Integrating quantitative energetics determines the microbiome's contribution to energy balance

 描述（由申请人提供）：临床文献中充斥着通过对 16S RNA 基因进行测序并将结果与包括肥胖在内的不同疾病状态相关联来表征肠道微生物组结构和多样性的研究。然而，基本问题仍然存在：从定量生物能学的角度来看，肠道微生物组的组成在肥胖的发展中是否重要？我们如何监测和操纵肠道微生物组以优化其对宿主的积极影响？现有文献的两个重要发现支持肠道微生物组对体重的关键作用，并为我们指出了这两个关键问题的答案。首先，动物模型支持这样一个全球假设：肠道微生物组的组成通过多种机制导致肥胖，包括从食物中提取更多的能量。其次，文献表明宿主因素——即遗传和代谢状态——在宿主/肠道微生物组相互作用中发挥重要作用。我们假设肠道微生物组以可量化的方式对宿主的能量平衡做出贡献，并且我们可以通过饮食管理微生物相互作用和活动来改变这种贡献的大小。目标 1：使用典型的西方饮食与由全食物组成的微生物组增强剂 (ME) 饮食，在代谢病房环境中创建、测试和完善能量平衡的综合计算机模型。临床和实验室数据将作为开发、测试和完善微生物生态/代谢模型的输入。一旦模型开发完善，我们将使用最先进的代谢病房技术将模型输出（预测）与直接测量（观察到）的能量吸收进行比较。目标 2：探索西方饮食与 ME 饮食对近端和远端肠道肠内分泌分泌物、胃排空和小肠转运时间的影响，并将这些结果与主观饥饿/饱腹感和测量的食物摄入量联系起来。目标 3：使用建模和测量的能量平衡，量化西方饮食与 ME 饮食对微生物对能量平衡贡献的影响。意义和创新：我们创建了一种新颖的模型，将微生物对人体能量平衡的影响与建模的体重变化明确联系起来。此外，我们提出的代谢病房研究将使我们能够测量影响长期体重增加或减少的能量吸收、TDEE 和/或食物摄入的微小变化。从未在受控代谢病房条件下研究过微生物生态变化对能量消耗（EE）或食物摄入的影响。影响：这些研究将首次量化肠道微生物群对宿主能量平衡的贡献。通过整合临床测量、生物反应器实验和数学模型，我们将能够描述因果机制。这些研究将使我们能够区分能量吸收的净变化与能量消耗的变化所产生的影响以及对饥饿/饱腹感的影响。我们的创新方法还将提供对微生物群贡献的定量见解，并促进未来对饮食相互作用作用的研究， 肠道微生物组和人体生理学。

 DESCRIPTION (provided by applicant): The clinical literature is replete with studies that characterize structure and diversity of the gut microbiome through sequencing the 16S RNA gene and correlating the results to different disease states, including obesity. Yet, fundamental questions remain: Does the make-up of the gut microbiome matter in the development of obesity from the perspective of quantitative bioenergetics? How might we monitor and manipulate the gut microbiome to optimize its positive impact on the host? Two key findings from the existing literature support the critical role of the gut microbiome on body weight and point us towards answers to these two key questions. First, animal models support the global hypothesis that the composition of the gut microbiome leads to obesity via multiple mechanisms, including more energy extraction from foods. Second, the literature suggests that host factors -- namely, genetics and metabolic status -- play important roles in host/gut microbiome interactions. We hypothesize that the gut microbiome contributes to the host's energy balance in a quantifiable way and that we can change the magnitude of that contribution by managing microbial interactions and activity through diet. Aim 1: Create, test, and refine an integrated in silico model of energy balance in a metabolic ward setting using a typical Western diet vs. a Microbiome Enhancer (ME) diet consisting of whole foods. Clinical and laboratory data will be inputs to develop, test, and refine the model of microbial ecology/metabolism. Once the model is well developed, we will compare model outputs (predictions) to directly measured (observed) energy absorption using state-of-the-art metabolic-ward techniques. Aim 2: Explore the effect of a Western vs. ME diet on proximal and distal gut enteroendocrine secretions, gastric emptying, and small bowel transit time and relate these results to subjective hunger/satiety and measured food intake. Aim 3: Using modeled and measured energy balances, quantify the effect of a Western diet vs. ME diet on the microbial contribution to energy balance. Significance and Innovation: We have created a novel model that explicitly links the effects of microorganisms on human energy balance and modeled weight change. In addition, our proposed metabolic ward studies will make it possible for us to measure small changes in energy absorption, TDEE, and/or food intake that affect long-term weight gain or loss. The effects of changes in the microbial ecology on energy expenditure (EE) or food intake have never been studied under controlled metabolic ward conditions. Impact: These studies will, for the first time, quantify the gut microbiota contributions to the host's energy balance. By integrating clinical measurements, bioreactor experiments, and mathematical modeling, we will be able to describe cause-and-effect mechanisms. The studies will allow us to distinguish among effects stemming from a net change in energy absorption vs. alterations in energy expenditure and effects on hunger/ satiety. Our innovative methods also will provide quantitative insights to the microbiota contribution and enable future studies on the interacting roles of diet, the gut microbiome, and human physiology.