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.

项目概要/摘要 克罗恩病和溃疡性结肠炎统称为炎症性肠病 (IBD) 影响美国超过一百万人的毁灭性疾病。目前的 IBD 疗法主要针对免疫 系统，使患者容易受到机会性感染。因此，新疗法的发现 IBD 是一个重要的优先事项。最近的研究发现了几种仅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）问世 作为迄今为止最令人兴奋的化合物，因为它特异性地与宿主受体结合并防止 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，包括产孢梭菌。调节 IPA 水平的策略可能代表 IBD 患者的新辅助治疗。尽管人们对该化合物产生了广泛的兴趣，但其特定的生化特性 其合成所涉及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 产孢梭菌的合成并建立增加其在肠道内产量的方法。具体的 目标是： 1) 通过以下方式确定代谢工程和营养可用性如何影响 IPA 生产： 体外产孢梭菌，2) 制定生态系统重建策略以促进治疗 小鼠肠道中 IPA 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 的细菌定植。最后，我们将利用这些社区来重新编程 小鼠中的 IPA 水平并测试我们是否可以预防实验性结肠炎。这些目标的成果将 代表了控制肠道细菌代谢输出以获得临床益处的第一步。这些知识 将与调节与人类疾病（例如尿毒症）有关的其他微生物代谢物广泛相关 肝脏疾病、心血管疾病和自闭症。 拟议的研究是实现学术生涯的指导职业发展计划的一部分 研究宿主-微生物相互作用。主要研究者是一位受过博士学位的微生物学家，接受过以下方面的培训： 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。该项目的导师是 Justin Sonnenburg 博士，他是研究领域的先驱。 肠道细菌对宿主生物学的贡献。职业发展计划包括研究顾问委员会、 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以及 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。