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）：一个密集的微生物社区生活在每个人的胃肠道（GI）中。该肠道菌群由10-100万亿个微生物细胞组成，它影响了人类生物学的许多方面，包括免疫状态和代谢。异常的肠道菌群组成与炎症性肠病和肥胖症有关，但目前造成微生物群改变的因素已定义不明。该提案的目的是深入了解肠道饮食中特定变化的肠道菌群如何影响。我们的长期目标是将微生物群纳入个性化医学的新兴范式，重点是靶向微生物群的诊断和治疗疗法，以治疗或预防肥胖，炎症性肠病和其他菌群疾病。 丰富的肠道细菌（例如菌豆体）（theta）的种类将其大部分基因组献给了未消化的饮食植物多糖（即饮食纤维）的利用。将饮食多糖摄入与微生物群组成和功能改变的机制是人类生物学不可或缺的。该提案的目的是（i）对使用丰富的饮食植物多糖（称为果糖）所需的细菌中保守的操纵子的功能获得机械洞察力； （ii）确定模型如何由细菌物种组成，其相对能力不同，以利用饮食果糖，inulin，适应Gnotobiotic小鼠肠道内饮食中补充饮食中的补充； （iii）确定宿主上皮基因表达以及全身性或粘膜细胞因子水平是否可以通过饮食诱导的模型微生物群体的改变来差异调节。为了追求上述（i），我们将使用遗传工具和生化测定法研究B. theta的果糖利用操纵子内基因的功能。比较基因组学和果糖生长测定法将阐明菌孢子中存在的果糖利用能力谱的基因组基础。在AIM（II）中，缺乏肠道菌群的无菌小鼠将通过简化的模型微生物群定植，该模型由theta菌株，菌孢子菌种和/或Eubacterium Grctale组成。对细菌基因表达，物种密度和肠道果实含量的调查将阐明模型社区如何由微生物群体的主要成员组成，以差异为果素，并适应组成和功能，以升高饮食中的肌蛋白。在AIM（III）中，无菌小鼠与thetab。theta共殖，并且是两种双歧杆菌种类不一致的二氨基蛋白使用。如AIM（II），细菌在体内对饮食中的功能和组成适应性将被表征。这些结果将确定我们是否可以根据基因组和功能数据来预测饮食（含糖蛋白 - 富集）的变化将如何影响模型菌群。将监测宿主反应，以确定上皮基因表达以及系统性和/或粘膜细胞因子反应是否可以通过饮食诱导的微生物群的变化来调节。