Developmental effects of intestinal microbes on metabolic and behavioral circadian rhythms

肠道微生物对代谢和行为昼夜节律的发育影响

• 批准号: 10581777
• 负责人: Vanessa Anne Leone
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-07 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581777
• 关键词: Abate; Address; Adolescent; Adult; Affect; Age; Automobile Driving; Behavior; Behavioral; Birth; Brain; Child; Circadian Dysregulation; Circadian Rhythms; Clinical Data; Consumption; Data; Development; Diet; Disease; Elements; Epidemic; Exhibits; Fatty acid glycerol esters; Feedback; Feeding behaviors; Gene Expression; Genetic Transcription; Genomics; Germ-Free; Gnotobiotic; Goals; Health; Health Resources; Healthcare; Hepatic; Individual; Intervention; Investments; Knowledge; Life; Longevity; Metabolic; Metabolic Diseases; Metabolism; Microbe; Molecular; Mus; Obese Mice; Obesity; Outcome; Output; Overweight; Pattern; Periodicity; Persons; Phenotype; Physiologic Thermoregulation; Physiology; Play; Population; Pregnancy; Prevalence; Prophylactic treatment; Public Health; Research; Ribosomal RNA; Risk; Role; Severities; Shapes; Signal Transduction; Specific qualifier value; Sterility; System; Telemetry; Testing; Thinness; Weaning; aged; care burden; circadian; circadian behavioral rhythms; circadian pacemaker; diet-induced obesity; dietary; disorder risk; effective intervention; experimental study; feeding; global health; gut microbes; gut microbiota; host-microbe interactions; innovation; insight; liver metabolism; microbial; microbial community; microbial host; microbiome; microbiota; novel; obese person; obesity development; obesity in children; obesogenic; pre-clinical; programs; sugar; transcriptome sequencing; transcriptomics; western diet; wireless

PROJECT SUMMARY Metabolic diseases are increasing worldwide in prevalence and severity. Globally, approximately 650 million people are obese or overweight, over half of whom are children. The healthcare burden of obesity is enormous and only growing. Circadian rhythms play a central role in healthy metabolism and in maintaining proper host- microbe interactions. Circadian rhythms in feeding and behavior create a feedback loop, driving rhythms in hepatic transcription, which in turn drive rhythms in host and microbial metabolism that ultimately feedback onto circadian rhythms in host behavior. This network of rhythms is severely disrupted in obese mice consuming a Western diet. Early-life diet interacts with the developing microbiome to program metabolism and disease risk, but how the early-life microbiota contribute to development of the host metabolic circadian network remains unknown. There is an urgent need to identify mechanisms by which gut microbes interact with diet early in life to shape these circadian networks that coordinate daily rhythms in metabolism. Mice devoid of all microbes (‘germ-free’) exhibit disrupted circadian rhythms in numerous aspects of host metabolism compared to mice that have had microbes since birth. Remarkably, repopulating germ-free mice later in adulthood with microbes (‘conventionalization') only partially normalizes their circadian rhythms. This indicates that the age at which gut microbes are acquired must play a critical role in the development of circadian networks that govern metabolism. But when and how healthy and obesogenic microbes first begin to normalize and disrupt, respectively, the circadian network remain unexamined. Our research will bridge this gap in knowledge by testing the hypothesis that the organismal circadian network is shaped by interactions between the type of gut microbes acquired and the developmental age of acquisition. Aim 1 tests the hypothesis that the age when mice acquire a normal, healthy microbiome determines the robustness of their circadian network in adulthood. We will conventionalize germ-free mice with microbes during gestation, at weaning, or in adulthood. Phenotypes across the entire circadian network will be examined later in life, including: hepatic clock and clock-controlled gene expression via RNA-seq, microbial community oscillations via 16S rRNA, and host behavioral circadian rhythms thermoregulation and via wireless telemetry inside sterile isolators. Aim 2 will test the hypothesis that obesogenic diets early in life disrupt normal development of the circadian network through a combination of microbe-dependent and microbe-independent mechanisms. Beginning early in life, germ-free mice will be administered an obesogenic diet alone, obesogenic microbes alone, or both obesogenic diet and microbes. Metabolic circadian networks will be examined as in Aim 1. These studies will specify how diet and microbes interact to affect the developing host-microbial circadian network. New insights into how metabolic programming impacts the circadian system will inform early-life dietary and microbial interventions that may afford prophylaxis against the development of obesity.

项目总结 代谢性疾病在全球范围内的流行率和严重性都在增加。在全球，约有6.5亿 人们肥胖或超重，其中一半以上是儿童。肥胖带来的医疗负担是巨大的 而且只会越来越多。昼夜节律在健康的新陈代谢和维持适当的宿主- 微生物相互作用。摄食和行为的昼夜节律创造了一个反馈循环，驱动着 肝脏转录，进而驱动宿主和微生物代谢的节律，最终反馈到 宿主行为的昼夜节律。这一节律网络在肥胖小鼠中被严重扰乱 西式饮食。早期饮食与发育中的微生物群相互作用，以编程新陈代谢和疾病风险， 但是，早期生命微生物区系如何对宿主代谢昼夜节律网络的发展做出贡献仍然存在 未知。迫切需要确定肠道微生物在生命早期与饮食相互作用的机制 塑造这些协调新陈代谢日常节律的昼夜节律网络。 没有所有微生物的小鼠在宿主的许多方面表现出昼夜节律被打乱。 与从出生起就有微生物的小鼠相比，它们的新陈代谢能力更强。值得注意的是，重新繁殖无菌小鼠 成年后，与微生物接触(“常规化”)只能部分恢复它们的昼夜节律。这 表明肠道微生物获得的年龄在肠道疾病的发展过程中一定起着关键作用。 控制新陈代谢的昼夜节律网络。但健康和肥胖微生物是在什么时候以及如何开始 为了分别恢复正常和扰乱，昼夜节律网络仍然没有被研究过。 我们的研究将通过检验生物昼夜节律的假设来弥合这一认识上的鸿沟 网络的形成是由获得的肠道微生物的类型和发育的 收购的时代。目的1检验假设，当小鼠获得正常、健康的微生物群的年龄 决定了他们成年后昼夜节律网络的稳定性。我们将使无菌小鼠常规化 孕期、断奶或成年期的微生物。整个昼夜节律网络的表型将是 生命后期的检查，包括：肝脏时钟和时钟控制的基因表达通过rna-seq，微生物 通过16S rRNA和宿主行为昼夜节律、体温调节和无线进行群落振荡 无菌隔离器内的遥测。目标2将检验这样一种假设，即生命早期的肥胖饮食破坏了正常 微生物依赖和非微生物结合的昼夜节律网络的发展 机制。从生命早期开始，无菌小鼠将被单独喂食肥胖饮食， 单独的微生物，或者同时存在肥胖饮食和微生物。代谢昼夜节律网络将在AIM中进行检查 1.这些研究将具体说明饮食和微生物如何相互作用来影响发育中的宿主-微生物昼夜节律 网络。对代谢编程如何影响昼夜节律系统的新见解将为早期饮食提供信息 以及可能提供预防肥胖发展的微生物干预措施。