MECHANISMS OF ALTERATION OF GASTROINTESTINAL MOTILITY BY GUT MICROBIOTA

肠道菌群改变胃肠动力的机制

基本信息

批准号：
9025781
负责人：
Purna C Kashyap
金额：
$ 14.7万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-03 至 2018-03-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9025781
关键词：
Address Affect Afferent Neurons Anabolism Area Bacteria Bathing Carbohydrates Cell Line Clinic Clinical Communities Complex Coupled Data Diet Dietary Carbohydrates Dietary Polysaccharide Distal Ecology Ecosystem Engineering Enterochromaffin Cells Enterochromaffin-like Cells Environmental Risk Factor Enzymes Epithelial Faculty Family member Feces Figs - dietary Gastroenterology Gastrointestinal Motility Gastrointestinal Physiology Gastrointestinal Transit Germ-Free Gnotobiotic Harvest Health Human Human Biology Hydroxyindoleacetic Acid International Interstitial Cell of Cajal Intestinal Motility Intestines K-Series Research Career Programs Liquid Chromatography Manometry Mass Spectrum Analysis Measurement Mediating Mediator of activation protein Mentorship Microbe Mind Molecular Biology Techniques Motor Movement Mucous Membrane Mucous body substance Mus Neuromodulator Nutrient Organ Pathway interactions Performance Physiological Play Probiotics Production Regulation Research Research Training Ribosomal RNA Role Seminal Sensory Serotonergic System Serotonin Serotonin Receptors 5-HT4 Signal Transduction Smooth Muscle Myocytes System Techniques Testing Training Tryptamines Tryptophan 5-monooxygenase Universities Work base cell motility clinically relevant fructooligosaccharide gastrointestinal gut microbiota humanized mouse in vivo microbial microbiota microorganism microorganism interaction motility disorder mouse model next generation sequencing paracrine receptor research study screening skills sound

项目摘要

DESCRIPTION (provided by applicant): The human gut harbors trillions of microorganisms that benefit the host by enabling harvest of nutrients/energy from otherwise indigestible components of our diet. Remarkably, the complex signaling between microbes and their human host, and the resulting impact on normal physiological functions, are still poorly understood. Gastrointestinal (GI) motility and the gut microbiota are clearly associated and environmental factors, including diet, can modify the relationship between GI motility and the gut microbiota. Serotonin (5-hydroxytryptamine; 5- HT) released from the enterochromaffin (EC) cells serves as an important paracrine messenger involved in motor and sensory transduction modulating GI motility. My preliminary studies strongly suggest the gut serotonergic pathway as a target for gut microbiota. My overall hypothesis is that gut microbiota alters GI motility in diet-dependent manner by release of specific metabolites, including tryptamine, which affect the gut serotonergic pathway. I will use germ-free (GF), gnotobiotic (defined/simplified microbiota), and humanized (ex-GF colonized by human-derived microbes) mice to address physiological effects of human gut microbes on the host in a mouse model. As GF mice completely lack microbiota they can be colonized with defined communities of bacteria to create distinct states of colonization. In specific aim 1, I will explore the effect of microbiota on the gut serotonergic pathway in GF and humanized mice. In specific aim 2, I will determine the differential effect on GI motility of decreasing the complexity of dietary polysaccharides with resulting alteration in gu microbiota. Finally, in specific aim 3, I will investigate the role of microbial metabolites such a tryptamine in modulating 5-HT biosynthesis and modulating GI motility. I have developed both ex vivo (organ bath) and in vivo (colonic manometry) physiological techniques as well as a screening strategy to use EC-like cell lines to test metabolites for their effect on synthesis and release of 5-HT using ultra performance liquid chromatography coupled with mass spectrometry. My previous research training in GI physiology delineating complex mechanisms regulating GI motility, as well as my recent training in microbial ecology as it relates to host function, along with my clinical training in Gastroenterology with a specific focus on GI motility disorders, gives me the ability to address these biologically sound and clinically relevant questions. This career development award will allow me to combine my skills in two very distinct areas of research, Neurogastroenterology and Microbial Ecology, to address important aspects of human biology. My mentorship team is comprised of Dr. Gianrico Farrugia at Mayo Clinic and Dr. Justin Sonnenburg at Stanford University; both are internationally renowned in their areas of research and have a successful track record in training young faculty. Dr. Gianrico Farrugia is an international leader in Neurogastroenterology, having made seminal contributions in elucidating roles of interstitial cells of Cajal in GI motility disorders. His long record of succesful mentorship is evidenced by mentorship of 31 fellows. Dr. Sonnenburg is an evolutionary minded glycobiologist who is internationally renowned for his ground-breaking work on carbohydrate utilization by gut microbes and the application of gnotobiotic mouse models to understanding microbial interactions in the gut. Both of their expertise will be invaluable for this cross-disciplinary project.

