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: 8460013
• 负责人: JUSTIN L SONNENBURG
• 金额: $ 31.72万
• 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/8460013
• 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.

描述（由申请人提供）：每个人的胃肠道（GI）内都有密集的微生物群落。这种肠道微生物群由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，包括免疫状态和代谢。异常的肠道微生物群组成与炎症性肠病和肥胖有关，但导致微生物群改变的因素目前尚不明确。该提案的目标是深入了解肠道微生物群如何受到宿主饮食中特定变化的影响。我们的长期目标是将微生物群整合到个性化医疗的新兴范式中，重点是微生物群靶向诊断和治疗，以治疗或预防肥胖，炎症性肠病和其他微生物群相关疾病。 肠道中存在大量的细菌，如多形拟杆菌（B.θ），将其基因组的大部分用于利用未消化的膳食植物多糖（即，膳食纤维）。将膳食多糖摄入与微生物群组成和功能改变联系起来的机制是人类生物学不可或缺的。该提议的目的是（i）获得对拟杆菌中保守的操纵子的功能的机理性洞察，所述操纵子是使用称为果聚糖的丰富膳食植物多糖所需的;（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菌群如何利用膳食果聚糖、菊粉，在知菌小鼠肠道内适应膳食菊粉补充剂;（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组成的模型微生物群落的改变来差异性地调节。theta和双歧杆菌属物种。为了实现上述（i），我们将使用遗传工具和生化测定来研究B内基因的功能。Theta果聚糖利用操纵子。比较基因组学和果聚糖生长测定将阐明类杆菌中果聚糖利用能力谱的基因组基础。在目标（ii）中，将用由B组成的简化模型微生物群定殖缺乏肠道微生物群的无菌小鼠。Theta菌株、拟杆菌属物种和/或直肠真杆菌（肠优势厚壁菌门（Firmicutes）的成员）。细菌基因表达，物种密度和肠道果聚糖含量的调查将阐明如何模型社区组成的微生物群的优势成员不同的果聚糖的使用，适应在组成和功能提高饮食菊粉。在目的（iii）中，无菌小鼠与B共定殖。θ和两种双歧杆菌中的一种，不适合菊粉的使用。功能和组成的细菌在体内适应饮食菊粉的特点，如在目标（ii）。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，以确定上皮基因表达和全身和/或粘膜细胞因子反应是否可以通过饮食诱导的微生物群变化来调节。