Carbohydrate Structure Controls on Human Gut Microbial Ecology

肠道微生物区系多样性低与包括II型代谢综合征在内的许多慢性疾病有关 糖尿病、肠易激综合征、炎症性肠病(IBD)和结直肠癌。人力成本 令人震惊且不断增加；仅IBD一项就影响了310万美国人，导致生活质量下降， 住院率和医疗费用超过68亿美元，特别是在社会经济水平较低的人群中 状态。与传统饮食相比，饮食西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，这种肠道微生物物种的丧失与高- 脂肪，低纤维的西式饮食，在小鼠身上，这些灭绝会随着世代的推移而加剧，而更高的 可发酵膳食纤维可适度增加肠道微生物群的多样性。使对光纤的理解复杂化 对肠道微生物群的影响是，尽管膳食纤维通常合并为单一类别，但 实际上是一组不同的分子上不同的碳水化合物结构。尽管已知微生物排除了 在简单的底物(例如葡萄糖)上相互竞争生长，人们对其复杂程度知之甚少 底物影响微生物群落的生态。因为这种复杂的衬底太大了，无法 直接通过细胞膜输入，外部降解酶必须首先作用转化 将复杂底物的成分转化为可运输的形式，可以输入到酶中- 生产细胞；在此之前，水解物仍可供任何微生物使用。因此，外部退化 由编码降解酶的特定微生物产生的复杂底物具有产生 “公共产品”与其他缺乏消耗复杂底物能力的有机体相互喂养。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 通过不同类型的键连接的残基。人类的肠道是一个富含复杂性的环境 多糖，以及这些底物的结构复杂性表明，生物体可能 能够在消耗一种复杂的底物中共存。这可能是一种保存或增加的机制 结肠中的微生物多样性。在这里，我们在三个方面描述了一种集成的实验和建模方法 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， 确定对体内多糖反应重要的水解和运输特性，并阐明和 碳水化合物发酵中微生物-宿主代谢相互作用模型。我们使用的是体外培养的组合 生态学实验，硅胶模型中的机械性和基因组规模的代谢，以化学生物学为基础 使用低聚糖模拟物和用于高通量筛选碳水化合物的微流控系统的探测- 微生物群与宿主的相互作用以实现这些目的。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区系和人体生理，使合理设计 碳水化合物和饮食策略，以管理肠道微生物区系的多样性和功能，以改善健康。

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.