Carbohydrate Structure Controls on Human Gut Microbial Ecology

肠道微生物群多样性低与许多慢性疾病有关，包括 II 型代谢综合征 糖尿病、肠易激综合症、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 就影响了 310 万美国人，导致生活质量下降、高 住院率和医疗费用超过 68 亿美元，尤其是社会经济地位较低的人群 状态。与传统饮食相比，饮食西化与肠道微生物多样性减少相关 饮食。最近，研究小组确定，肠道微生物物种的丧失与高 脂肪、低纤维的西方饮食，在老鼠身上，这些灭绝会随着世代的推移而复合，并且更高的摄入量 可发酵膳食纤维可适度增加肠道微生物组的多样性。对纤维的理解变得复杂 对肠道微生物群的影响是，虽然膳食纤维经常被合并为一个类别，但 实际上是一组不同的分子上不同的碳水化合物结构。尽管已知微生物可以排除 彼此竞争在简单底物（例如葡萄糖）上的生长，但人们对其复杂性知之甚少 基质影响微生物群落的生态。因为这种复杂的基底太大了 直接通过细胞膜输入，外部降解酶必须首先起作用才能转化 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，任何微生物都可以利用水解产物。因此，外部降解 编码降解酶的特定微生物对复杂底物的处理有能力产生 交叉喂养缺乏消耗复杂底物能力的其他生物体的“公共物品”。这是 多糖尤其如此，因为碳水化合物由许多不同类型的糖基组成 由不同类型的键连接的残基。人体肠道是一个富含复杂物质的环境 多糖，以及这些底物的结构复杂性表明生物体可能 能够共存于消耗复杂的底物。这可能是一种保持或增加的机制 结肠中微生物的多样性。在这里，我们从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-宿主代谢相互作用的模型。我们采用体外组合 生态实验、计算机模型中的机械和基因组规模代谢、基于化学生物学 使用寡糖模拟物和微流体系统进行探测，以进行碳水化合物的高通量筛选 微生物群与宿主的相互作用来实现这些目标。我工作的目标是确定管理原则 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来管理肠道微生物群多样性和功能，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.