MECHANISMS OF ALTERATION OF GASTROINTESTINAL MOTILITY BY GUT MICROBIOTA

肠道菌群改变胃肠动力的机制

• 批准号: 8815306
• 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
• 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/8815306
• 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; in vivo; microbial; microorganism; microorganism interaction; motility disorder; mouse model; next generation sequencing; paracrine; receptor; research study; screening; skills; sound

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）：人类肠道含有数万亿微生物，这些微生物通过从我们饮食中其他不可消化的成分中收获营养物质/能量而使宿主受益。值得注意的是，微生物与其人类宿主之间的复杂信号传导以及对正常生理功能的影响仍然知之甚少。胃肠道（GI）运动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GI运动和肠道微生物群之间的关系。5-羟色胺（5-hydroxytryptamine，5- HT）是肠嗜铬细胞（EC）分泌的一种重要的旁分泌信使，参与胃肠运动的运动和感觉传导。我的初步研究强烈表明，肠道β-胡萝卜素能途径是肠道微生物群的靶点。我的总体假设是，肠道微生物群通过释放特定代谢物（包括色胺）以饮食依赖性方式改变GI运动，这些代谢物影响肠道激素途径。我将使用无菌（GF），gnotobiotic（定义/简化的微生物群）和人源化（由人类来源的微生物定殖的前GF）小鼠来解决人类肠道微生物对小鼠模型中宿主的生理影响。由于GF小鼠完全缺乏微生物群，因此它们可以被确定的细菌群落定殖以产生不同的定殖状态。在具体目标1中，我将探索微生物群对GF和人源化小鼠中的肠道孕酮能途径的影响。在具体目标2中，我将确定降低膳食多糖的复杂性对GI运动的不同影响，从而改变gu微生物群。最后，在具体目标3中，我将研究微生物代谢产物如色胺在调节5-HT生物合成和调节GI运动中的作用。我已经开发了体外（器官浴）和体内（结肠测压）的生理技术，以及筛选策略，使用EC样细胞系测试代谢物的合成和释放的5-HT的影响，使用超高效液相色谱法结合质谱。我以前在GI生理学方面的研究训练描绘了调节GI运动的复杂机制，以及我最近在微生物生态学方面的训练，因为它与宿主功能有关，沿着我在胃肠病学方面的临床训练，特别关注GI运动障碍，使我有能力解决这些生物学上合理和临床相关的问题。这个职业发展奖将使我能够联合收割机结合我在两个非常不同的研究领域，神经胃肠病学和微生物生态学的技能，以解决人类生物学的重要方面。我的导师团队由马约诊所的Gianrico Farrugia博士和斯坦福大学的Justin Sonnenburg博士组成;他们都在各自的研究领域享有国际声誉，并在培训年轻教师方面取得了成功。Gianrico Farrugia博士是神经胃肠病学的国际领导者，在阐明Cajal间质细胞在GI运动障碍中的作用方面做出了开创性的贡献。他长期以来成功指导的记录可以通过指导31名研究员来证明。Sonnenburg博士是一位具有进化思想的糖生物学家，因其在肠道微生物碳水化合物利用方面的开创性工作以及应用gnotobiotic小鼠模型来了解肠道中微生物的相互作用而享誉国际。他们的专业知识对这个跨学科项目将是无价的。