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）： 人类肠道微生物群提供了我们不必自行进化的生理属性，包括处理其他难以消化的膳食聚糖的能力。拟杆菌 (Bacteroides thetaiotaomicron) {B. theta）和卵形拟杆菌是微生物群的两个成员，它们具有不同但仅部分重叠的处理饮食和宿主衍生聚糖的能力，这些进化的特征可能会影响它们在拥挤的肠道生态系统中的适应性。这些生物体中至少有一种，B. theta，优先考虑植物果胶聚糖的代谢，而不是宿主粘蛋白聚糖，这表明当膳食聚糖丰富时，它已经进化到避免使用宿主粘膜作为营养基础。我将定义并比较这两个物种的碳水化合物利用层次结构，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 B.theta 中聚糖优先顺序的分子机制，从而使我能够测试这种现象在限生小鼠肠道中的体内适应性价值。我还将探索卵形 B. ovatus 以丰富且有时溶解度较低的植物细胞壁聚糖半纤维素类为目标的机制，这是一组 B. theta 无法代谢的底物。从卵形芽胞杆菌基因组中删除半纤维素利用基因，然后将所得的半纤维素缺陷突变体与其同基因亲本进行体内竞争，将揭示这些表型的表达是否为喂食富含这些基因的饮食的限生小鼠提供了健康优势或劣势。基材。最后，我将探讨聚糖利用表型可以在拟杆菌属物种之间横向转移的可能性，我们的数据表明这种现象是自然发生的。这一假设的支持将产生有关微生物群细菌中聚糖利用的基因组进化的基本机制信息。我目前的训练环境是华盛顿大学医学院的杰弗里·戈登实验室，它为开始这项研究提供了一个独特的场所，并且可能是世界上唯一一个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础，并过渡到作为终身教授助理教授的独立职业。在这个指导研究计划中获得的实验和专业培训将为我提供自己取得成功所需的经验。 公共健康相关性：人类肠道细菌对于将复杂的膳食多糖转化为我们容易吸收的形式至关重要，其中许多多糖是我们无法自行消化的。我将描述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。结果将揭示哪些膳食聚糖细菌“可以”代谢，哪些膳食聚糖细菌“想要”代谢，从而提供有关我们的肠道微生物群如何收获膳食营养素的新知识。