Role of Vitamin B12 in sustaining trophic interactions between human gut symbionts

维生素 B12 在维持人类肠道共生体之间营养相互作用中的作用

• 批准号: BB/V01093X/1
• 负责人: Nathalie Juge
• 金额: $ 67.82万
• 依托单位: Quadram Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV01093X%2F1
• 关键词: Role; Vitamin; B12; sustaining; trophic

The aim of the proposal is to provide molecular and biochemical detail on the different forms of vitamin B12 (VitB12) that can be synthesised or utilised by gut bacteria in the gastrointestinal lining and understand how bacteria are able to participate in this nutrient provisioning and sharing. This fundamental knowledge is required to develop adapted nutritional approaches targeting gut microbes for the benefit of human health.Trillions of bacteria live in our large intestine (the gut microbiota) where they play a vital role in maintaining good health. Bacteria in complex communities share resource and one of the key molecules that is communally distributed in such ecosystems is VitB12, a molecule that is made by only relatively few bacteria but utilised by most. Bacteria can make a range of up to 15 different VitB12-like molecules that collectively are called cobamides. Cobamides are expensive for the bacteria to make, requiring a complex biochemical pathway of around 30 enzymes for their biogenesis, but once made they provide the host with significant metabolic advantages. However, it is not clear to what extent these VitB12 variants or analogues are active across gut bacterial strains. With the gut microbiota now being linked to so many different health conditions, there is a growing interest in developing nutritional strategies that look to alter the balance of microbes to improve health. This could be through dietary supplement or 'probiotic' approaches. Bacteria living in the gut lining (mucus-associated bacteria), close to our body, are particularly prone to affect or respond to changes in our health status. However, it is not usually known how to modulate these bacteria. We previously showed that human strains of Lactobacillus reuteri are able to produce ViB12. In the work leading to this proposal, we demonstrated that Ruminoccus gnavus, a keystone mucus colonising bacterium in humans, requires VitB12 to grow but that, in the absence of VitB12, the presence of L. reuteri is also able to promote its growth. R. gnavus has been implicated as a key modulator of human health and there is therefore strong interest from academics and clinicians in better understanding the biology and requirements of this organism and how we can modulate it to improve human health. To address this mutualism and VitB12 requirement, we will determine the type of VitB12 forms required to sustain the growth of R. gnavus. We will identify the component parts in the bacteria that are required for the bacteria to utilise VitB12. By using anaerobic fermentation facilities and models to mimic the human colon we will determine the ability of VitB12-producers such as L. reuteri and/or VitB12 analogues to modulate VitB12-requirers such as R. gnavus and assess the impact of the treatments on the gut microbial community. We will then investigate the modulation of mucus-associated strains by investigating similar effects in vivo using mouse models harbouring a human gut microbiota. This will also inform on the impact of a 'probiotic' approach (in situ-production of VitB12) versus supplementation with specific VitB12 analogues. Together, this collaborative proposal will provide long-sought information on the basic question of how bacteria have evolved their complex trade-offs by sharing metabolic burden. Furthermore, the research will gain and exploit fundamental knowledge on how VitB12 can lead to novel strategies for manipulating microbial composition in the gut for the benefit of human health.

该提案的目的是提供关于不同形式的维生素B12（VitB 12）的分子和生物化学细节，这些维生素B12可以由胃肠道细菌合成或利用，并了解细菌如何能够参与这种营养供应和共享。这些基础知识是开发针对肠道微生物的适应性营养方法以造福人类健康所必需的。数万亿的细菌生活在我们的大肠（肠道微生物群）中，它们在维持健康方面发挥着至关重要的作用。复杂群落中的细菌共享资源，在这种生态系统中共同分布的关键分子之一是VitB 12，这种分子仅由相对较少的细菌产生，但被大多数细菌利用。细菌可以产生多达15种不同的维生素B12样分子，统称为钴酰胺。钴酰胺对于细菌来说是昂贵的，需要大约30种酶的复杂生化途径来进行生物合成，但是一旦制造出来，它们就为宿主提供了显着的代谢优势。然而，目前尚不清楚这些VitB 12变体或类似物在肠道细菌菌株中的活性程度。 随着肠道微生物群与许多不同的健康状况联系在一起，人们越来越有兴趣制定营养策略，以改变微生物的平衡来改善健康。这可能是通过膳食补充剂或“益生菌”的方法。生活在肠道内壁的细菌（粘液相关细菌），靠近我们的身体，特别容易影响或响应我们健康状况的变化。然而，通常不知道如何调节这些细菌。我们以前表明，罗伊氏乳杆菌的人类菌株能够产生ViB 12。在导致这一提议的工作中，我们证明了在人类中的关键粘液定植细菌Ruminoccus gavus需要VitB 12才能生长，但是，在缺乏VitB 12的情况下，L. reuteri也能够促进其增长。R. gnavus被认为是人类健康的关键调节剂，因此学术界和临床医生对更好地了解这种生物体的生物学和需求以及我们如何调节它以改善人类健康有着浓厚的兴趣。为了解决这种互惠关系和维生素B12的需求，我们将确定维生素B12的类型需要维持R的增长。gnavus。我们将确定细菌中利用VitB 12所需的组成部分。通过利用厌氧发酵设备和模型来模拟人结肠，我们将确定维生素B12生产者如L。reuteri和/或VitB 12类似物来调节VitB 12-需要者如R. gnavus，并评估治疗对肠道微生物群落的影响。然后，我们将通过使用含有人类肠道微生物群的小鼠模型研究体内类似的作用来研究粘液相关菌株的调节。这也将告知“益生菌”方法（VitB 12的原位生产）与补充特定VitB 12类似物的影响。总之，这一合作提案将提供长期寻求的关于细菌如何通过分担代谢负担来进化其复杂权衡的基本问题的信息。此外，该研究将获得和利用关于VitB 12如何能够导致操纵肠道微生物组成以造福人类健康的新策略的基础知识。