Personalizing prebiotic therapies that target human gut microbiota

膳食碳水化合物滋养人体肠道细菌群落（微生物群），抵抗病原体，代谢 药物，训练免疫系统。短链脂肪酸是微生物代谢的最终产物， 多糖发酵也是人类结肠细胞的重要代谢前体和能量来源。 饮食中碳水化合物刺激肠道生长和活动的潜在健康益处 细菌（益生元）导致数百万美国人每年消耗这些化合物。然而， 已知益生元对肠道微生物群的影响及其发酵在个体之间有很大差异。我们 本研究的目的是了解为什么以及如何根据个人及其肠道情况定制益生元 微生物群为了解决先进的益生元研究，我们开发了创新的新工具：微流体 用于创建和分析数百万个细菌培养物的技术;用于 纵向微生物群数据;以及，人造人类肠道，我们可以任意采样和操纵 频率.我们建议结合这些新方法来测试我们的中心假设， 益生元治疗可以通过个体及其微生物群的个性化来最大化。我们的建议 三个具体目标：1）使用我们的微流控培养技术来测量不同碳水化合物 这些化合物影响数千种不同的人类肠道细菌物种的生长和代谢。通过 确定哪些细菌物种直接受到益生元的刺激，我们可以开始了解这些细菌是如何被益生元刺激的。 治疗重塑了每个人的肠道微生物群。2)建立微生物的概率状态空间模型 社区动态，并将其应用于我们现有的跟踪人类饮食，肠道微生物群和短链的数据集 脂肪酸水平随着时间的推移。由此产生的模型将精确定位细菌物种生长之间的相互作用， 微生物发酵和受试者饮食影响对益生元治疗的反应。3)使用我们的人工 人类肠道模型对人类肠道微生物群进行益生元试验，剂量固定， 根据微生物群结构和功能的变化定期更新。由此产生的数据将建立 益生元治疗引起的初始微生物群变化如何影响后期剂量反应，以及评估 消除宿主顺应性和反应的差异是否会影响益生元影响的变化。 最后，预计拟议的目标将提供关于潜在机制的第一个系统研究 推动对益生元治疗的个性化反应，并帮助建立一个新的研究领域，重点是 个性化益生元治疗这里开发的计算和实验技术也将 作为一个临床前平台，可以直接将潜在的益生元转化为人体临床试验。更 概括地说，这些技术被设计成是可推广的，因此可以用于合理的优化 其他微生物群功能，包括宿主体内的药物或激素代谢，甚至毒素生物修复 或环境中的营养物质生产。

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.