Personalizing prebiotic therapies that target human gut microbiota

针对人类肠道微生物群的个性化益生元疗法

• 批准号: 9438737
• 负责人: Lawrence Anthony David
• 金额: $ 35.78万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9438737
• 关键词: Address; Adoption; Affect; American; Automobile Driving; Bacteria; Biological Assay; Bioremediations; Butyrates; Carbohydrates; Catalogs; Cells; Clinical Trials; Cohort Studies; Colon; Computer Simulation; Culture Techniques; Data; Data Set; Diet; Dietary Carbohydrates; Dose; Energy-Generating Resources; Environment; Exhibits; Fermentation; Frequencies; Goals; Growth; Habits; Health Benefit; Heterogeneity; Hormonal; Human; Immune system; Individual; Intake; Intestines; Knowledge; Measures; Metabolic; Metabolism; Methods; Microbe; Microfluidics; Modeling; Nutrient; Nutritional; Outcome; Persons; Pharmaceutical Preparations; Polysaccharides; Production; Research; Sampling; Scheme; Space Models; Structure; Surveys; Techniques; Testing; Therapeutic; Time; Toxin; Training; Translating; Update; Variant; Volatile Fatty Acids; Work; bacterial community; base; cohort; design; experimental study; gut bacteria; gut microbes; gut microbiota; host microbiota; human microbiota; individual response; individual variation; innovation; insight; microbial; microbial community; microbiota; novel; pathogen; pre-clinical; prebiotics; response; targeted treatment; theories; tool

Dietary carbohydrates nourish human gut bacterial communities (microbiota) that resist pathogens, metabolize drugs, and train the immune system. Short-chain fatty acids, which are end products of microbial polysaccharide fermentation, are also crucial metabolic precursors and energy sources for human colon cells. The potential health benefits of dietary carbohydrates that stimulate the growth and activity of intestinal bacteria (prebiotics) have led millions of Americans to consume these compounds annually. Yet, the effects of prebiotics on gut microbiota and their fermentation are known to vary substantially between individuals. Our objective here is to understand why and how prebiotics should be tailored to individuals and their gut microbiota. To address advance prebiotic research, we have developed innovative new tools: a microfluidic technique for creating and assaying millions of individual bacterial cultures; Bayesian state-space models for longitudinal microbiota data; and, an artificial human intestine that we can sample and manipulate with arbitrary frequency. We propose combining these new methods to test our central hypothesis that the impact of prebiotic treatments can be maximized by personalization to individuals and their microbiota. Our proposal has three specific aims: 1) Use our microfluidic culture techniques to measure how different carbohydrate compounds affect the growth and metabolism of thousands of distinct human gut bacterial species. By identifying which bacterial species are directly stimulated by prebiotics, we can begin to understand how these treatments reshape each individuals' gut microbiota. 2) Develop a probabilistic state-space model of microbial community dynamics and apply it our existing datasets tracking human diet, gut microbiota, and short chain fatty acid levels over time. The resulting model will pinpoint interactions between bacterial species growth, microbial fermentation, and subject diet that influence response to prebiotic treatments. 3) Use our artificial human gut models to carry out prebiotic trials on human gut microbiota with doses that are either fixed or periodically updated based on changes to microbiota structure and function. The resulting data will establish how initial microbiota shifts caused by prebiotic treatment affect later dose responses, as well as assess whether eliminating differences in host compliance and response affect variations in prebiotic impact. Ultimately, the proposed aims are expected to provide the first systematic study on the underlying mechanisms driving individualized responses to prebiotic treatments and help establish a new research field focused on personalized prebiotic treatments. The computational and experimental techniques developed here will also serve as a preclinical platform that could directly translate potential prebiotics to human clinical trials. More broadly, these techniques are designed to be generalizable and could thus be used for the rational optimization of other microbiota functions, including drug or hormonal metabolism within hosts, or even toxin bioremediation or nutrient production in the environment.

饮食碳水化合物滋养抗病原体，代谢的人类肠道细菌群落（微生物群） 毒品，并训练免疫系统。短链脂肪酸，这是微生物的最终产物 多糖发酵也是人类结肠细胞的关键代谢前体和能源。 饮食碳水化合物的潜在健康益处，刺激肠道的生长和活性 细菌（益生元）导致数百万美国人每年食用这些化合物。但是， 肠道微生物群的益生元及其发酵在个体之间的差异很大。我们的 目的是了解为什么以及如何为个人及其肠子量身定制益生元 微生物群。为了解决进步的益生元研究，我们开发了创新的新工具：微流体 创造和分析数百万个单个细菌培养的技术；贝叶斯州空间模型 纵向微生物群数据；而且，我们可以随意采样和操纵的人造肠道 频率。我们建议将这些新方法结合起来，以检验我们的中心假设，即 可以通过个性化个人及其菌群来最大化益生元治疗。我们的建议有 三个具体目的：1）使用我们的微流体培养技术来测量不同的碳水化合物 化合物会影响数千种不同人类肠道细菌物种的生长和代谢。经过 确定益生元直接刺激哪些细菌物种，我们可以开始了解这些细菌 治疗重塑每个人的肠道菌群。 2）开发微生物的概率状态空间模型 社区动态并应用我们的现有数据集跟踪人类饮食，肠道微生物群和短链 脂肪酸水平随着时间的流逝。由此产生的模型将指出细菌物种生长之间的相互作用， 微生物发酵和影响对益生元治疗反应的受试者饮食。 3）使用我们的人造 人类肠道模型以固定或 根据微生物群结构和功能的更改定期更新。结果数据将建立 益生元治疗引起的初始菌群转移如何影响后来的剂量反应以及评估 消除宿主依从性和反应的差异是否影响益生元影响的变化。 最终，拟议的目标有望提供有关基本机制的首次系统研究 推动对益生元治疗的个性化反应，并帮助建立一个专注于的新研究领域 个性化的益生元治疗。这里开发的计算和实验技术也将 用作临床前平台，可以将潜在的益生元直接转化为人类临床试验。更多的 从广义上讲，这些技术被设计为可推广，因此可以用于合理优化 其他微生物群的功能，包括宿主中的药物或激素代谢，甚至毒素生物修复 或环境中的营养生产。