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: 9920125
• 负责人: JUSTIN L SONNENBURG
• 金额: $ 35.33万
• 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 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9920125
• 关键词: Biology; Carbohydrates; Collection; Colon; Colon Carcinoma; Complex; Diet; Dietary Carbohydrates; Dietary Fiber; Disease; Dose; Eating; Ecology; Ecosystem; Effectiveness; Engineering; Engraftment; Enzymes; Exposure to; Food; Gastrointestinal tract structure; Goals; Health; Human; Human Biology; Image; Immunotherapy; Individual; Industrialization; Inflammatory Bowel Diseases; Invaded; Knowledge; Left; Location; Metabolic syndrome; Methods; Microbe; Mus; Nutrient; Obesity; Organism; Pathogenicity; Pathology; Persons; Play; Polysaccharides; Population; Population Sizes; Prevention; Probiotics; Psychological reinforcement; Reproducibility; Research; Research Project Grants; Role; Source; Testing; Therapeutic; Therapeutic Use Study; Time; Western World; absorption; colonic crypt; density; dysbiosis; effective therapy; fecal transplantation; genomic locus; glucose metabolism; gut microbes; gut microbiome; gut microbiota; host microbiota; human disease; human microbiota; humanized mouse; in vivo; insight; interest; microbial; microbial community; microbiome; microbiome composition; microbiota; mouse model; novel; prevent; repaired; repository; restoration; stool sample; synthetic biology; tool

The human gut harbors a dense and complex community of microbes known as the intestinal microbiota. A disrupted or dysbiotic microbial ecosystem has been connected to several diseases including inflammatory bowel diseases, metabolic syndrome, and colon cancer. Therapeutic manipulation of the gut microbiota has broad implications for human health. However, the abundance of bacterial strains that reside within an individual is largely stable over time and can be difficult to alter in a predictable, robust, and reproducible fashion. Fecal microbiota transplants are being increasingly used to repair a dysbiotic microbiota, however, the fate of the introduced strains is unpredictable and largely individualized (i.e., influenced by the recipient's microbiota). If microbiota reprogramming is to become an effective therapy for a broad range of diseases, a better understanding of the factors that control entrenchment of therapeutic strain integration and the role of diet in the reinforcement of new strains is critically important. In Aim 1, microbiota accessible carbohydrates (MACs), powerful levers on microbiota composition and function, will be used to elucidate the mechanisms by which exogenous bacterial species entrench within an established microbiota. Furthermore, new environmental niches will be established through novel dietary carbohydrates to replace pathogenic bacterial strains with commensal isogenic strains. State-of-the-art synthetic biology tools and imaging will be employed to quantify the biogeographical location of newly entrenching strains within the colon. In Aim 2, microbes and genetic loci will be isolated from the microbiomes of hunter-gatherer populations and cognate polysaccharides will be identified. Since the diet and carbohydrate utilization enzymes encoded within the microbiota of traditional populations is distinct from that of US residents, these pre-industrialized microbiomes possess a large collection of carbohydrate active enzymes not present or exceedingly rare in the Western world. Isolation and utilization of unique MACs will be tested to enable engraftment of therapeutic strains that have been engineered to utilize these carbohydrates. Whether using multiple privileged MACs is an effective strategy to entrench and control the abundance of multiple species independently within multiple established microbiotas will be tested in a humanized mouse model (mice harboring a human microbiota). This proposal establishes a new paradigm for reprogramming a dysbiotic microbiota, which makes possible the robust and reproducible entrenchment of exogenous bacterial strains. The ultimate goal of this strategy is to enable stable incorporation of new species and functions that could be tailored to an individual's specific microbiota and disease state.

人类的肠道藏有一个被称为肠道微生物群的密集而复杂的微生物群落。一个 破坏或失调的微生物生态系统已连接到包括炎症在内的几种疾病 肠病，代谢综合征和结肠癌。肠道菌群的治疗操作具有 对人类健康的广泛影响。但是，存在于 随着时间的流逝，个人在很大程度上是稳定的，并且在可预测，健壮和可重复性的可预测，稳健和可重复的情况下可能很难改变 时尚。粪便菌群移植越来越多地用于修复失调的微生物群 引入菌株的命运是不可预测的，并且在很大程度上是个性化的（即受接收者的影响 微生物群）。如果微生物群重编程是成为多种疾病的有效疗法，则 更好地理解控制治疗菌株整合的因素和饮食的作用 在加强新菌株的过程中至关重要。在AIM 1中，微生物群可访问的碳水化合物 （MAC），对微生物群组成和功能的强大杠杆将用于阐明机制 在既定的微生物群中，哪种外源细菌种子根深蒂固。此外，新的环境 壁ni将通过新颖的饮食碳水化合物建立 共生等源性菌株。将使用最先进的合成生物学工具和成像来量化 结肠内新牢固菌株的生物地理位置。在AIM 2中，微生物和遗传基因座 将从猎人 - 采集者种群的微生物中分离出来，而多糖将是 确定。由于饮食和碳水化合物利用酶在传统的微生物群中编码 人口与我们居民不同，这些预工业化的微生物组具有大型收藏 在西方世界中，碳水化合物活性酶的存在或极为罕见。隔离和利用 将测试独特的Mac，以促进已设计用于使用的治疗菌株 这些碳水化合物。使用多个特权Mac是否是巩固和控制的有效策略 多种物种在多个已建立的微生物中独立的多种物种将在A中测试 人源化的小鼠模型（具有人类微生物群的小鼠）。该提案为 重新编程不植物微生物群，这使得 外源细菌菌株。该策略的最终目标是稳定地融入新物种 以及可以根据个人的特定微生物群和疾病状态量身定制的功能。