Discovery of gut microbiota-targeted small molecules: new tools and therapeutics

发现肠道微生物群靶向小分子：新工具和疗法

• 批准号: 7853143
• 负责人: JUSTIN L SONNENBURG
• 金额: $ 240万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7853143
• 关键词: Address; Animal Model; Biology; Communities; Complex; Crohn' s disease; Disease; Eating; Food; Gastrointestinal tract structure; Genomics; Gnotobiotic; Goals; Health; Human; Immune response; Inflammatory Bowel Diseases; Intestines; Investigation; Link; Medicine; Microbe; Microscopic; Modeling; Monitor; Mus; Nature; Nutrient; Obesity; Pathologic; Persons; Play; Research; Research Project Grants; Research Proposals; Role; Structure; Symptoms; Taxon; Testing; Therapeutic; Therapeutic Agents; Ulcerative Colitis; absorption; abstracting; gut microbiota; improved; in vivo; member; public health relevance; small molecule; therapeutic target; tool

DESCRIPTION (Provided by the applicant) Abstract: The composition and function of the human intestinal microbiota is tightly linked to diverse aspects of host biology. Several diseases, including obesity and inflammatory bowel diseases, have been associated with altered microbiota composition. While much research is currently aimed at a genomic definition of the microbiota in both healthy and diseased states, there is a paucity of studies aimed at understanding this community at a mechanistic and ecological level, and how changes in its function and composition directly impact host biology. The question of whether disease-associated alterations in microbiota composition are a cause or symptom of disease is difficult to address due to the current lack of tools that allow us to test the effect of perturbations in microbiota structure and function on the host in a controlled experimental setting. And once we are able to identify a pathologic microbiota definitively, how will we return it to a healthy state? The goal of this research proposal is to identify small molecules that can alter the microbiota at the level of function and composition, providing (i) tools to aid investigation of altered microbiotas in model organisms and (ii) a model pipeline for identifying a new class of therapeutics that targets the intestinal microbiota. The ability to monitor host responses in gnotobiotic mice colonized with a normal human gut microbiota provides an unprecedented capacity to search for compounds that will be useful in human medicine. While others have speculated on the promise of targeting the microbiota to manipulate human health, specific plans of how this would be achieved are lacking. This proposal lays out a plan to screen for compounds that target specific taxa of the microbiota, characterize the targeted microbiota in vivo, and determine the impact on host biology. Public Health Relevance: A dense and complex community of microbes resides within each person's gastrointestinal tract and plays many important roles in our health, including aiding in our absorption of energy and nutrients from the foods we eat. In rare instances, members of this community can promote diseases, such as inflammatory bowel diseases (e.g. Crohn's disease or ulcerative colitis), demonstrating the precarious nature of our relationship with some of our microscopic associates. The goal of this research project is to identify small molecules that can be used as therapeutic agents to intentionally alter the composition and function of disease-associated gut microbes and thereby improve human health.

描述（由申请人提供） 翻译后摘要：人体肠道菌群的组成和功能是紧密相连的宿主生物学的各个方面。包括肥胖和炎症性肠病在内的几种疾病都与微生物群组成的改变有关。虽然目前许多研究都是针对健康和疾病状态下微生物群的基因组定义，但缺乏旨在从机制和生态层面了解该群落的研究，以及其功能和组成的变化如何直接影响宿主生物学。微生物群组成的疾病相关改变是否是疾病的原因或症状的问题很难解决，因为目前缺乏工具，使我们能够在受控的实验环境中测试微生物群结构和功能扰动对宿主的影响。一旦我们能够确定病理微生物群，我们如何将其恢复到健康状态？这项研究提案的目标是确定可以在功能和组成水平上改变微生物群的小分子，提供（i）帮助研究模型生物中改变的微生物群的工具，以及（ii）用于确定靶向肠道微生物群的一类新疗法的模型管道。在用正常人类肠道微生物群定殖的gnotobiotic小鼠中监测宿主反应的能力为寻找可用于人类医学的化合物提供了前所未有的能力。虽然其他人已经推测了针对微生物群来操纵人类健康的承诺，但缺乏如何实现这一目标的具体计划。该提案提出了一项计划，以筛选针对微生物群特定类群的化合物，表征体内目标微生物群，并确定对宿主生物学的影响。 公共卫生相关性：一个密集而复杂的微生物群落存在于每个人的胃肠道内，在我们的健康中起着许多重要作用，包括帮助我们从所吃的食物中吸收能量和营养。在极少数情况下，这个社区的成员可以促进疾病，如炎症性肠病（如克罗恩病或溃疡性结肠炎），这表明我们与我们的一些微观伙伴的关系是不稳定的。该研究项目的目标是确定可用作治疗剂的小分子，以有意改变疾病相关肠道微生物的组成和功能，从而改善人类健康。