The Role of Mucin-type O-glycosylation in Fitness and Transmission of Intestinal Symbiotic Bacteria In Vivo

粘蛋白型O-糖基化在肠道共生菌体内适应性和传播中的作用

• 批准号: RGPIN-2020-04418
• 负责人: Bergstrom, Kirk
• 金额: $ 2.7万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=739949
• 关键词: Role; Mucin; type; glycosylation; Fitness

BACKGROUND AND RATIONALE. The human gut is home to trillions of bacteria of many different types. We know now this vast microbial community plays many roles in host physiology, including digestion, energy acquisition, and vitamin production. However, we are not clear how the host provides an environment that allows such beneficial bacteria to thrive in the gut. One emerging factor is intestinal mucus, which is secreted by cells of the gut lining and intermixes with the microbiota. This mucus is mostly comprised of structures called "O-glycans", which are made up of sugar molecules of different types joined together in unique conformations that are presented to the microbiota. Despite this knowledge, we still are unclear how important these O-glycans are in promoting a thriving microbial population, largely due to the lack of effective tools to study them in a living system. We also do not know whether differences in males and females exist in regards to how O-glycans impact the microbiota. This leaves a serious gap in our understanding of mammalian colon ecosystems and maintenance of beneficial bacteria in a population. Fortunately, we now have access to novel genetic and bacterial tools that allow us to manipulate the O-glycosylation system, as well as visualize and track specific bacterial responses, in a model mammalian gut (mouse). OBJECTIVES AND METHODS. My long-term objective is to determine how the host glycosylation program of the secreted mucus influences the mammalian colon ecosystem to promote mutually beneficial interactions with our microbiota. I have three short-term objectives for this five-year Discovery Grant, which focus on how host O-glycans contribute to microbial survival in the gut. My hypothesis is that the O-glycans on mucus are essential for promoting stability of the microbiota in the face of a changing luminal environment due to dietary and other interventions. Using my expertise with genetic tools to create various O-glycan deficiencies in the mammalian (mouse) colon, in combination with my "reporter" bacteria, I will use techniques in microbiology, microscopy, and computational approaches to test how different glycosylation programs impact the ability of my reporter to colonize, find their niche, and thrive in male and female intestines. IMPACT AND HQP. These studies will boost Canada's international research impact in the natural sciences by addressing a fundamental question in microbiology and microbiota research. Specifically, it will generate findings relevant to microbiologists interested in the mammalian microbiota; glycobiologists seeking to understand how O-glycans impact microbiota communities; researchers studying sex- and gender-based biology, and the general public who wish to understand how their intestines help support their microbial populations. This research program will additionally provide an ideal training ground for Canadian HQP who will be competitive for positions in academia and industry.

背景和依据。人类肠道是数万亿多种不同类型细菌的家园。我们现在知道这个庞大的微生物群落在宿主生理学中起着许多作用，包括消化，能量获取和维生素生产。然而，我们还不清楚宿主如何提供一个环境，让这些有益的细菌在肠道中茁壮成长。一个新出现的因素是肠粘液，它由肠道细胞分泌，并与微生物群混合。这种粘液主要由称为“O-聚糖”的结构组成，这些结构由不同类型的糖分子以独特的构象连接在一起组成，这些构象呈现给微生物群。尽管有这些知识，我们仍然不清楚这些O-聚糖在促进微生物种群繁荣方面的重要性，这主要是由于缺乏有效的工具来研究它们在生命系统中的作用。我们也不知道男性和女性在O-聚糖如何影响微生物群方面是否存在差异。这在我们对哺乳动物结肠生态系统的理解和在种群中维持有益细菌方面留下了严重的空白。幸运的是，我们现在可以获得新的遗传和细菌工具，使我们能够操纵O-糖基化系统，以及可视化和跟踪特定的细菌反应，在模型哺乳动物肠道（小鼠）。 替代品和方法。我的长期目标是确定分泌粘液的宿主糖基化程序如何影响哺乳动物结肠生态系统，以促进与我们微生物群的互利相互作用。我为这个为期五年的发现资助计划制定了三个短期目标，重点是宿主O-聚糖如何促进肠道中微生物的存活。我的假设是，粘液上的O-聚糖对于促进微生物群的稳定性至关重要，因为饮食和其他干预措施会导致管腔环境发生变化。利用我的专业知识与遗传工具，以创造各种O-聚糖缺陷的哺乳动物（小鼠）结肠，结合我的“记者”细菌，我将使用微生物学，显微镜技术，和计算方法来测试不同的糖基化程序如何影响我的记者的能力，殖民化，找到他们的利基，并在男性和女性肠道中茁壮成长。影响和HQP。这些研究将通过解决微生物学和微生物群研究中的一个基本问题来提高加拿大在自然科学领域的国际研究影响力。具体来说，它将产生与对哺乳动物微生物群感兴趣的微生物学家相关的发现;糖生物学家试图了解O-聚糖如何影响微生物群;研究基于性别和性别的生物学的研究人员，以及希望了解他们的肠道如何帮助支持他们的微生物种群的普通公众。该研究计划还将为加拿大HQP提供一个理想的培训基地，他们将在学术界和工业界具有竞争力。