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

项目总结 在肠道微生物对宿主产生的众多影响中，新陈代谢的调节可以说是 最重要的是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是一个如此巨大和令人烦恼的公共卫生问题，以至于人们一致认为有效和实用 必须找到解决方案。基于微生物组的干预作为纠正能源的一种方法大有可为 以一种更自然、更生理的方式进行平衡，而不是经常偏离靶点的药物 效果。为了实现这一点，我们必须找到新的解决方案来解开复杂和动态的 肠道微生物群和寄主代谢系统之间的关系，以推动该领域的发展 描述和关联。为了取得进展，我们的团队提议深入研究，以揭示 在器官特定的背景下，宿主代谢的特定微生物驱动因素的作用靶标和作用机制。 我们建议定义饮食诱导的肠道微生物区系变化如何通过晶状体影响宿主新陈代谢。 肝脏的昼夜节律和代谢网络(肝脏是主要的代谢器官)。这些研究建立了 在一项范式转换的发现后，我们的团队发现肠道微生物群经历了一天一次的 变异是必不可少的，与影响寄主的昼夜节律(CRS)错综复杂地交织在一起 新陈代谢。我们将检验这一假设，即HF饮食对肠道微生物区系进行重新编程，以促进 影响下游宿主肝脏的关键微生物诱导剂(目标1)和干扰物的收益(目标2) 昼夜节律和代谢网络，导致DIO。为了获得机制上的清晰，每一个都将被研究 分开的。此外，我们将测试微生物区系衍生的诱导物和干扰物的假设 与核心或辅助的肝脏昼夜节律成分不同地相互作用，这些成分在功能上影响 起搏器的相位和/或幅度。在这些研究中，我们选择了两个土著肠道 微生物菌株(新近鉴定和培养的酪酸Ilealbaculum[E14]和华氏毕氏杆菌 [BW])由LF或HF饮食及其已知的代谢产物(分别为丁酸盐和硫化氢)促进。 为了达到更高的机械和时间分辨率，我们将使用对昼夜节律的遗传操作 系统，即条件性肝脏特异性BMal1基因敲除小鼠，GnotoBiotic小鼠技术，和肝脏 所有经过验证的有机系统。在目标3中，我们将探索这种知识的顶峰 可以通过检验丁酸盐和丁酸盐的假设而被利用到基于微生物组的DIO干预中 潜在的其他LF饮食诱导的微生物来源的诱导剂可以覆盖现有HF饮食的作用- 诱导微生物CR干扰物(H_2S)。这些研究是一个起点，可以彻底地 了解饮食和微生物调控所涉及的细胞、组织和系统的复杂性 由宿主昼夜节律网络调节的代谢。

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.