Diet induced obesity from gut microbial disruption of host metabolic networks

肠道微生物破坏宿主代谢网络导致饮食诱发肥胖

• 批准号: 9129870
• 负责人: EUGENE B CHANG
• 金额: $ 40.9万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9129870
• 关键词: Address; Adult; Affect; American; Animals; Biochemical Pathway; Bioinformatics; Biological Assay; Blood; Brain; Chicago; Chronobiology; Circadian Rhythms; Cues; Data; Development; Diabetes Mellitus; Diagnosis; Diet; Disease; Environment; Exhibits; Fat-Restricted Diet; Feedback; Functional disorder; Future; Gene Expression; Gene Targeting; Generations; Genes; Genetic; Germ-Free; Goals; Health; Health Care Costs; Hepatic; Homeostasis; Human; Hypothalamic structure; Intervention; Investigation; Knowledge; Life; Life Style; Liver; Mediating; Mediator of activation protein; Metabolic; Metabolism; Microbe; Molecular; Mus; Neuraxis; Nutritional Study; Obesity; Organ; Organism; Organoids; Pathway interactions; Peripheral; Phase; Physiological; Plants; Play; Regulation; Research; Research Personnel; Risk Assessment; Role; Running; System; Testing; Therapeutic; Time; Tissues; Universities; Work; base; circadian pacemaker; defined contribution; disorder prevention; energy balance; feeding; gut microbiota; improved; in vivo; liver function; member; metabolomics; metagenomic sequencing; microbial; microbiome; multidisciplinary; non-genetic; novel; personalized medicine; prevent; saturated fat; suprachiasmatic nucleus; trend; western diet

 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.

 描述（适用提供）：拟议的多学科的多学科研究将解决饮食引起的肥胖症（DIO）的基本基础，目前困扰着三分之一的成年美国人，预计到2050年将影响> 90％的美国人。到2050年，美国人> 90％的美国人。而遗传因素扮演了西方饮食和生活的范围，而遗传因素引入了人类肥胖的变化。最近，已经提出了肠道微生物组在介导DIO中的作用，我们自己的初步数据支持了一份通知，该数据显示出无菌株（GF）小鼠免受dio的影响，并且高饱和脂肪饮食引起的营养不良破坏了昼夜节律循环（CC）核核（CC）网络的核（CC）网络（CC）核（CC）核（CC）和核（CC）核（CC）和核（Scn）和Liver。昼夜节律对于所有生命形式都是必不可少的，无论是人类，动物界，植物还是微生物的成员。昼夜节律是内源性的，可以使生活组织能够进入外部线索（Zeitgebers），以便它们可以适应环境中的变化并同步。我们将检验以下假设：高饱和脂肪“西方”饮食的“肥胖”作用是由于它们对肠道微生物群的年级生物学和功能的影响，从而导致特定的微生物代谢产物生成扰动肝CC/NR调节性网络的特定微生物代谢产物，并产生对物体开发的生成。将采用一种协作方法，其中包括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，代谢组学，营养研究和相关生物信息方面具有广泛而广泛的专业知识。提出了三个具体目的：（1）确定高饱和脂肪饮食的“肥胖性”作用是否是由于它们对肠道微生物生物学，功能和代谢组的影响是否构成，这些影响是针对肝脏和中央CC调节网络的特定靶向肝脏和中央CC调节网络的（2）对反馈进行了反馈对Cirpad System firf cipd ciff infir in the Ciff infir in n of civf infir in n of civf infi in infi infi infir in confive cons in ciff infir提出的。 Conv和SPF小鼠。 （3）从代谢组中鉴定特定的微生物代谢产物，以介导饮食诱导的肝脏CC基因网络和/或使用高通量的肝脏类器官的调节的作用和/或其下游效应途径。然后，在涉及常规化（CORS）和GF小鼠的研究中，将对体内对肝脏调节网络的影响以及代谢/生理功能。总的来说，这些数据将提供大量新颖和临床用途的信息，以更好地了解西方饮食诱发的肠胃疾病在人类肥胖症中的作用，机制和介体。这些信息将与有效的治疗化合物的开发直接相关，这些化合物可以纠正由西方偏见引起的营养不良引起的大脑和肝调节网络的失衡，从而使宿主代谢状态恢复健康。