Impact of Diet on Intestinal Microbiota-Host Dynamics

饮食对肠道微生物群-宿主动态的影响

• 批准号: 8277958
• 负责人: JUSTIN L SONNENBURG
• 金额: $ 32.87万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-07 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277958
• 关键词: Ablation; Affect; Bacteria; Bacterial Genes; Bacteroides; Bacteroides thetaiotaomicron; Bifidobacterium; Biochemical; Biological Assay; Biology; Carbon; Cells; Communities; Complex; Consumption; Data; Diagnostic; Diet; Dietary Fiber; Dietary Polysaccharide; Disease; Eating; Energy-Generating Resources; Epithelial; Eubacterium; Exhibits; Family member; Food; Fructans; Fructokinases; Fructose; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Genome; Genomics; Germ-Free; Glycoside Hydrolases; Gnotobiotic; Goals; Growth; Health; Human; Human Biology; Immune; Immune response; In Vitro; Inferior; Inflammatory Bowel Diseases; Intake; Intestines; Inulin; Life; Link; Medicine; Metabolism; Microbe; Minor; Modeling; Monitor; Mus; Nutrient; Obesity; Operon; Persons; Plants; Play; Polysaccharides; Relative (related person); Research Project Grants; Role; Serum; Specific qualifier value; Supplementation; Surveys; TNF gene; Testing; Therapeutic; absorption; base; chemical genetics; comparative genomics; cytokine; density; dietary supplements; extracellular; feeding; functional genomics; gene function; gut microbiota; improved; in vivo; insight; levan; member; microbial; microbial community; prevent; public health relevance; response; tool

DESCRIPTION (provided by applicant): A dense community of microbes lives within the gastrointestinal (GI) tract of each human. This intestinal microbiota is composed of 10-100 trillion microbial cells and it impacts numerous aspects of human biology including immune status and metabolism. Aberrant intestinal microbiota composition has been linked to inflammatory bowel diseases and to obesity, yet the factors contributing to microbiota alterations are currently ill defined. The goal of this proposal is to gain insight into how the intestinal microbiota is impacted by specified changes in host diet. Our long-term goal is to integrate the microbiota into the emerging paradigm of personalized medicine, with a focus on microbiota-targeted diagnostics and therapeutics to treat or prevent obesity, inflammatory bowel diseases, and other microbiota-relevant diseases. Species of abundant gut-dwelling bacteria, such as Bacteroides thetaiotaomicron (B. theta), devote vast portions of their genomes to the utilization of undigested dietary plant polysaccharides (i.e., dietary fiber). Mechanisms that link dietary polysaccharide intake to alterations in microbiota composition and function are integral to human biology. The aims of this proposal are to (i) gain mechanistic insight into the function of an operon conserved in Bacteroides required for use of abundant dietary plant polysaccharides called fructans; (ii) determine how model microbiotas composed of bacterial species with differing relative abilities to utilize the dietary fructan, inulin, adapt within the gnotobiotic mouse gut to dietary inulin supplementation; (iii) determine if host epithelial gene expression and systemic or mucosal cytokine levels can be differentially modulated by diet-induced alterations in model microbiotas composed of B. theta and Bifidobacterium species. To pursue (i) above, we will use genetic tools and biochemical assays to investigate the function of genes within B. theta's fructan utilization operon. Comparative genomics and fructan-growth assays will elucidate the genomic basis for the spectrum of fructan utilization capability that exists in the Bacteroides. In aim (ii), germ-free mice, which lack a gut microbiota, will be colonized with simplified model microbiotas composed of B. theta strains, Bacteroides species, and/or Eubacterium rectale, a member of the gut-dominant Firmicutes division. Surveys of bacterial gene expression, species density, and gut fructan content will illuminate how model communities composed of dominant members of the microbiota disparate for fructan use, adapt in composition and function to elevated dietary inulin. In aim (iii), germ-free mice are co-colonized with B. theta and one of two Bifidobacterium species discordant for inulin use. Functional and compositional adaptation of bacteria in vivo to dietary inulin will be characterized, as in aim (ii). These results will determine whether we can predict, based on genomic and functional data, how a change in diet (inulin-enrichment) will impact a model microbiota. Host responses will be monitored to determine if epithelial gene expression and systemic and/or mucosal cytokine responses may be modulated via diet-induced changes in the microbiota. PUBLIC HEALTH RELEVANCE: A dense and complex community of microbes resides within each person's gastrointestinal tract that plays many important roles in our health, including aiding in our absorption of energy and nutrients from the foods we eat. Alterations in composition of the gut-resident microbial community are associated with certain disease states, such as obesity and inflammatory bowel disease. The goal of this research project is to understand the impact of dietary fiber on the intestinal microbial community and the host to determine how we may avoid or reverse deleterious changes within our intestinal microbiota to improve human health.

