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的结构和多样性的研究。然而，根本的问题仍然存在：从定量生物能量学的角度来看，肠道微生物群的组成在肥胖的发展中是否起到重要作用？我们如何监测和操纵肠道微生物群，以优化其对宿主的积极影响？现有文献中的两个关键发现支持肠道微生物群对体重的关键作用，并为我们指明了这两个关键问题的答案。首先，动物模型支持这样的全球假设，即肠道微生物群的组成通过多种机制导致肥胖，包括从食物中提取更多能量。其次，文献表明，宿主因素--即遗传和代谢状态--在宿主/肠道微生物群相互作用中发挥重要作用。我们假设肠道微生物群以一种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的相互作用和活动来改变这种贡献的大小。目标1：在代谢病房环境中，使用典型的西式饮食和由全食组成的微生物组增强型(ME)饮食，创建、测试和改进能量平衡的集成电子计算机模型。临床和实验室数据将作为开发、测试和改进微生物生态/新陈代谢模型的输入。一旦模型被很好地开发，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)的能量吸收进行比较。目的2：探讨西方饮食与ME饮食对近端和远端肠道内分泌、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。目的3：利用模拟和测量的能量平衡，量化西方饮食和ME饮食对微生物对能量平衡的贡献的影响。意义和创新：我们创建了一个新的模型，明确地将微生物对人体能量平衡的影响与模拟的体重变化联系起来。此外，我们建议的代谢病房研究将使我们有可能测量能量吸收、TDEE和/或食物摄入量的微小变化，这些变化会影响长期体重的增加或减少。微生物生态的变化对能量消耗(EE)或食物摄入量的影响从未在受控代谢病房条件下进行过研究。影响：这些研究将首次量化肠道微生物区系对宿主能量平衡的贡献。通过将临床测量、生物反应器实验和数学建模相结合，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以及对饥饿/饱腹感的影响。我们的创新方法还将为微生物区系的贡献提供定量的见解，并使未来能够研究饮食的相互作用， 肠道微生物群和人类生理学。

 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.