Complex glycan utilization by human gut Bacteroides

人类肠道拟杆菌对复杂聚糖的利用

• 批准号: 8055482
• 负责人: Eric C Martens
• 金额: $ 12.75万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055482
• 关键词: Address; Bacteria; Bacteroides; Bacteroides thetaiotaomicron; Biological; Carbohydrates; Carbon; Cell Wall; Cells; Complex; Crowding; Data; Development Plans; Diet; Dietary Polysaccharide; Disadvantaged; Ecosystem; Elements; Engineering; Environment; Evolution; Foundations; Genes; Genome; Genomics; Gnotobiotic; Hand; Harvest; Health; Human; Individual; Investigation; Knowledge; Mentors; Metabolism; Molecular; Molecular Genetics; Monosaccharides; Mucins; Mucous Membrane; Mus; Nutrient; Organism; Parents; Phenotype; Physiological; Physiology; Plants; Polysaccharides; Process; Research; Research Proposals; Scheme; Shapes; Source; Testing; Training; Universities; Washington; base; career; career development; experience; feeding; fitness; gut microbiota; hemicellulose; in vivo; medical schools; member; microbial; microbiome; mutant; nutrition; professor; tool

DESCRIPTION (provided by applicant): The human gut microbiota provides physiologic attributes that we have not had to evolve on our own, including the ability to process otherwise indigestible dietary glycans. Bacteroides thetaiotaomicron {B. theta) and Bacteroides ovatus, two members of the microbiota, have diverse but only partially overlapping abilities to process dietary and host-derived glycans - evolved features that likely influence their fitness in the crowded gut ecosystem. At least one of these organisms, B. theta, prioritizes metabolism of plant pectic glycans over host mucin glycans, suggesting that it has evolved to avoid using the host mucosa as a nutrient base when dietary glycans are abundant. I will define and compare the carbohydrate utilization hierarchies of these two species to determine if they evolved the same or different priorities. Moreover, I will explore the molecular mechanisms that underlie glycan prioritization in B. theta, allowing me to test the fitness value of this phenomenon in vivo in the gnotobiotic mouse gut. I will also explore the mechanisms through which B. ovatus targets the abundant and sometimes less soluble hemicellulose class of plant cell wall glycans, a group of substrates that B. theta is not able to metabolize. Deletion of hemicellulose utilization genes from the B. ovatus genome followed by in vivo competition of the resulting hemicellulose-deficient mutants with their isogenic parents, will reveal if expression of these phenotypes provides a fitness advantage or disadvantage in gnotobiotic mice fed a diet rich in these substrates. Finally, I will explore the possibility that glycan utilization phenotypes can be laterally transferred between Bacteroides species, a phenomenon that our data suggest occurs naturally. Support of this hypothesis will yield fundamental mechanistic information about genomic evolution of glycan utilization among microbiota bacteria. My current training environment, Jeffrey Gordon's lab at Washington University Medical School, provides a unique place to begin this research and may be the only lab in the world equipped with all of the necessary tools to answer the experimental questions at hand. My career development plan includes building a robust research foundation in the Gordon lab and transitioning into an independent career as a tenure track Assistant Professor. The experimental and professional training achieved during this mentored research proposal will provide the experience I need to be successful on my own. PUBLIC HEALTH RELEVANCE: Human gut bacteria are essential for the transformation of complex dietary polysaccharides, many of which we cannot digest on our own, into forms that we readily absorb. I will characterize the dynamic interrelationships between abundant plant glycans that enter our diets and the physiology and evolution of our gut bacteria. The results will reveal which dietary glycans bacteria 'can' metabolize and which ones they 'want' to metabolize, providing new knowledge about how our gut microbiota harvests dietary nutrients.

描述（由申请人提供）： 人类的肠道微生物群提供了我们不必自行发展的生理属性，包括处理原本不可消化的饮食聚糖的能力。细菌thetaiotaomicron {B. theta）和杀菌剂Ovatus是微生物群的两个成员，具有多种多样但只有部分重叠的能力来处理饮食和宿主衍生的聚糖 - 进化的特征，可能会影响其在拥挤的肠道生态系统中的健康状况。这些生物中至少有一种theta在植物长聚糖上优先考虑植物果糖的代谢，这表明当饮食中饮食中的聚糖丰富时，它已经避免使用宿主粘膜作为营养基础。我将定义和比较这两个物种的碳水化合物利用率层次结构，以确定它们是否进化出相同或不同的优先级。此外，我将探索theta中聚糖优先次序基础的分子机制，从而使我能够在gnotobiotic小鼠肠道中测试这种现象的适应性值。我还将探索卵形芽孢杆菌靶向植物细胞壁糖的丰富且有时易溶的半纤维素类别的机制，植物细胞壁糖（B. theta）无法代谢。从卵巢基因组中删除半纤维素利用基因，然后在体内竞争与同基因父母的半纤维素缺乏的突变体的体内竞争，将揭示这些表型的表达是否能在这些基生长的饮食中提供适应性优势或缺点。最后，我将探讨可以在菌孢子物种之间横向转移的聚糖利用表型的可能性，这是我们的数据自然存在的现象。对这一假设的支持将产生有关微生物群中糖化利用基因组进化的基本机械信息。我目前的培训环境，华盛顿大学医学院的杰弗里·戈登（Jeffrey Gordon）实验室，为开始这项研究提供了一个独特的场所，可能是世界上唯一配备了所有必要工具来回答手头实验问题的实验室。我的职业发展计划包括在戈登实验室建立强大的研究基金会，并过渡到独立职业，成为任期助理助理教授。在这项指导的研究建议中，实现的实验和专业培训将为我自己取得成功所需的经验。 公共卫生相关性：人类肠道细菌对于复杂的饮食多糖的转化至关重要，其中许多我们无法自行消化为我们容易吸收的形式。我将表征进入我们饮食的丰富植物聚糖与肠道细菌的生理和进化之间的动态相互关系。结果将揭示哪些饮食中的饮食中的细菌“可以”代谢以及他们“想要”代谢的细菌，从而提供了有关我们的肠道微生物群如何收获饮食营养素的新知识。