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.

项目摘要 在肠道微生物组对宿主引起的许多影响中，代谢的调节可以说是 最重要的是，它对人类健康的潜在影响以及与饮食诱导的肥胖症（DIO）相关的影响。 DIO是一个如此巨大而烦人的公共卫生，以至于有效而实用 必须找到解决方案。基于微生物组的干预措施具有巨大的希望，以纠正能源 比通常没有目标方面的药理学剂以更自然，生理的平衡 效果。为了实现这一目标，我们必须找到新颖的解决方案来揭示复杂而动态的 肠道微生物组和宿主代谢系统之间的关系，以使现场超越 描述和关联。为了移动针头，我们的小组建议深入研究研究 在器官特异性的情况下，宿主代谢的特定微生物驱动因素的靶标和机制。 我们建议定义饮食诱导的肠道菌群的变化如何通过镜头影响宿主代谢 肝脏和代谢网络（肝脏是主要的代谢器官）。这些研究建立 在范式转移发现时，我们的小组提出了肠道微生物组发生的昼夜 变异，这是必不可少的，并且与影响宿主的宿主昼夜节律（CRS）相互交织 代谢。我们将测试HF饮食对肠道菌群的重新编程以促进损失的假设 关键的微生物诱导剂（AIM 1）和影响下游宿主肝的破坏者的增益（AIM 2） 昼夜节律和代谢网络，通往Dio。为了获得机理清晰度，将研究每个 分别地。此外，我们将检验以下假设，即微生物群衍生的诱导剂和破坏者 与核心或辅助肝昼夜节律组件差异相互作用，这些成分在功能上影响 起搏器的相位和/或振幅。对于这些研究，我们选择了两个土著肠道 微生物菌株（最近鉴定和培养的叶叶丁丁基[E14]和双毛虫wadsworthia [BW]）由LF或HF饮食及其已知的代谢产物（分别为丁酸酯和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纵 系统，即有条件的肝特异性BMAL1敲除小鼠，Gnotobiotic Mouse技术和肝 所有验证的器官系统。在AIM 3中，我们将探索是否达到这一知识 可以通过测试丁酸酯和 潜在的其他LF饮食诱导的微生物衍生诱导剂可以覆盖现有的HF饮食的作用 - 诱导的微生物CR干扰物（H2S）。这些研究是彻底的起点 了解饮食和微生物调节的细胞，组织和系统的复杂性 由主机昼夜节律网络介导的代谢。