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的肥胖（DIO）的根本基础，DIO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。虽然遗传学发挥了作用，但通过西方饮食和生活方式的变化引入的非遗传因素更可能是人类肥胖惊人趋势的原因。最近，已经提出了肠道微生物组在介导DIO中的作用，这一观点得到了我们自己的初步数据的支持，这些数据显示无菌（GF）小鼠受到DIO的保护，并且高饱和脂肪饮食诱导的生态失调破坏了视交叉上核（SCN）和肝脏的昼夜节律钟（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，动物王国的成员，植物还是微生物。昼夜节律是内源性的，并为生物体提供了吸引外部线索（zeitgeber）的能力，以便它们能够适应环境的变化并与之同步。我们将检验这样一个假设，即高饱和脂肪“西方”饮食的“致肥”效应是由于它们对肠道微生物群的时间生物学和功能的影响，导致产生特定的微生物代谢产物，扰乱肝脏CC/NR调节网络，并使能量状态偏向肥胖的发展。将采取合作方法，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研究和最先进的肠道微生物宏基因组测序分析、代谢组学、营养研究和相关生物信息学方面拥有广泛而广泛的专业知识。提出了三个具体目标：（1）确定高饱和脂肪饮食的“致肥胖”效应是否是由于它们对肠道微生物时间生物学、功能和代谢组的影响，所述代谢组特异性靶向肝脏和中央CC调节网络，（2）使用GF、CONV、SPF小鼠和（3）使用高通量肝类器官测定系统从代谢物组鉴定介导饮食诱导的肝CC基因网络调节和/或其下游效应子途径的作用的特定微生物依赖性代谢物。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。总的来说，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态失调在人类肥胖中的作用，机制和介质。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由西方饮食诱导的生态失调引起的脑和肝调节网络的失衡，从而使宿主代谢状态恢复健康。

 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.