Complex glycan utilization by human gut Bacteroides

人类肠道微生物群提供了我们不必自己进化的生理属性， 包括加工否则难以消化的膳食聚糖的能力。多形拟杆菌{B. theta） 和卵形拟杆菌，微生物群的两个成员，具有不同的，但只有部分重叠的能力， 加工饮食和宿主来源的聚糖-进化的特征，可能影响他们的健身， 拥挤的肠道生态系统。至少有一种生物，6。f/iefa，优先考虑植物果胶的代谢 这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，我将定义和比较碳水化合物的利用层次 这两个物种来确定它们是进化出了相同还是不同的优先级。此外，我将探讨 B中聚糖优先化的分子机制。tfieta，允许我测试 这种现象在体内的gnotobiotic小鼠肠道。我还将探讨通过哪些机制6. ovatus靶向植物细胞壁聚糖的丰富的和有时不太可溶的半纤维素类， B. theta不能代谢半纤维素利用基因的缺失 色葡萄随后在体内竞争所得到的半纤维素缺陷突变体， 它们的同基因亲本，将揭示这些表型的表达是否提供了适应性优势， 在gnotobiotic小鼠喂养富含这些底物的饮食的不利。最后，我将探讨一种可能性， 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 我们的数据显示是自然发生的支持这一假设将产生基本的机械信息 关于微生物中聚糖利用的基因组进化。我目前的训练环境， 华盛顿大学医学院的杰弗里·戈登实验室为开始这项研究提供了一个独特的场所 研究，并可能是世界上唯一的实验室配备了所有必要的工具来回答 实验性的问题我的职业发展计划包括建立一个强大的研究基础 在戈登实验室和过渡到一个独立的职业生涯作为终身助理教授。的 实验和专业培训期间取得的指导研究建议将提供 我需要靠自己成功的经验。 相关性（参见说明）： 人类肠道细菌对于复杂的膳食多糖的转化是必不可少的， 我们不能自己消化，变成我们容易吸收的形式。我会描述 进入我们饮食的丰富植物聚糖与植物的生理学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聚糖细菌'可以'代谢， “想要”代谢，提供关于我们的肠道微生物群如何收获膳食营养素的新知识。

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.