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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：
8617551
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/8617551
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 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 Oligosaccharides Organ Pathway interactions Performance Physiological Play Probiotics Production Regulation Research Research Training Ribosomal RNA Role Seminal Sensory 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 gastrointestinal gut microbiota in vivo microbial microorganism microorganism interaction motility disorder mouse model next generation sequencing paracrine public health relevance receptor research study screening skills sound

项目摘要

Abstract 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 gut microbiota. Finally, in specific aim 3, I will investigate the role of microbial metabolites such as 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 successful 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.

摘要