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

描述(由申请人提供) 摘要：人体肠道微生物区系的组成和功能与宿主生物学的各个方面密切相关。包括肥胖和炎症性肠道疾病在内的几种疾病都与微生物区系组成的改变有关。虽然目前许多研究都是针对健康和患病状态下的微生物区系的基因组定义，但旨在从机制和生态水平上理解这个群落，以及其功能和组成的变化如何直接影响宿主生物学的研究很少。微生物区系组成中与疾病相关的变化是否是疾病的原因或症状的问题很难解决，因为目前缺乏工具来允许我们在受控的实验环境中测试微生物区系结构和功能的扰动对宿主的影响。一旦我们能够确定一个病理性微生物区系，我们将如何将其恢复到健康状态？这项研究提案的目标是识别能够在功能和组成水平上改变微生物区系的小分子，提供(1)工具，以帮助研究模式生物体中改变的微生物区系，(2)确定针对肠道微生物区系的新型治疗药物的模型管道。在寄生在正常人类肠道微生物群中的诺生菌小鼠中，监测宿主反应的能力提供了前所未有的能力，以寻找将在人类医学中有用的化合物。虽然其他人猜测有可能以微生物区系为目标来操纵人类健康，但如何实现这一目标还缺乏具体计划。该提案提出了一项计划，以筛选针对微生物区系特定分类群的化合物，在体内表征目标微生物区系，并确定对宿主生物学的影响。 与公共健康相关：一个密集而复杂的微生物群落存在于每个人的胃肠道中，在我们的健康中扮演着许多重要的角色，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，如炎症性肠道疾病(例如克罗恩病或溃疡性结肠炎)，表明我们与一些显微镜同事的关系是不稳定的。这一研究项目的目标是识别可用作治疗剂的小分子，以故意改变与疾病相关的肠道微生物的组成和功能，从而改善人类健康。

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.