描述（由申请人提供）：人类肠道蕴藏着数万亿微生物，这些微生物能够从我们饮食中其他难以消化的成分中获取营养/能量，从而使宿主受益。值得注意的是，人们对微生物与其人类宿主之间复杂的信号传导以及由此产生的对正常生理功能的影响仍然知之甚少。胃肠道 (GI) 动力和肠道微生物群明显相关，包括饮食在内的环境因素可以改变胃肠道动力和肠道微生物群之间的关系。肠嗜铬细胞 (EC) 释放的血清素（5-羟色胺；5-HT）是重要的旁分泌信使，参与调节胃肠道运动的运动和感觉转导。我的初步研究强烈表明肠道血清素通路是肠道微生物群的目标。我的总体假设是，肠道微生物群通过释放特定代谢物（包括影响肠道血清素途径的色胺），以饮食依赖性方式改变胃肠道运动。我将使用无菌（GF）、无菌（定义/简化的微生物群）和人源化（由人源微生物定植的前 GF）小鼠来解决小鼠模型中人类肠道微生物对宿主的生理影响。由于 GF 小鼠完全缺乏微生物群，它们可以被特定的细菌群落定植，从而形成不同的定植状态。在具体目标 1 中，我将探讨微生物群对 GF 和人源化小鼠肠道血清素通路的影响。在具体目标 2 中，我将确定降低膳食多糖复杂性对胃肠道运动的不同影响，从而改变肠道微生物群。最后，在具体目标 3 中，我将研究微生物代谢物（例如色胺）在调节 5-HT 生物合成和调节胃肠道运动中的作用。我开发了离体（器官浴）和体内（结肠测压）生理技术以及使用 EC 样细胞系的筛选策略，以使用超高性能液体测试代谢物对 5-HT 合成和释放的影响色谱法与质谱联用。我之前在胃肠道生理学方面的研究培训描述了调节胃肠道运动的复杂机制，以及我最近在与宿主功能相关的微生物生态学方面的培训，以及我在胃肠病学方面的临床培训，特别关注胃肠道运动障碍，这些都使我有能力解决这些生物学上合理且临床相关的问题。这个职业发展奖将使我能够将我在神经胃肠病学和微生物生态学这两个截然不同的研究领域的技能结合起来，以解决人类生物学的重要方面。我的导师团队由梅奥诊所的 Gianrico Farrugia 博士和斯坦福大学的 Justin Sonnenburg 博士组成；两者在各自的研究领域都享有国际声誉，并且在培训年轻教师方面拥有成功的记录。 Gianrico Farrugia 博士是神经胃肠病学领域的国际领导者，在阐明 Cajal 间质细胞在胃肠道运动障碍中的作用方面做出了开创性贡献。他对 31 名研究员的指导证明了他长期成功的指导记录。 Sonnenburg 博士是一位具有进化思想的糖生物学家，因其在肠道微生物利用碳水化合物方面的开创性工作以及应用无菌小鼠模型来了解肠道微生物相互作用而享誉国际。他们的专业知识对于这个跨学科项目来说都是无价的。