The Relationship of Gut Microbiome and Time Restricted Feeding in Metabolism

肠道微生物组与代谢中限时喂养的关系

• 批准号: 9352840
• 负责人: Amir Zarrinpar
• 金额: $ 17.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9352840
• 关键词: Adult; Advisory Committees; Affect; Agonist; Americas; Antibiotics; Asthma; Bacteria; Bacterial Genes; Bile Acids; Biochemical; Biology; Carbohydrates; Characteristics; Circadian Rhythms; Colon Carcinoma; Development; Development Plans; Diet; Digestion; Disease; Doctor of Philosophy; Ensure; Environment; Environmental Risk Factor; Enzymes; Family; Fasting; Gastroenterology; Gene Expression; Genes; Genetic; Genomics; Germ-Free; Glass; High Fat Diet; Homeostasis; Human; Inflammatory; Institutes; Institution; Intake; Learning; Mediating; Medical; Mentors; Metabolic; Metabolic Diseases; Metabolism; Morbidity - disease rate; Mus; Nutritional; Obese Mice; Obesity; Pathway interactions; Periodicity; Pharmacology; Phenotype; Phylogenetic Analysis; Physicians; Physiological; Play; Population; Process; Protocols documentation; RNA; Receptor Signaling; Recruitment Activity; Regulation; Research; Research Personnel; Role; Scientist; Signal Pathway; Signal Transduction; Source; Testing; Time; Training; Transgenic Organisms; Transplantation; United States; Wild Type Mouse; absorption; career; career development; clinical application; cost; experience; experimental study; fecal transplantation; feeding; gastrointestinal function; gut microbiome; gut microbiota; intestinal homeostasis; metabolic phenotype; microbiome; mortality; mouse model; novel therapeutics; obesogenic; prevent; professor; programs; public health relevance; receptor; transcriptome

 DESCRIPTION (provided by applicant): The candidate, Dr. Amir Zarrinpar, presents a 5-year career development plan that seeks to characterize the relationship of the gut microbiome and metabolism while establishing an academic career as a physician scientist in the field of gastroenterology. Obesity and its associated metabolic disease afflict more than one third of the population of the United States and are a source of considerable morbidity and mortality. Dr. Zarrinpar and his colleagues co-discovered time restricted feeding (TRF), a paradigm that preserves normal feeding/fasting cycles and prevents obesity and other metabolic disorders associated with a high fat diet. By maintaining the natural feeding rhythms without altering nutritional intake, mice on a TRF protocol do not become obese or have hallmarks of dysmetabolism. However, the mechanism for TRF still remains elusive, though it likely alters gut luminal signaling and the gut microbiome. Our primary hypothesis for the proposed studies is that TRF imparts its beneficial effects by altering the gut microbiome and the genes that the microflora express (i.e. "the metatranscriptome"). This hypothesis will be pursued with three specific aims that investigate the relationship between the gut microbiome, metabolism, and gut gene expression in context of the TRF paradigm. Specific aim 1 tests the hypothesis that specific TRF-induced changes protect against obesity by altering host-microbiome homeostasis and luminal signaling. TRF will help identify a small set of candidate bacterial species/genes that play a protective role and another set that play a detrimental role in metabolism. Specific aim 2 tests the hypothesis that TRF's beneficial effects result from changes in the gut microbiome. The microbiome will be changed by either using antibiotics, shared bedding in wild-type mice, or transplantation into germ-free mice. Lastly, specific aim 3 tests the hypothesis that the gut microbiome and TRF mediate their beneficial effects through bile acid signaling pathways. By pharmacologically manipulating this signaling pathway, its necessity in mediating the beneficial effects of TRF and gut microbiome changes can be observed. These specific aims will help us understand the role of gut microbiome to intestinal homeostasis, gut gene expression, and luminal signaling. The anticipated results of these experiments are that the gut microbiome is a dynamic environment with cyclical changes in microflora populations and their gene expressions. Diet induced obesity disrupts this dynamic environment and selects for obesogenic bacteria. TRF on the other hand, maintains the cyclical changes in the gut microbiome and selects for obesity-protective species in the microflora. Any changes in the microbiome will be correlated to changes in the gut gene expression to find physiological consequences of these shifts. Alteration of the gut microbiome in antibiotic induced microbiome depletion and germ-free mice would confirm that microbiome changes are necessary for the metabolic phenotype observed in these mice. Furthermore, the bile acid signaling pathway is the main way that the gut microbiome mediates its protection against obesity. The three specific aims proposed will substantially advance our understanding of the physiological role that the gut microbiome plays in metabolism. By better understanding the gut microbiome's relationship to intestinal homeostasis, gut gene expression, and luminal signaling, these pathways can then be physiologically manipulated to treat and prevent obesity and its associated metabolic diseases. Dr. Zarrinpar is well qualified to carry out the research outlined in this proposal. He has successfully completed projects of comparable complexity as part of his PhD thesis. He will further his training by acquiring expertise in performing high quality gut microbiome experiments as well as further establish expertise in circadian biology, metabolic regulation, and intestinal homeostasis. Dr. Zarrinpar has recruited a team of outstanding mentors from three different local institutions. His mentor, Dr. Satchidananda Panda, has experience in studying circadian circuitry and using genetic, genomic, and biochemical approaches to identify numerous genes that are under circadian regulation. Dr. Mark Adams, Professor and Scientific Director of J. Craig Venter Institute (JCVI) will provide expertise in studying the gut microbiome. Dr. Christopher Glass, who has extensive experience training physician scientists, will advise him on major career related issues and help navigate the academic promotion process. In addition, Dr. Sheila Crowe, a nationally recognized educator and mentor, will serve on the advisory committee. She will mentor Dr. Zarrinpar as he finds translational and clinical applications of the studies proposed in his application. The advisory committee will meet, at minimum, every 6 months to ensure a successful scientific program. Successful completion of the specific aims and career development plan outlined in this proposal will allow Dr. Zarrinpar to learn how to perform high quality gut microbiome projects and to develop into an independent investigator in the field of gastroenterology and metabolism.

