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.

人类肠道微生物区系提供了我们不必自己进化的生理属性， 包括处理原本无法消化的膳食多糖的能力。Thetaiotaomicron(B.theta) 和卵拟杆菌是微生物群中的两个成员，它们的能力不同，但只有部分重叠 处理饮食和宿主来源的多糖-进化的特征，可能影响它们在 拥挤的肠道生态系统。这些生物中至少有一种，6.f/iefa，优先考虑植物果胶的代谢。 多糖覆盖宿主粘蛋白多糖，这表明它已经进化到避免使用宿主粘膜作为营养物质 当饮食中的糖类丰富时，就可以作为基础。我将定义和比较碳水化合物利用等级 以确定它们是否进化出相同或不同的优先顺序。此外，我还将探讨 在B.tfieta中多糖优先排列的分子机制，使我能够测试 这种现象在活体中存在于灵生小鼠的肠道中。我还将探索通过哪些机制。 卵子针对的是植物细胞壁多糖中丰富的、有时不易溶解的半纤维素类，一种 一组B.theta不能代谢的底物。半纤维素利用基因的缺失 卵形链霉菌基因组与半纤维素缺陷型突变体的体内竞争 他们的同基因双亲，将揭示这些表型的表达是否提供了适应优势或 在喂食富含这些底物的饮食的诺生菌小鼠中处于不利地位。最后，我将探讨是否有可能 利用多糖的表型可以在类杆菌属物种之间横向转移，这一现象 我们的数据表明，这是自然发生的。对这一假设的支持将产生基本的机械信息 关于微生物区系细菌利用多糖的基因组进化。我目前的训练环境， 杰弗里·戈登在华盛顿大学医学院的实验室提供了一个独特的地方来开始这项研究 而且可能是世界上唯一一个配备了所有必要工具来回答 手头的实验问题。我的职业发展计划包括建立坚实的研究基础 在戈登实验室，并过渡到一个独立的职业生涯，作为终身教职跟踪助理教授。这个 在此指导性研究提案期间完成的实验和专业培训将提供 经验：我需要靠自己取得成功。 相关性(请参阅说明)： 人体肠道细菌对于转化复杂的膳食多糖是必不可少的，其中许多 我们不能自己消化，变成我们容易吸收的形式。我将描述这一动态 丰富的植物多糖进入我们的饮食与植物的生理和进化的相互关系 我们的肠道细菌。研究结果将揭示细菌能代谢哪些膳食糖链，以及它们能代谢哪些糖链。 “想”代谢，为我们的肠道微生物区系如何获取膳食营养提供了新的知识。

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