Diet induced obesity from gut microbial disruption of host metabolic networks

 描述(由申请人提供)：拟议的多PI、多学科研究将解决饮食诱导肥胖(DIO)的基本基础，该疾病目前困扰着三分之一的美国成年人，预计到2050年将影响90%的美国人。虽然遗传因素起了作用，但通过改变西方饮食和生活方式引入的非遗传因素更有可能是人类肥胖趋势令人担忧的原因。最近，肠道微生物组在介导DIO中的作用被提出，这一观点得到了我们自己的初步数据的支持，这些数据表明无菌(GF)小鼠受到DIO的保护，高饱和脂肪饮食引起的生物失调扰乱了视交叉上核(SCN)和肝脏的生物钟(CC)网络。昼夜节律对所有生命形式都是必不可少的，无论是人类、动物界的一员、植物还是微生物。昼夜节律是内源性的，并为生物体提供了捕捉外部线索(斑点)的能力，以便它们能够适应并与环境的变化同步。我们将测试这一假设，即高饱和脂肪“西方”饮食的“肥胖”效应是由于它们对肠道微生物区系的时间生物学和功能的影响，导致特定微生物代谢产物的产生，扰乱肝脏CC/NR调节网络，并使能量状态偏向肥胖的发展。将采取一种合作的方法，包括来自芝加哥大学和埃默里大学的研究人员，他们在疾病病理生理学和肠道微生物元基因组测序、代谢组学、营养研究和相关生物信息学的最新分析方面拥有广泛和广泛的专业知识。我们提出了三个具体目标：(1)确定高饱和脂肪饮食的“肥胖”效应是否源于它们对肠道微生物的时间生物学、功能和代谢产物的影响，这些代谢产物专门针对肝脏和中央CC调节网络；(2)利用经典的时间生物学方法，在GF、Conv和SPF小鼠中描述肠道微生物对中枢和肝脏昼夜节律系统提供反馈影响的机制。以及(3)使用高通量的肝脏类有机物检测系统，从代谢组中鉴定特定的微生物依赖的代谢物，这些代谢物介导了饮食诱导的肝脏CC基因网络和/或其下游效应通路的调节效应。它们在体内对肝脏调节网络和代谢/生理功能的影响将在涉及常规(CONV)和GF小鼠的研究中进行审查。总而言之，这些数据将提供丰富的新的和临床有用的信息，以更好地了解西方饮食诱导的肠道生物失调在人类肥胖中的作用、机制和媒介。这些信息将与开发有效的治疗化合物直接相关，这些化合物可以纠正西方饮食诱导的生物失调导致的大脑和肝脏调节网络的失衡，从而使宿主的代谢状态恢复健康。

 DESCRIPTION (provided by applicant): The proposed multi-PI, multidisciplinary investigations will address the fundamental basis of diet-induced obesity (DIO) that currently afflicts one third of adult Americans and is projected to affect >90% of Americans by 2050. While genetics play a role, non-genetic factors introduced through changes in Western diet and lifestyle are the more likely causes for the alarming trends in human obesity. Recently, the role of the gut microbiome in mediating DIO has been suggested, a notion supported by our own preliminary data that show germ-free (GF) mice are protected from DIO and that dysbiosis induced by a high saturated fat diet disrupts the circadian clock (CC) networks of the suprachiasmatic nucleus (SCN) and liver. Circadian rhythms are essential to all life forms, whether human, a member of the animal kingdom, plant, or microbe. Circadian rhythms are endogenous and provide living organisms with the ability to entrain to external cues (zeitgebers) so that they can adapt to, and synchronize with, changes in the environment. We will test the hypothesis that the "obesogenic" effects of high saturated fat "western" diets are due to their effects on the chronobiology and function of the gut microbiota, resulting in the generation of specific microbial metabolites that perturb hepatic CC/NR regulatory networks and skew energy states towards the development of obesity. A collaborative approach will be undertaken that includes investigators from The University of Chicago and Emory University who have broad and extensive expertise in research of disease pathophysiology and state-of-the-art analytics for gut microbial metagenomic sequencing, metabolomics, nutritional studies, and relevant bioinformatics. Three specific aims are proposed: (1) to determine if the "obesogenic" effects of high saturated fat diets are due to their impact on gut microbial chronobiology, function, and metabolomes that specifically target hepatic and central CC regulatory networks, (2) Characterize mechanisms by which gut microbes provide feedback effects on the circadian system in the CNS and liver using classical chronobiological approaches in GF, CONV, and SPF mice. and (3) to identify specific microbe- dependent metabolites from the metabolome that mediate the effects of diet-induced regulation of hepatic CC gene networks and/or their downstream effector pathways using high throughput, hepatic organoid assay systems. Their effects in vivo on hepatic regulatory networks and metabolic/physiological functions will then be vetted in studies involving conventionalized (CONV) and GF mice. Collectively, these data will provide a wealth of novel and clinically-useful information to better understand the role, mechanisms, and mediators of western diet-induced gut dysbiosis in human obesity. This information will have direct relevance to the development of effective therapeutic compounds that can correct the imbalances in brain and hepatic regulatory networks caused by western-diet induced dysbiosis, thereby restoring host metabolic states to health.