How glycans shape gut microbiota function and assembly

聚糖如何塑造肠道微生物群的功能和组装

• 批准号: 8811444
• 负责人: Eric C Martens
• 金额: $ 30.6万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811444
• 关键词: Affect; Bacteria; Bacterial Genes; Bacteroides; Bacteroides thetaiotaomicron; Bacteroidetes; Biochemical; Biosensor; Calories; Carbohydrates; Chemical Structure; Colon; Colon Carcinoma; Communities; Complex; Custom; Data; Diet; Dietary Carbohydrates; Digestion; Disease; Distal; Environment; Epithelial; Feces; Fermentation; Gene Cluster; Gene Expression; Genes; Genetic Transcription; Goals; Growth; Harvest; Health; Heterogeneity; Human; In Vitro; Individual; Inflammatory Bowel Diseases; Intestines; Knowledge; Lead; Length; Link; Location; Measurable; Measures; Metabolism; Metagenomics; Microbe; Microbiology; Modeling; Mucous Membrane; Mucous body substance; Mus; Nutrient; Obesity; Pathology; Pattern; Phenotype; Phylogenetic Analysis; Physiological; Physiology; Play; Polysaccharides; Population; Process; Proliferating; Property; Relative (related person); Role; Route; Sampling; Series; Shapes; Site; Spatial Distribution; Structure; Taxon; Testing; Time; Tissues; Variant; Width; Work; base; chemical property; design; feeding; functional food; gut microbiota; ileum; in vivo Model; insight; interest; laser capture microdissection; microbial; microbial community; prebiotics; research study; response; trait

DESCRIPTION (provided by applicant): The microbial community (microbiota) that inhabits the human distal gut provides physiologic attributes that humans have not evolved, including the ability to process otherwise indigestible dietary glycans. Species in this community have evolved strategies to compete for the dozens of different glycans that inundate their environment. These complex carbohydrates vary immensely in chemical structure and digestibility, a feature that likely dictates the particular region of the gut (ileum, proximal or distal colon) in which each glycan is metabolized. The relationship between glycan availability and microbiota physiology in different gut regions has not been explored. However, this knowledge will be essential to understand the forces that shape the microbiota as well as to design strategies to manipulate its function using approaches like prebiotics (functional foods, most often glycans, designed to enrich the abundance and/or physiology of beneficial microbes). We will establish a tripartite colonization model using 1) germfree mice, 2) synthetic communities of fully sequenced human gut bacteria, and 3) a defined diet that contains variable amounts of all major dietary glycans that are typically consumed by humans. Using this model, we will test our central hypothesis that glycans in the intestine are present in a series of gradients (determined by their diet or hos origin and biochemical properties) and that individual bacterial species will be enriched in regions where their preferred glycans are abundant. Preliminary data suggest that the protective epithelial mucus layer is a major glycan niche that selects for a sub-community of gut bacteria based on the ability of only some species to metabolize the host-derived glycans present in mucus. Bacterial populations from the lumen and the mucus layer will be directly harvested along the length of the intestine or captured microscopically using laser-capture microdissection (LCM). In Aim 1, transcription of bacterial genes that are known to respond to specific glycans will be used as biosensors to measure variation in bacterial glycan metabolism between separate gut regions. The abundance of individual dietary glycans will be subsequently varied to observe the corresponding changes in microbiota metabolism. In Aim 2, the abundance of 44 different human gut Bacteroidetes species, for which we have empirically measured several dozen glycan-degrading phenotypes, will be measured in the mucosa and lumen along the length and width of the gut. Assembly of this community will be observed in both the absence and presence of 43 additional sequenced bacterial species representing the other dominant phyla in the human gut. Although the human gut microbiota plays many beneficial roles, abnormalities in this community (dysbiosis) have been postulated to underlie pathological conditions such as inflammatory bowel disease and obesity. The proposed experiments will provide data regarding where and why different species assemble in response to one important and externally manipulable parameter (dietary glycans). Our results will facilitate approaches to intentionally manipulate the human microbiota to influence intestinal health.

描述（由申请人提供）：居住在人类远端肠道的微生物群落（微生物群）提供了人类没有进化的生理属性，包括可以处理原本可观的饮食大麻的能力。这个社区中的物种发展了策略，以争夺数十种淹没环境的不同聚糖。这些复杂的碳水化合物在化学结构和消化率上差异很大，该特征可能决定了肠道的特定区域（回肠，近端或远端结肠），在其中将每个聚糖都代谢。尚未探索不同肠道区域的聚糖可用性与微生物群生理之间的关系。但是，这种知识对于了解塑造微生物群的力以及设计策略来使用益生元（功能性食品，通常是聚糖，旨在丰富有益微生物的丰度和/或生理学）来操纵其功能的策略至关重要。我们将使用1）无毛小鼠，2）完全测序的人类肠道细菌的合成群落建立三方定殖模型，以及3）含有所有主要饮食中饮食中通常被人类消耗的主要饮食类似物的定义饮食。使用该模型，我们将测试我们的中心假设，即肠中的聚糖存在于一系列梯度中（取决于其饮食或HOS起源和生化特性），并且各个细菌物种将在其首选的聚糖丰富的区域富集。初步数据表明，保护性上皮粘液层是一个主要的聚糖生态位，基于仅某些物种代谢粘液中存在的宿主衍生的聚糖的能力来选择肠道细菌的亚社区。来自管腔和粘液层的细菌种群将直接沿着肠的长度收获，或使用激光捕获显微解剖（LCM）进行显微镜。在AIM 1中，已知对特定聚糖反应的细菌基因的转录将用作生物传感器，以测量单独的肠道区域之间细菌聚糖代谢的变异。随后将有多种饮食聚糖的丰度来观察微生物群代谢的相应变化。在AIM 2中，将在粘膜和肠道的长度和宽度中测量44种不同的人类肠道细菌种类的丰度，我们在经验上测量了数十个降解的聚糖表型。在不存在和存在43种代表人类肠道其他主要门的其他测序细菌物种的情况下，将观察到该群落的组装。尽管人类肠道菌群起着许多有益的作用，但该社区的异常（营养不良）被认为是病理状况（例如炎症性肠病和肥胖症）的基础。提出的实验将提供有关在何处和为什么不同物种响应一个重要和外部操纵参数（饮食聚糖）的数据。我们的结果将促进有意操纵人类微生物群以影响肠道健康的方法。