描述（由申请人提供）：每个人的胃肠道内生活着一个密集的微生物群落。肠道微生物群由 10-100 万亿个微生物细胞组成，它影响人类生物学的许多方面，包括免疫状态和新陈代谢。肠道微生物群组成异常与炎症性肠病和肥胖有关，但目前尚不清楚导致微生物群改变的因素。该提案的目的是深入了解宿主饮食的特定变化如何影响肠道微生物群。我们的长期目标是将微生物群整合到新兴的个性化医疗范例中，重点是针对微生物群的诊断和治疗，以治疗或预防肥胖、炎症性肠病和其他微生物相关疾病。 丰富的肠道细菌种类，例如多形拟杆菌 (B. theta)，将其基因组的很大一部分用于利用未消化的膳食植物多糖（即膳食纤维）。将膳食多糖摄入量与微生物群组成和功能的改变联系起来的机制是人类生物学不可或缺的一部分。该提案的目的是（i）从机制上深入了解拟杆菌中保守的操纵子的功能，该操纵子需要使用丰富的膳食植物多糖（称为果聚糖）； (ii) 确定由具有不同相对能力的细菌物种组成的模型微生物群如何利用膳食果聚糖、菊粉，在无菌小鼠肠道内适应膳食菊粉补充； (iii) 确定宿主上皮基因表达和全身或粘膜细胞因子水平是否可以通过饮食诱导的由 B.theta 和双歧杆菌组成的模型微生物群的改变进行差异调节。为了实现上述 (i)，我们将使用遗传工具和生化检测来研究 B. theta 果聚糖利用操纵子内基因的功能。比较基因组学和果聚糖生长测定将阐明拟杆菌中存在的果聚糖利用能力谱的基因组基础。在目标 (ii) 中，缺乏肠道微生物群的无菌小鼠将被由 B. theta 菌株、拟杆菌属和/或直肠真杆菌（肠道优势厚壁菌门的成员）组成的简化模型微生物群定植。对细菌基因表达、物种密度和肠道果聚糖含量的调查将阐明由不同的微生物群主要成员组成的模型群落如何使用不同的果聚糖，以及如何在组成和功能上适应膳食菊粉的升高。在目标 (iii) 中，无菌小鼠与 B. theta 和与菊粉使用不一致的两种双歧杆菌之一共定殖。将表征体内细菌对膳食菊粉的功能和组成适应，如目标 (ii) 所示。这些结果将决定我们是否可以根据基因组和功能数据预测饮食的变化（菊粉富集）将如何影响模型微生物群。将监测宿主反应，以确定是否可以通过饮食诱导的微生物群变化来调节上皮基因表达和全身和/或粘膜细胞因子反应。 公共健康相关性：每个人的胃肠道内存在一个密集而复杂的微生物群落，它们在我们的健康中发挥着许多重要作用，包括帮助我们从所吃的食物中吸收能量和营养。肠道微生物群落组成的变化与某些疾病状态有关，例如肥胖和炎症性肠病。该研究项目的目标是了解膳食纤维对肠道微生物群落和宿主的影响，以确定我们如何避免或逆转肠道微生物群的有害变化，从而改善人类健康。