 描述（由申请人提供）：候选人 Amir Zarrinpar 博士提出了一个 5 年职业发展计划，旨在描述肠道微生物组和新陈代谢的关系，同时建立胃肠病学领域医师科学家的学术职业生涯。肥胖及其相关代谢疾病困扰着美国三分之一以上的人口，是相当大的发病率和死亡率的根源。 Zarrinpar 博士和他的同事共同发现了限时进食 (TRF)，这是一种保持正常进食/禁食周期并预防肥胖和其他与高脂肪饮食相关的代谢紊乱的范例。通过在不改变营养摄入的情况下保持自然喂养节律，接受 TRF 方案的小鼠不会变得肥胖或出现代谢障碍的特征。然而，TRF 的机制仍然难以捉摸，尽管它可能会改变肠道腔信号和肠道微生物组。我们对拟议研究的主要假设是，TRF 通过改变肠道微生物组和微生物区系表达的基因（即“元转录组”）来发挥其有益作用。这一假设将针对三个具体目标进行研究，即在 TRF 范式的背景下研究肠道微生物组、代谢和肠道基因表达之间的关系。具体目标 1 测试了以下假设：特定 TRF 诱导的变化通过改变宿主微生物组稳态和管腔信号传导来预防肥胖。 TRF 将帮助识别一小部分发挥保护作用的候选细菌物种/基因，以及另一组在新陈代谢中发挥有害作用的细菌物种/基因。具体目标 2 检验了 TRF 的有益作用源于肠道微生物组变化的假设。通过使用抗生素、野生型小鼠共用垫料或移植到无菌小鼠体内，可以改变微生物组。最后，特定目标 3 检验假设 肠道微生物组和 TRF 通过胆汁酸信号通路介导其有益作用。通过药理学操纵该信号通路，可以观察到其介导 TRF 有益作用和肠道微生物组变化的必要性。这些具体目标将帮助我们了解肠道微生物组对肠道稳态、肠道基因表达和管腔信号传导的作用。这些实验的预期结果是肠道微生物组是一个动态环境，微生物群落及其基因表达发生周期性变化。饮食引起的肥胖会破坏这种动态环境并选择致肥细菌。另一方面，TRF 维持肠道微生物群的周期性变化，并选择微生物群中的肥胖保护物种。微生物组的任何变化都将与肠道基因表达的变化相关联，以发现这些变化的生理后果。抗生素诱导的微生物组耗竭和无菌小鼠肠道微生物组的改变将证实微生物组的变化对于在这些小鼠中观察到的代谢表型是必要的。此外，胆汁酸信号通路是肠道微生物介导其预防肥胖的主要方式。提出的三个具体目标将极大地增进我们对肠道微生物组在新陈代谢中所发挥的生理作用的理解。通过更好地了解肠道微生物组与肠道稳态、肠道基因表达和管腔信号传导的关系，可以从生理上操纵这些途径来治疗和预防肥胖及其相关代谢疾病。 Zarrinpar 博士完全有资格开展本提案中概述的研究。作为博士论文的一部分，他成功地完成了相当复杂的项目。他将通过获得进行高质量肠道微生物组实验的专业知识来进一步接受培训，并进一步建立昼夜节律生物学、代谢调节和肠道稳态​​方面的专业知识。 Zarrinpar博士从当地三个不同的机构招募了一支由优秀导师组成的团队。他的导师 Satchidananda Panda 博士在研究昼夜节律回路以及使用遗传、基因组和生化方法来识别众多受昼夜节律调节的基因方面拥有丰富的经验。 J. Craig Venter Institute (JCVI) 教授兼科学主任 Mark Adams 博士将提供研究肠道微生物组的专业知识。克里斯托弗·格拉斯 (Christopher Glass) 博士在培训医师科学家方面拥有丰富的经验，他将就重大职业相关问题向他提供建议，并帮助指导他的学术晋升过程。此外，全国公认的教育家和导师 Sheila Crowe 博士将担任顾问委员会成员。她将指导 Zarrinpar 博士寻找该技术的转化和临床应用。 他的申请中提出的研究。咨询委员会将至少每 6 个月举行一次会议，以确保科学计划的成功。成功完成该提案中概述的具体目标和职业发展计划将使 Zarrinpar 博士能够学习如何进行高质量的肠道微生物组项目，并发展成为胃肠病学和代谢领域的独立研究者。