Personalizing prebiotic therapies that target human gut microbiota

饮食中的碳水化合物滋养人类肠道细菌群落(微生物区系)，这些细菌群落抵抗病原体，代谢 药物，并训练免疫系统。短链脂肪酸，这是微生物的最终产物 多糖发酵也是人结肠细胞重要的代谢前体和能量来源。 促进肠道生长和活动的饮食碳水化合物的潜在健康益处 细菌(益生元)导致数百万美国人每年消费这些化合物。然而，它的影响是 肠道微生物区系上的益生菌及其发酵已知在个体之间有很大的不同。我们的 这里的目标是了解为什么以及如何为个人和他们的肠道量身定做益生元 微生物区系。为了解决先进的益生菌研究，我们开发了创新的新工具：微流控 创造和分析数百万个单独细菌培养物的技术.贝叶斯状态空间模型 纵向微生物区系数据；以及我们可以任意采样和操纵的人造人体肠道 频率我们建议结合这些新方法来检验我们的中心假设，即 益生菌治疗可以通过对个人及其微生物区系的个性化而最大化。我们的建议已经 三个具体目标：1)使用我们的微流控培养技术来测量不同的碳水化合物 化合物影响成千上万种不同的人类肠道细菌的生长和代谢。通过 识别哪些细菌物种直接受到益生元的刺激，我们就可以开始了解这些 治疗会重塑每个人的肠道微生物区系。2)建立了微生物的概率状态空间模型 群落动态，并将其应用于我们跟踪人类饮食、肠道微生物区系和短链的现有数据集 随着时间的推移，脂肪酸水平。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，以及影响对益生素治疗反应的受试者饮食。3)使用我们的人工 人体肠道模型，对人体肠道微生物区系进行益生菌试验，剂量固定或 根据微生物区系结构和功能的变化定期更新。生成的数据将建立 益生素治疗引起的初始微生物区系变化如何影响后来的剂量反应，以及评估 消除宿主顺应性和反应的差异是否会影响益生菌影响的变化。 最终，拟议的目标预计将提供对潜在机制的第一次系统研究 推动对益生菌治疗的个性化反应，并有助于建立一个专注于 个性化的益生菌治疗。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菌转化为人类临床试验。更多 总的来说，这些技术被设计成可推广的，因此可以用于合理的优化 其他微生物区系功能，包括宿主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.