CAREER: Engineering Bacterial two Component Sensors to Study the Dynamics of Anaerobic Gut Terminal Electron Acceptors and Microbial Dysbiosis

人类的肠道孕育着大约100万亿个细菌的生长。作为回报，这些细菌中的大多数从饮食中获得额外的能量，并保护自己免受感染。然而，一系列因素可以触发肠道免疫系统激活炎症反应，并产生抗微生物分子，这些分子会损害有益细菌，同时导致非有益细菌的大量繁殖。肠道微生物群的重要性已被广泛接受，然而，饮食和细菌组成的波动如何影响免疫系统以及“好”细菌如何保持健康状态的理解在很大程度上仍然未知。一个主要的限制是缺乏非侵入性测量肠道免疫系统产生的分子的技术。研究人员试图通过设计无害的、可口服的“传感器细菌”来克服这一限制，这种细菌可以特异性地检测这些分子，并通过表达一种报告基因（例如，这可能导致细菌的颜色变化）做出反应，这种报告基因可以在通过肠道后进行评估。研究者将使用计算和实验技术的结合来评估这些传感器细菌探测影响肠道微生物群的分子相互作用的能力。这项工作支持了nsf的使命，即在分子水平上理解一个基本的、复杂的、鲜为人知的生物过程。它也可能提供下游的机会，以减少或消除一些流行的肠道疾病。计划中的更广泛的影响活动强调学生教育和公众宣传，以展示基础研究如何对社会产生深远的有益影响。哺乳动物的肠道维持着一个庞大而多样的细菌群落，发挥着许多有益的功能。所谓的肠道微生物群主要由消化宿主和饮食来源的低聚糖的厌氧发酵罐组成。然而，少数成员产生的代谢物可诱发宿主炎症反应，使局部环境富含活性氧，导致氧化代谢物积累。在某些条件下，这些代谢物可以被兼性厌氧菌呼吸，导致其他罕见的肠道成员大量繁殖。其后果可能是长期的微生物失衡或生态失调。氧化代谢物生产和消耗的时间动态之间的确切联系导致不希望的微生物繁殖仍然知之甚少。该项目使用系统和合成生物学方法来设计细菌来感知肠道中的生理相关信号。传感器细菌将报告肠道微生物群在其短暂通过肠道时的状态，提供对肠道生理学和动力学的分子水平理解。

The human intestine (gut) nurtures the growth of approximately 100 trillion bacteria. In return, most of these bacteria harvest extra energy from the diet and protect against infection. However, a range of factors can trigger the gut immune system to activate an inflammation response and produce anti-microbial molecules that harm beneficial bacteria while leading the a bloom of non-beneficial bacterial. It has become widely accepted the that gut microbiome is important, nevertheless, the understanding how the fluctuations in diet and bacterial composition affect the immune system and how the 'good' bacteria maintain a healthy state remains largely unknown. A major limitation is a lack of technologies for non-invasively measuring the molecules produced by the gut immune system. The investigator seeks to overcome this limitation by engineering harmless, orally ingestible 'sensor bacteria' that specifically detect these molecules and respond by expression of a reporter (that might give rise to a color change of the bacteria, for example) that can be evaluated after passage through the gut. The investigator will use a combination of computational and experimental techniques to evaluate the ability of these sensor bacteria to probe molecular interactions that impact the gut microbiome. This work supports NSFs mission to understand a fundamental complex and poorly understood biological processes at a molecular level. It may also offer down-stream opportunities to reduce or eliminate some of the prevalent bowel diseases. The planned broader impact activities emphasize student education and public outreach to demonstrate how basic research can have profound beneficial impacts on society.The mammalian gut maintains a large and diverse community of bacteria that performs numerous beneficial functions. The so-called gut microbiota is largely comprised of anaerobic fermenters that digest host- and diet-derived oligosaccharides. However, metabolites produced by minority members can induce a host inflammatory response, which enriches the local environment with reactive oxygen species, leading to the accumulation of oxidized metabolites. These metabolites can be respired by facultative anaerobes leading to blooms of otherwise rare gut members, under certain conditions. The consequence can be long-term microbial imbalance, or dysbiosis. The precise connection between the temporal dynamics of oxidized metabolite production and consumption leading to undesirable microbial blooms remains poorly understood. This project uses a systems and synthetic biology approach to engineer bacteria to sense physiologically-relevant signals in the gut. The sensor bacteria would report on the state of the gut microbiome during its transient passage through the gut, providing a molecular-level understanding of gut physiology and dynamics.