Modulation of gut bacteria-derived host metabolites

项目总结/摘要 克罗恩病和溃疡性结肠炎，统称为炎症性肠病（IBD）， 在美国有超过100万人感染了这些毁灭性的疾病。目前的IBD治疗靶向免疫 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代谢产物专门由肠道产生 在粘膜界面发挥免疫调节作用的细菌。吲哚丙酸（IPA） 作为迄今为止最令人兴奋的化合物，它特异性地与宿主受体结合， 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 包括生孢梭菌在内的微生物。调整IPA水平的战略可能是一种 IBD患者的新辅助治疗。尽管对这种化合物有广泛的兴趣， 参与其合成的途径完全未知。 我们的长期目标是开发新的治疗策略，旨在控制肠道代谢输出 细菌群落当前提案的目标是解开IPA的生物化学途径 C.产孢菌的方法，并建立用于增加其在肠道内的产量的方法。具体 目的是：1）确定代谢工程和养分供应如何影响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的细菌的定植。最后，我们将利用这些社区重新编程 IPA水平的小鼠和测试我们是否可以防止实验性结肠炎。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 将广泛地与调节与人类疾病如尿毒症有关的其它微生物代谢物有关， 肝病心血管疾病和自闭症 拟议的研究是一个指导职业发展计划的一部分，以实现学术生涯 研究宿主与微生物的相互作用主要研究者是一位经过博士培训的微生物学家， 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 我们体内的生化物质这个项目的导师是Justin Sonnenburg博士，他是研究 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咨询委员会， 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， 生态学，并在微生物组和人类代谢会议上发表演讲。这些活动将提供 发展独立研究事业所需的环境和经验。

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.