Microbiota-based probiotics to treat inborn errors in metabolism

基于微生物群的益生菌可治疗先天性代谢缺陷

• 批准号: 10574622
• 负责人: Dylan Dodd
• 金额: $ 58.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-16 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574622
• 关键词: Alternative Therapies; Amino Acids; Bacteria; Biochemical; Biochemistry; Blood; Chemicals; Classical phenylketonuria; Defect; Development; Diet; Distal; Drug Metabolic Detoxication; Engineered Probiotics; Enzymes; Foundations; Future; Gastrointestinal tract structure; Gene Cluster; Gene Combinations; Gene Expression Profiling; Genes; Genetic; Genetic Diseases; Gnotobiotic; Goals; Hereditary Disease; Home; Human; Human Genetics; Human body; Immune; In Vitro; Individual; Injectable; Investigation; Libraries; Measures; Mediating; Metabolic; Metabolic Control; Metabolic Pathway; Metabolism; Microbe; Modeling; Mus; Mutation; Oral Administration; Organ; Pathway interactions; Patients; Peptides; Phenylalanine; Phenylalanine Metabolism Pathway; Phenylketonurias; Plasma; Poison; Polysaccharides; Probiotics; Regulatory Pathway; Resources; Role; Running; Sampling; Small Intestines; Testing; Work; bacterial genetics; beneficial microorganism; gut bacteria; gut microbes; gut microbiota; host microbiota; insight; member; metabolomics; microbial; microbiome; microbiota; mouse model; novel; novel strategies; public health relevance; side effect; stable isotope; transcriptome sequencing; transcriptomics; unpublished works

Project Summary/Abstract The human gut is a metabolic organ where anaerobic microbial pathways run at high capacity, expanding the biochemical landscape of the human body. Exploiting members of the gut microbiota and the metabolic pathways they encode represents an exciting new strategy to treat genetically encoded biochemical defects in humans such as Phenylketonuria. There are three reasons why identifying new microbiota probiotics should be a priority: 1) Gut microbes represent an important yet untapped resource for new metabolic pathways that influence human biochemistry. 2) Microbiota pathways are present in healthy individuals, and their metabolic end products are unlikely to be toxic to humans. 3) Native, non-genetically modified strains are likely to have a straightforward regulatory pathway for use in humans. While this proposal is focused on identifying microbes and pathways to reduce blood phenylalanine levels to treat phenylketonuria, our long-term goal is to lay the foundation for an entirely new approach to treat inborn errors in metabolism: controlling metabolic circuits via the gut microbiota. Our proposal is organized into the following two aims: In Aim 1, we will use gene cluster searches, transcriptomics, genetics, and metabolomics to identify and characterize anaerobic pathways for phenylalanine metabolism by gut bacteria. In Aim 2, we will assess the ability of microbial pathways to reduce plasma Phe levels in a gnotobiotic mouse model of phenylketonuria (PKU). Our results will not only provide new insights into how the microbiome expands the biochemical landscape of the host but will also lay the groundwork for a new approach to treating inborn errors in metabolism.

项目总结/摘要 人类肠道是一个代谢器官，其中厌氧微生物途径以高容量运行，扩大了肠道的生物量。 人体的生化景观。利用肠道微生物群和代谢 它们编码的途径代表了一种令人兴奋的新策略，可以治疗遗传编码的生化缺陷， 人类如苯丙酮尿症。有三个原因表明，识别新的微生物群益生菌应该 优先考虑：1）肠道微生物是新代谢途径的重要但尚未开发的资源， 影响人类生物化学。2)微生物群途径存在于健康个体中，其代谢 最终产品不太可能对人类有毒。3)天然的、非转基因的菌株可能具有 用于人类的直接调控途径。虽然这项提案的重点是识别微生物 以及降低血液苯丙氨酸水平以治疗苯丙酮尿症的途径，我们的长期目标是奠定 一个全新的方法来治疗先天性代谢缺陷的基础：通过 肠道菌群。我们的建议分为以下两个目标：在目标1中，我们将使用基因簇 搜索，转录组学，遗传学和代谢组学，以确定和表征厌氧途径， 苯丙氨酸代谢的肠道细菌。在目标2中，我们将评估微生物途径减少 苯丙酮尿症（PKU）的无菌小鼠模型中的血浆Phe水平。我们的研究结果不仅能提供 关于微生物组如何扩大宿主的生化景观的新见解，但也将奠定 为治疗先天性代谢缺陷的新方法奠定基础。