶溶解微生物后产生的物质,竟然是胰岛素分泌的通行证。若通行证没有发放到位,胰岛素的分泌就会受阻。相关论文发表在著名学术期刊《细胞研究》上,并选为封面论文。

这个封面设计挺有意思的......

2016年,科学家在小鼠中发现,肠道微生物分泌的乙酸盐,竟然能直接刺激宿主的迷走神经,促进胰岛β细胞分泌胰岛素。该研究发表在Nature上。

同年,又有科学家在斑马鱼中发现,在发育阶段,肠道微生物分泌的一种蛋白会诱导胰岛β细胞的增殖,促进胰岛的生长扩大。该研究发表在eLife上。

这些研究揭示了肠道微生物与胰岛之间密不可分的联系。作为胰岛素的唯一供应商,胰岛β细胞能否直接感应肠道微生物的信号,调节胰岛素分泌呢?现在仍不清楚。


图片来自everydayhealth.com

刘志华教授实验室一直在进行这方面的研究。

在胰岛β细胞中,胰岛素需要经历一个:前胰岛素原——胰岛素原——成熟胰岛素的加工过程。每一道工序都要在不同的部位进行,就像是一条流水生产线。而这条生产线的正常运转,以及胰岛素向胞外的分泌,都依赖于囊泡运输。

研究人员在小鼠中发现,若没有肠道微生物,胰岛β细胞内的囊泡运输无法正常进行,胰岛素的加工和分泌就无从谈起了。


胰岛素的加工和运输过程

不过,肠道微生物到底是如何影响宿主细胞的囊泡运输的呢?

2015年时,刘教授实验室就发现,肠道微生物被溶菌酶溶解后产生的寡聚糖,竟然能促进宿主的潘氏细胞分泌溶菌酶,灭杀自己的同类。

这个寡聚糖促进潘氏细胞分泌溶菌酶的方式,就是与潘氏细胞内的免疫受体Nod2结合,调节细胞内的货物分拣工作,也就是促进囊泡运输,促进溶菌酶的分泌,该研究发表在Nature Immunology上。


Nod2调节潘氏细胞物质运输

Nod2所属家族的另外一个受体Nod1,被发现与胰岛素抵抗有关。

因此,刘教授推测,Nod1可能了介导肠道微生物对胰岛素分泌的调节。

研究人员通过实验证实了这一点。他们发现,由溶菌酶溶解微生物产生Nod1配体,能通过血液进入β细胞,激活Nod1,使Nod1结合囊泡表面,并招募其他蛋白,促进囊泡运输,推动胰岛素的加工与转运。

简单来说就是,Nod1配体是β细胞内囊泡的通行证。没有这个通行证,胰岛素的加工和分泌都没法正常进行。而这,最终会降低血液中胰岛素的水平,损害宿主对葡萄糖的耐受能力。

令人惊讶的是,这个通行证竟然是由肠道微生物来发放的……


肠道微生物影响胰岛素分泌的机制

不过,其实Nod1配体的作用也并非完全正面,过量的Nod1会在高脂饮食诱导的肥胖小鼠中引发炎症发应,诱导胰岛素抵抗。

因此,Nod1配体实际上是具有双重作用,只有在水平适当的情况下才会发挥正面作用,过低或过高都不好。

过去一段时间,科学家揭秘了肠道微生物与2型糖尿病的各种关系。

刚发布的HMP2结果,就揭示了数百种在前驱糖尿病发展为2型糖尿病过程中发生变化的分子,会引起胰岛素抵抗,可能有助于解释2型糖尿病的发病机制,也可以用作早期筛查

2019年初,发表在《自然遗传学》上一项研究也发现,肠道微生物产生的丁酸,能改善人体的胰岛素响应;而另一种产物丙酸的异常,则会提高2型糖尿病的发病风险。

不仅如此,就连神药二甲双胍也可以通过肠道微生物来起作用。

不过,最让奇点糕感到惊讶的还是这个研究的发现,那可是胰岛素呀!胰岛素行使着生命活动最基本的功能,既能促进葡萄糖吸收,又是调节生物钟的关键,竟然还需要肠道微生物存在才能分泌,真不知道在进化中是怎么形成的。

原始出处:Qin Zhang, Ying Pan, Benhua Zeng, et al. Intestinal lysozyme liberates Nod1 ligands from microbes to direct insulin trafficking in pancreatic beta cells. Cell Res.14 June 2019

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    2019-11-10 维他命
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    2019-09-03 gwc392
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    2020-05-22 baoya
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已有的研究显示,个体在药物反应方面差异很大,这可能会导致治疗延迟和不良反应,引起危险和昂贵的后果。 越来越多的证据表明肠道微生物组对于这种可变性的贡献,但至今为止,其分子机制仍然很大程度上未知。

Nat Microbiol:与炎症性肠病和抑郁症有关的肠型

比利时VIB-KU Leuven微生物学中心教授Jeroen Raes于2012年成立了Flemish Gut Flora计划,旨在确定健康相关肠道微生物群的普遍界限,对3000多名健康志愿者的粪便样本进行了测序。最近,他们在《Nature Microbiology》发表文章,描述了缺乏某些抗炎细菌的B2肠型在多诊断中的高患病率研究。

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