Conceptual and mechanistic insights into the development of diet-induced obesity through disruption of hepatic circadian rhythms by the gut microbiome

通过肠道微生物组扰乱肝脏昼夜节律来了解饮食诱发肥胖的概念和机制

• 批准号: 10308705
• 负责人: EUGENE B CHANG
• 金额: $ 58.8万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-17 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308705
• 关键词: ARNTL gene; Address; Affect; Animals; Bilophila wadsworthia; Biochemical Pathway; Butyrates; Circadian Rhythms; Complex; Data; Deltaproteobacteria; Development; Diet; Dietary Intervention; Diurnal Rhythm; Epidemic; Exhibits; Fat-Restricted Diet; Fatty acid glycerol esters; Fiber; Foundations; Genes; Genetic; Germ-Free; Gnotobiotic; Goals; Health; Hepatic; High Fat Diet; Homeostasis; Human; Indigenous; Intervention; Jet Lag Syndrome; Knockout Mice; Knowledge; Lead; Life; Life Style; Liver; Mediating; Mediator of activation protein; Medical; Metabolic; Metabolism; Microbe; Molecular; Mus; Needles; Obesity; Organ; Organism; Organoids; Outcome; Pacemakers; Pharmacology; Phase; Physiological; Plants; Play; Preventive measure; Preventive treatment; Production; Public Health; Publishing; Regulation; Resistance; Role; Sleep Disorders; System; Technology; Testing; Tissues; Work; base; circadian; circadian pacemaker; diet-induced obesity; dietary; energy balance; environmental change; gain of function; genetic manipulation; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; insight; lens; liver metabolism; loss of function; metabolome; microbial; microbiome; microbiota; molecular clock; multiple omics; non-genetic; novel; prevent; shift work; side effect; sugar; temporal measurement; therapeutic target; trend; western diet

PROJECT SUMMARY Among the many effects that the gut microbiome elicits on its host, the regulation of metabolism is arguably the most significant because of its potential impact on human health and relevance to diet-induced obesity (DIO). DIO is such an enormous and vexing public health concern that there is unanimity that effective and practical solutions must be found. Microbiome-based interventions hold great promise as a way to correct energy balance in a more natural, physiological manner than pharmacological agents that often have off target side effects. In order to accomplish this, we must find novel solutions to unravel the complex and dynamic relationships between the gut microbiome and host metabolic systems in order to advance the field beyond description and association. To move the needle, our group proposes a deep dive into studies that will reveal targets and mechanisms of action of specific microbial drivers of host metabolism in an organ-specific context. We propose to define how diet-induced changes of the gut microbiota affect host metabolism through the lens of hepatic circadian and metabolic networks (the liver being the main metabolic organ). These studies build upon a paradigm-shifting discovery our group made showing that the gut microbiome undergoes diurnal variation, which is essential and intricately intertwined with host circadian rhythms (CRs) that influence host metabolism. We will test the hypothesis that HF diet reprograms the gut microbiota to promote loss of critical microbial inducers (Aim 1) and gain of disruptors (Aim 2) that impact downstream host hepatic circadian and metabolic networks, leading to DIO. To gain mechanistic clarity, each will be studied separately. Additionally, we will test the hypothesis that microbiota-derived inducers and disruptors differentially interact with the core or auxiliary hepatic circadian components, which functionally affect the phase and/or amplitude of the pacemaker. For these studies, we have selected two indigenous gut microbial strains (the recently identified and cultivated Ilealbaculum butyricum [E14] and Bilophila wadsworthia [Bw]) promoted either by LF or HF diet and their known metabolic products (butyrate and H2S, respectively). To achieve higher mechanistic and temporal resolution, we will use genetic manipulation of the circadian system i.e. conditional liver-specific Bmal1 knock-out mice, gnotobiotic mouse technology, and hepatic organoid systems which have all been validated. In Aim 3, we will explore if the culmination of this knowledge can be leveraged into microbiome-based interventions for DIO by testing the hypothesis that butyrate and potentially other LF diet-induced microbe-derived inducers can override the actions of existing HF diet- induced microbial CR disruptors (H2S). These studies serve as a starting point towards a thorough understanding of cellular, tissue, and systems complexity involved in dietary and microbial regulation of metabolism mediated by host circadian networks.

项目概要 在肠道微生物组对其宿主产生的众多影响中，新陈代谢的调节可以说是最重要的。 最重要的是因为它对人类健康的潜在影响以及与饮食引起的肥胖（DIO）的相关性。 DIO 是一个巨大且令人烦恼的公共卫生问题，因此一致认为有效且实用 必须找到解决方案。基于微生物组的干预措施作为一种纠正能量的方法具有巨大的前景 与通常具有偏离目标的药物相比，以更自然、生理的方式实现平衡 影响。为了实现这一目标，我们必须找到新颖的解决方案来解决复杂且动态的问题 肠道微生物组和宿主代谢系统之间的关系，以推动该领域超越 描述和关联。为了取得进展，我们的小组建议深入研究，这些研究将揭示 在特定器官环境中宿主代谢的特定微生物驱动因素的目标和作用机制。 我们建议定义饮食引起的肠道微生物群变化如何通过透镜影响宿主代谢 肝脏昼夜节律和代谢网络（肝脏是主要的代谢器官）。这些研究建立 我们的团队做出了一项范式转变的发现，表明肠道微生物组经历了昼夜变化 变异，这是必不可少的，并且与影响宿主的宿主昼夜节律（CR）错综复杂地交织在一起 代谢。我们将检验这样的假设：高频饮食会重新编程肠道微生物群，以促进肠道微生物群的流失。 影响下游宿主肝脏的关键微生物诱导剂（目标 1）和干扰剂增益（目标 2） 昼夜节律和代谢网络，导致 DIO。为了获得机制的清晰度，将对每一项进行研究 分别地。此外，我们将检验以下假设：微生物群衍生的诱导剂和干扰剂 与核心或辅助肝脏昼夜节律成分有不同的相互作用，从而在功能上影响 起搏器的相位和/或幅度。在这些研究中，我们选择了两种本土肠道 微生物菌株（最近鉴定和培养的丁酸回肠杆菌 [E14] 和 Bilophila wadsworthia [Bw]）通过 LF 或 HF 饮食及其已知的代谢产物（分别为丁酸盐和 H2S）促进。 为了实现更高的机械和时间分辨率，我们将使用昼夜节律的基因操作 系统，即条件性肝脏特异性 Bmal1 敲除小鼠、gnotobiotic 小鼠技术和肝脏 类器官系统均已得到验证。在目标 3 中，我们将探讨这些知识是否达到顶峰 通过检验丁酸盐和 潜在的其他 LF 饮食诱导的微生物诱导剂可以覆盖现有 HF 饮食的作用 诱导微生物 CR 干扰物 (H2S)。这些研究是全面研究的起点 了解饮食和微生物调节所涉及的细胞、组织和系统的复杂性 由宿主昼夜节律网络介导的新陈代谢。