《自然》翻开肠道微生物研究新篇章:人体肠道菌群摄取营养素过程被破译

  2017年1月11日,英国《自然》在线发表英国纽卡斯尔大学、德国不来梅雅各布大学、英国牛津大学的研究报告,通过结构生物学方法深入了解了肠道细菌摄取营养素的过程,公布了首个底物结合蛋白(SusCD)复合体三维原子结构,并由此解答了肠道菌群营养素摄入的相关问题,这为众多肠道菌群研究提供了重要的基础。

  人体肠道分布着极其丰富的细菌群体,被称为肠道菌群或微生物区系(microbiota),可谓人体的第二个基因组,其所编码的基因有100万个以上。这个基因组与人体本身基因组相互协调、和谐一致,保证了人体的健康。

  近年来的研究表明,肠道微生物对人体健康和营养非常重要,而且也与自身免疫疾病、癌症和肥胖有关。要分析这些微生物,需要先弄清楚其如何摄取营养素,因为肠道微生物的功能和组成取决于每一种微生物如何在人体肠道的高度竞争环境中获取营养素(例如淀粉和其他膳食多糖)的能力。

  细菌获取营养素的过程通过细胞膜蛋白机器完成,对于肠道菌群中的许多细菌,这个机器就是由底物结合蛋白(SusD)和通道形成转运蛋白(SusC)组成的双组分复合体。

  本研究通过X射线晶体成像技术,首次纯化并公布了SusCD复合体的三维原子结构,并由此发现了营养素如何转运到细菌内部的分子机制。

  SusCD复合体的功能类似于脚踏式垃圾桶,上面的盖子是SusD,下面的桶是SusC。当出现底物时,盖子就会打开,而在捕获底物后,盖子关闭,底物进入桶中传递给细胞。

  本研究为了解微生物组如何发挥功能,以及人体肠道菌群共生关系提供了重要结构基础、提出了新的基本观点,这些观点也是针对目前肠道菌群研究的必要补充,回答了系统生物学的问题,例如事件发生的参与者和时间。而且本研究也将机制与系统生物学联系在一起,未来可以通过感染关键营养素摄取过程,改变微生物组成。为借助肠道菌群干预手段寻找疾病治疗方法提供了新的方向。

Nature. 2017 Jan 11. [Epub ahead of print]

Structural basis for nutrient acquisition by dominant members of the human gut microbiota.

Glenwright AJ, Pothula KR, Bhamidimarri SP, Chorev DS, Baslé A, Firbank SJ, Zheng H, Robinson CV, Winterhalter M, Kleinekathofer U, Bolam DN, van den Berg B.

Newcastle University, Newcastle, UK; Jacobs University Bremen, Bremen, Germany; University of Oxford, Oxford, UK.

The human large intestine is populated by a high density of microorganisms, collectively termed the colonic microbiota, which has an important role in human health and nutrition. The survival of microbiota members from the dominant Gram-negative phylum Bacteroidetes depends on their ability to degrade dietary glycans that cannot be metabolized by the host. The genes encoding proteins involved in the degradation of specific glycans are organized into co-regulated polysaccharide utilization loci, with the archetypal locus sus (for starch utilisation system) encoding seven proteins, SusA-SusG. Glycan degradation mainly occurs intracellularly and depends on the import of oligosaccharides by an outer membrane protein complex composed of an extracellular SusD-like lipoprotein and an integral membrane SusC-like TonB-dependent transporter. The presence of the partner SusD-like lipoprotein is the major feature that distinguishes SusC-like proteins from previously characterized TonB-dependent transporters. Many sequenced gut Bacteroides spp. encode over 100 SusCD pairs, of which the majority have unknown functions and substrate specificities. The mechanism by which extracellular substrate binding by SusD proteins is coupled to outer membrane passage through their cognate SusC transporter is unknown. Here we present X-ray crystal structures of two functionally distinct SusCD complexes purified from Bacteroides thetaiotaomicron and derive a general model for substrate translocation. The SusC transporters form homodimers, with each β-barrel protomer tightly capped by SusD. Ligands are bound at the SusC-SusD interface in a large solvent-excluded cavity. Molecular dynamics simulations and single-channel electrophysiology reveal a 'pedal bin' mechanism, in which SusD moves away from SusC in a hinge-like fashion in the absence of ligand to expose the substrate-binding site to the extracellular milieu. These data provide mechanistic insights into outer membrane nutrient import by members of the microbiota, an area of major importance for understanding human-microbiota symbiosis.

PMID: 28077872

DOI: 10.1038/nature20828

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