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.

人类肠道微生物群提供了我们不必自行进化的生理属性， 包括处理难以消化的膳食聚糖的能力。拟杆菌 (Bacteroides thetaiotaomicron) {B. θ) 和卵形拟杆菌是微生物群的两个成员，具有不同但仅部分重叠的能力 处理饮食和宿主衍生的聚糖 - 可能影响它们在环境中的适应性的进化特征 拥挤的肠道生态系统。这些生物体中至少有一种，6.f/iefa，优先考虑植物果胶的代谢 聚糖超过宿主粘蛋白聚糖，表明它已经进化到避免使用宿主粘膜作为营养物质 当膳食聚糖丰富时为碱。我将定义并比较碳水化合物利用层次结构 确定这两个物种是否进化出相同或不同的优先级。此外，我将探索 B. tfieta 中聚糖优先顺序的分子机制，使我能够测试其适合度值 这种现象存在于限生小鼠肠道中。我还将探讨 6. 的机制。 ovatus 的目标是植物细胞壁聚糖中丰富且有时溶解度较低的半纤维素类， B. theta 无法代谢的一组底物。删除半纤维素利用基因 S. ovatus 基因组，然后与产生的半纤维素缺陷突变体进行体内竞争 他们的同基因亲本，将揭示这些表型的表达是否提供了适应性优势或 喂养富含这些底物的饮食的限生小鼠的缺点。最后我会探讨一下这种可能性 聚糖利用表型可以在拟杆菌属物种之间横向转移，这种现象 我们的数据表明自然发生。支持这一假设将产生基本的机制信息 关于微生物群细菌中聚糖利用的基因组进化。我现在的训练环境， 华盛顿大学医学院的杰弗里·戈登实验室提供了一个独特的场所来开始这一研究 研究，可能是世界上唯一配备所有必要工具来回答这个问题的实验室 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础 在戈登实验室工作，并作为终身教授助理教授过渡到独立职业生涯。这 在本指导性研究计划期间实现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（参见说明）： 人类肠道细菌对于复杂膳食多糖的转化至关重要，其中许多多糖 我们无法自行消化成我们容易吸收的形式。我将描述动态 进入我们饮食中的丰富植物聚糖与植物的生理和进化之间的相互关系 我们的肠道细菌。结果将揭示哪些膳食聚糖细菌“可以”代谢以及哪些可以代谢 “想要”代谢，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。

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