Carbohydrate Structure Controls on Human Gut Microbial Ecology

低肠道微生物群多样性与许多慢性疾病相关，包括代谢综合征，II型 糖尿病、肠易激综合征、炎症性肠病（IBD）和结肠直肠癌。人的代价 IBD正在惊人地增长;仅IBD就影响了310万美国人，导致生活质量降低， 住院率和医疗费用超过68亿美元，特别是在社会经济地位较低的人中， status.与传统饮食相比，饮食西方化与肠道微生物多样性减少有关。 节食。最近，研究小组已经确定，肠道微生物物种的这种损失与高- 脂肪，低纤维的西方饮食，在小鼠中，这些预防化合物经过几代人， 可发酵膳食纤维适度增加肠道微生物组多样性。对纤维的复杂理解 对肠道微生物组的影响是，虽然经常合并成一个类别，但膳食纤维 实际上是一组不同的分子结构的碳水化合物。尽管微生物可以排除 彼此竞争在简单衬底上生长（例如，葡萄糖），很少有人知道如何复杂 基质影响微生物群落的生态学。因为这种复杂的基底太大， 如果这些蛋白质直接通过细胞被膜输入，则外部降解酶必须首先起作用以将其转化为 将复杂底物的组分转化为可运输的形式，该形式可以输入到酶中- 生产细胞;在此之前，水解产物仍然可用于任何微生物。因此，外部退化 由编码降解酶的特定微生物对复杂底物的降解具有产生 “公共产品”，交叉喂养其他缺乏消耗复杂底物能力的生物。这是 尤其是多糖，因为碳水化合物是由许多不同类型的糖基组成的。 由不同类型的键连接的残基。人类肠道是一个富含复杂 多糖，以及这些底物的结构复杂性表明，生物体可能 能够共存于复杂的基质中。这可能是一种机制， 微生物的多样性。在这里，我们描述了一个综合的实验和建模方法，在三个 相互关联的项目，以确定影响复杂碳水化合物竞争力的肠道微生物特征， 确定体内多糖反应的重要水解和转运特性，并阐明和 碳水化合物发酵中微生物-宿主代谢相互作用的模型。我们采用体外结合 生态实验，机制和基因组规模的代谢在硅片模型，基于化学生物学 使用寡糖模拟物的探测，以及用于高通量筛选碳水化合物的微流体系统， 微生物与宿主的相互作用来达到这些目的。我工作的目标是找出 碳水化合物结构如何控制肠道微生物群和人体生理学，以实现合理设计 碳水化合物和饮食策略，以管理肠道微生物群的多样性和功能，改善健康。

Low gut microbiota diversity is associated with many chronic diseases including metabolic syndrome, type II diabetes, irritable bowel syndrome, inflammatory bowel disease (IBD), and colorectal cancer. The human costs are staggering and increasing; IBD, alone, impacts 3.1 million Americans, causing lower quality of life, high hospitalization rates, and healthcare costs of over $6.8 billion, especially among those of low socioeconomic status. Westernization of diet is correlated with reduced gut microbial diversity compared to that of traditional diets. Recently, research groups have determined that this loss of gut microbial species is linked to the high- fat, low-fiber Western diet, in mice, these extinctions compound over generations, and higher consumption of fermentable dietary fibers modestly increases gut microbiome diversity. Complicating understanding of fiber influences on the gut microbiome is that, although often combined into a single category, dietary fibers are actually a diverse set of molecularly-distinct carbohydrate structures. Though microbes are known to exclude each other in competition for growth on simple substrates (e.g., glucose), little is known about how complex substrates affect the ecology of microbial communities. Because such complex substrates are too large to directly be imported through the cell envelope, external degradative enzymes must first act to convert components of the complex substrate into a transportable form that can be imported into the enzyme- producing cell; until then, the hydrolyzed products remain available to any microbe. Thus, external degradation of complex substrates by specific microbes that encode the degradative enzymes has the capacity to produce “public goods” that cross-feed other organisms lacking the ability to consume the complex substrate. This is especially true of polysaccharides, as carbohydrates are composed of many different types of glycosyl residues connected by diverse types of bonds. The human gut is an environment rich in complex polysaccharides, and the structural complexity of these substrates suggest the possibility that organisms might be able to co-exist in consuming a complex substrate. This may be one mechanism preserving or increasing microbial diversity in the colon. Here, we describe an integrated experimental and modeling approach in three interconnected projects to identify gut microbe traits that influence competitiveness for complex carbohydrates, determine hydrolysis and transport traits important for polysaccharide response in vivo, and elucidate and model microbe-host metabolic interactions in carbohydrate fermentation. We employ a combination of in vitro ecological experiments, mechanistic and genome-scale metabolic in silico models, chemical biology-based probing using oligosaccharide mimics, and microfluidic systems for high-throughput screening of carbohydrate- microbiota-host interactions to achieve these ends. The goal of my work is to identify the principles governing how carbohydrate structure controls the gut microbiota and human physiology, to enable rational design of carbohydrates and dietary strategies to manage gut microbiota diversity and function for improved health.