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）是 在美国影响超过一百万人的毁灭性疾病。当前的IBD疗法靶向免疫 系统，使患者容易受到机会性感染。因此，发现新的治疗剂 IBD是重要的优先事项。最近的研究发现了肠仅产生的几种代谢产物 在粘膜界面上发挥免疫调节作用的细菌。吲哚酸（IPA）已经出现 作为迄今为止最令人兴奋的化合物，它专门与宿主受体接合并保护 小鼠实验性结肠炎。该化合物由分散数量的严格厌氧肠产生 共生细菌，包括梭状芽胞杆菌。调节IPA级别的策略可以代表 IBD患者的新辅助疗法。尽管对这种化合物具有广泛的兴趣，但特定的生化 与其合成有关的途径完全未知。 我们的长期目标是制定旨在控制肠道代谢产量的新治疗策略 细菌群落。当前建议的目的是揭开IPA的生化途径 在孢子梭菌中的合成，并建立增加肠内产生的方法。具体 目的是：1）确定代谢工程和养分的可用性如何通过 体外梭状芽胞杆菌的梭状芽胞杆菌，以及2）制定生态系统重组的策略以促进治疗 鼠标中的IPA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。使用这些信息，我们将在肠道中组装合成微生物群落 旨在通过IPA产生细菌促进定植。最后，我们将使用这些社区重新编程 小鼠的IPA水平并测试我们是否可以预防实验性结肠炎。这些目标的结果将 代表控制肠道细菌的代谢输出以获得临床益处的第一步。这个知识 将与调节其他微生物代谢物有关人类疾病（例如尿毒症）的代谢物广泛相关， 肝病，心血管疾病和自闭症。 拟议的研究是实现学术职业的指导职业发展计划的一部分 研究宿主 - 微生物相互作用。首席研究员是一名受过博士培训的微生物学家 临床病理。我作为独立科学家的目标是了解微生物对 我们体内的生化清单。该项目的导师是贾斯汀·索南堡（Justin Sonnenburg）博士， 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，细菌遗传学的正式课程和 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 发展独立研究职业的必要环境和经验。