Modulation of gut bacteria-derived host metabolites

肠道细菌衍生的宿主代谢物的调节

• 批准号: 9453251
• 负责人: Dylan Dodd
• 金额: $ 13.69万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-08 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9453251
• 关键词: Acids; Adverse effects; Affect; Amino Acids; Anaerobic Bacteria; Animal Model; Autistic Disorder; Automobile Driving; Bacteria; Biochemical; Biochemical Pathway; Biology; Carbohydrates; Carbon Dioxide; Cardiovascular Diseases; Cells; Clinical; Clinical Pathology; Clostridium; Colitis; Communities; Complex; Crohn' s disease; Dangerousness; Data; Development Plans; Diet; Disease; Doctor of Philosophy; Ecology; Ecosystem; Electron Transport; Elements; Enterocytes; Environment; Equipment and supply inventories; Genes; Genetic; Gnotobiotic; Goals; Healthcare Industry; Human; Hydrogenase; Immune Targeting; Immune system; In Vitro; Individual; Indomethacin; Inflammatory Bowel Diseases; Knowledge; Liver diseases; Mentors; Metabolic; Metabolic Diseases; Metabolism; Methods; Microbial Physiology; Mucosal Immune System; Mucous Membrane; Mus; Mutation; Nutrient; Opportunistic Infections; Organism; Outcome; Output; Patients; Phenotype; Population; Predisposition; Principal Investigator; Production; Proteins; Research; Role; Scientist; Serum; Source; System; Testing; Therapeutic; Tight Junctions; Training; Tryptamines; Tryptophan; Tryptophan Metabolism Pathway; Ulcerative Colitis; Uremia; Work; bacterial community; bacterial genetics; bacterial metabolism; career; career development; commensal bacteria; design; dietary manipulation; experience; experimental study; fortification; gut bacteria; gut microbes; gut microbiome; gut microbiota; host-microbe interactions; human disease; immunoregulation; improved; indoleacetic acid; interest; metabolic engineering; microbial; microbial community; microbiome; microbiota; microbiota metabolites; mouse model; mutant; novel strategies; novel therapeutic intervention; novel therapeutics; occludin; pregnane X receptor; receptor; small molecule; symposium; targeted treatment; tool

Project Summary/Abstract Crohn's disease and Ulcerative Colitis, collectively referred to as inflammatory bowel disease (IBD) are devastating diseases that affect over one million people in the US. Current IBD therapies target the immune system, leaving patients susceptible to opportunistic infections. Therefore, the discovery of new therapeutics for IBD is an important priority. Recent studies have discovered several metabolites produced exclusively by gut bacteria that exert immunomodulatory effects at the mucosal interface. Indolepropionic acid (IPA) has emerged as the most exciting compound thus far in that it specifically engages host receptors and protects from experimental colitis in mice. This compound is produced by a discrete number of strictly anaerobic gut commensal bacteria including Clostridium sporogenes. Strategies to modulate levels of IPA could represent a new adjunct therapy for IBD patients. Despite the broad interest in this compound, the specific biochemical pathways involved in its synthesis are entirely unknown. Our long-term objective is to develop new therapeutic strategies aimed at controlling the metabolic output of gut bacterial communities. The goal of the current proposal is to unravel the biochemical pathway for IPA synthesis in C. sporogenes and to establish methods for increasing its production within the gut. The specific aims are to: 1) Determine how metabolic engineering and nutrient availability influence IPA production by Clostridium sporogenes in vitro, and 2) Develop strategies for ecosystem restructuring to promote therapeutic IPA production in the mouse gut. We will leverage newly developed genetic tools to understand how and why gut bacteria produce IPA. Using this information, we will assemble synthetic microbial communities in the gut designed to promote colonization by IPA producing bacteria. Finally, we will use these communities to reprogram IPA levels in mice and test whether we can protect against experimental colitis. The outcomes of these aims will represent the first steps toward controlling the metabolic output of gut bacteria for clinical benefit. This knowledge will be broadly relevant to modulating other microbial metabolites implicated in human diseases such as uremia, liver disease, cardiovascular disease, and autism. The proposed research is part of a mentored career development plan to achieve an academic career studying host-microbe interactions. The principal investigator is a PhD-trained microbiologist with training in Clinical Pathology. My goal as an independent scientist is to understand the microbial contribution to the biochemical inventory within our body. The mentor for this project is Dr. Justin Sonnenburg, a pioneer in studying the contribution of gut bacteria to host biology. The career development plan includes a research advisory board, a career development committee, seminars in microbial physiology, formal coursework in bacterial genetics and ecology, and presentations at microbiome and human metabolic conferences. These activities will provide the necessary environment and experiences for developing an independent research career.

项目摘要/摘要 克罗恩病和溃疡性结肠炎，统称为炎症性肠病(IBD) 影响美国100多万人的毁灭性疾病。目前IBD的治疗针对的是免疫 系统，使患者容易受到机会性感染。因此，新的治疗方法的发现 IBD是一个重要的优先事项。最近的研究发现了几种完全由肠道产生的代谢物 在粘膜界面发挥免疫调节作用的细菌。吲哚丙酸(IPA)已经出现 作为迄今为止最令人兴奋的化合物，因为它专门与宿主受体结合，并保护 小鼠实验性结肠炎。这种化合物是由离散数量的严格厌氧肠道产生的。 共生细菌包括产孢子梭菌。调节IPA水平的策略可能代表着一种 IBD患者的新辅助治疗。尽管人们对这种化合物有广泛的兴趣，但特定的生化物质 参与其合成的途径是完全未知的。 我们的长期目标是开发新的治疗策略，旨在控制肠道的代谢输出 细菌群落。当前提案的目标是解开IPA的生化途径。 在产孢子链霉菌中合成，并建立提高其在肠道内产量的方法。具体的 目的是：1)确定代谢工程和养分供应如何通过以下方式影响IPA生产 产孢子梭菌的体外培养，以及2)开发生态系统重建策略以促进治疗 IPA在小鼠肠道中的产生。我们将利用新开发的遗传工具来了解如何以及为什么 肠道细菌产生IPA。利用这些信息，我们将在肠道中组装合成微生物群落 旨在促进产生IPA的细菌的定居。最后，我们将使用这些社区重新编程 在小鼠体内检测IPA水平，并测试我们能否预防实验性结肠炎。这些目标的结果将是 代表了控制肠道细菌代谢输出的第一步，从而使临床受益。这一知识 将广泛地与调节与尿毒症等人类疾病有关的其他微生物代谢物有关， 肝脏疾病、心血管疾病和自闭症。 这项拟议的研究是为实现学术生涯而指导的职业发展计划的一部分。 研究宿主与微生物的相互作用。首席调查员是一位受过博士培训的微生物学家，受过 临床病理学。作为一名独立科学家，我的目标是了解微生物对 我们体内的生化库存。这个项目的导师是贾斯汀·索南伯格博士，他是研究的先驱 肠道细菌对宿主生物学的贡献。职业发展计划包括一个研究顾问委员会， 职业发展委员会，微生物生理学研讨会，细菌遗传学正式课程和 生态学，以及在微生物组和人类代谢会议上的演讲。这些活动将提供 发展独立研究事业所需的环境和经验。