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

基本信息

批准号：
10365689
负责人：
Dylan Dodd
金额：
$ 58.79万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
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/10365689
关键词：
Alternative Therapies Amino Acids Anaerobic Bacteria Bacteria Biochemical Biochemistry Blood Chemicals Classical phenylketonuria Defect Development Diet Distal 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 Pathway Metabolism Microbe Modeling Mus Mutation Oral 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 base 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novel novel strategies public health relevance side effect stable isotope transcriptome sequencing transcriptomics unpublished works

项目摘要

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.

项目摘要/摘要人肠道是一种代谢器官人体的生化景观。利用肠道微生物群和代谢成员它们编码的途径代表了一种令人兴奋的新策略，用于处理遗传编码的生化缺陷人类，例如苯酮尿症。识别新的微生物益生菌应识别的原因有三个原因优先：1）肠道微生物代表了新代谢途径的重要但尚未开发的资源影响人类的生物化学。 2）健康个体及其代谢中存在菌群途径最终产品不太可能对人类有毒。 3）天然，非遗传修饰的菌株可能具有直接用于人类使用的调节途径。虽然该提案的重点是识别微生物和降低血液苯丙氨酸水平以治疗苯酮尿症的途径，我们的长期目标是放置为治疗新陈代谢中的天生错误的全新方法的基础：通过肠道菌群。我们的建议组织为以下两个目标：在AIM 1中，我们将使用基因群集搜索，转录组学，遗传学和代谢组学以识别和表征厌氧途径肠道细菌的苯丙氨酸代谢。在AIM 2中，我们将评估微生物途径减少的能力苯酮尿症（PKU）的gnotobiotic小鼠模型中的血浆PHE水平。我们的结果不仅会提供关于微生物组如何扩展宿主生化景观的新见解，但也将放置一种新方法来治疗新陈代谢错误的基础。