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: 8449162
• 负责人: Eric C Martens
• 金额: $ 9.4万
• 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/8449162
• 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; Human; Individual; Instruction; 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

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, 6. f/iefa, 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. tfieta, 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 6. 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 S. 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. RELEVANCE (See instructions): 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.

人类的肠道菌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） 和菌群Ovatus，两个微生物群的成员，具有多种多样，但仅部分重叠的能力 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。这些生物中至少有一个，6。f/iefa，优先考虑植物果酱的代谢 宿主粘蛋白聚糖上的聚糖表明它已经进化为避免使用宿主粘膜作为营养素 当饮食糖丰富时，基础。我将定义和比较碳水化合物利用率层次结构 在这两个物种中，确定它们是否进化出相同或不同的优先级。而且，我将探索 tfieta中聚糖优先级的分子机制，使我能够测试适应性值 这种现象在gnotobiotic小鼠肠道中。我还将探索6个机制。 Ovatus靶向植物细胞壁Glycans的丰富，有时不那么可溶性半纤维素类别 B. theta无法代谢的底物组。从半纤维素利用基因中缺失 卵形链球菌基因组随后进行了体内竞争，导致的半纤维素缺陷突变体与 他们的同基因父母，将揭示这些表型的表达是否提供了适应性优势或 gnotobiotic小鼠的劣势喂养了富含这些底物的饮食。最后，我将探讨 聚糖利用表型可以横向转移在杆菌物种之间，这一现象是 我们的数据表明自然发生。对此假设的支持将产生基本的机械信息 关于微生物细菌中聚糖利用的基因组进化。我目前的培训环境， 华盛顿大学医学院的杰弗里·戈登（Jeffrey Gordon）的实验室提供了一个独特的开始 研究，可能是世界上唯一具有所有必要工具来回答的实验室 手头的实验问题。我的职业发展计划包括建立强大的研究基金会 在戈登实验室，并过渡到独立职业，担任任期助理教授。这 在这项指导的研究建议中，实现的实验和专业培训将为 经验我需要自己成功。 相关性（请参阅说明）： 人肠道细菌对于复杂的饮食多糖的转化至关重要，其中许多是 我们不能独自消化，变成很容易吸收的形式。我将表征动态 进入我们饮食的丰富植物聚糖与生理和进化之间的相互关系 我们的肠道细菌。结果将揭示哪些饮食甘氨酸细菌可以代谢，以及哪些饮食 “想要”代谢，提供有关我们肠道微生物群如何收获饮食营养的新知识。

项目成果

Multifunctional nutrient-binding proteins adapt human symbiotic bacteria for glycan competition in the gut by separately promoting enhanced sensing and catalysis.

• DOI: 10.1128/mbio.01441-14
• 发表时间: 2014-09-09
• 期刊: mBio
• 影响因子: 6.4
• 作者: Cameron EA;Kwiatkowski KJ;Lee BH;Hamaker BR;Koropatkin NM;Martens EC
• 通讯作者: Martens EC

A discrete genetic locus confers xyloglucan metabolism in select human gut Bacteroidetes.

• DOI: 10.1038/nature12907
• 发表时间: 2014-02-27
• 期刊: Nature
• 影响因子: 64.8

The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes.

• DOI: 10.1016/j.jmb.2014.06.022
• 发表时间: 2014-11-25
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Martens, Eric C.;Kelly, Amelia G.;Tauzin, Alexandra S.;Brumer, Harry
• 通讯作者: Brumer, Harry

Symbiotic Human Gut Bacteria with Variable Metabolic Priorities for Host Mucosal Glycans.

• DOI: 10.1128/mbio.01282-15
• 发表时间: 2015-11-10
• 期刊: mBio
• 影响因子: 6.4
• 作者: Pudlo NA;Urs K;Kumar SS;German JB;Mills DA;Martens EC
• 通讯作者: Martens EC