Engineering Transmissible Health

项目总结/摘要（总体） 该计划项目资助的总体研究目标是发展知识基础和实验 和工程学传播健康的理论框架。自从细菌学说建立以来， 在19世纪末，一个主要的公共卫生目标是限制致病性疾病的传播。 微生物相比之下，通常居住在宿主体内的微生物越来越重视它们的健康- 促进作用，包括促进正常发育，建立适当的免疫基调， 防止病原体入侵。常驻微生物作为治疗性益生菌的潜力 有很大的希望，但目前的益生菌设计策略只集中在管理益生菌， 个别主机，忽略了传播的可能性，除非是需要预防的威胁。 然而，正如病原体一样，个体之间和社会内部的肠道微生物群的传播， 这可能会发生，甚至可能有助于与社会联系相关的健康益处。在 与此相反，微生物隔离是现代化社会的一个显著特征，现代化社会正在经历令人担忧的 自身免疫性疾病和其他微生物群失调疾病的增加。之间的相互作用 宿主内外的微生物及其环境，以及这些微生物 相互作用塑造了传播、传播和宿主健康，仍然不透明，阻碍了社区的设计， 水平的战略，以利用我们的肠道微生物群的有益潜力。我们建议探讨 宿主相关细菌和细菌群落的宿主间传播参数， 用于治疗目的。我们认为，常驻细菌的特性可以调整到 促进个人和人口的健康。特别是，我们建议设计智能 益生菌可以感知并治疗炎症。在局部水平上，在个体宿主的肠道中，这些 微生物将被工程化以抑制有利于促炎菌株的宿主环境的特征。 在种群水平上，这些微生物将被改造成成功地在宿主之间传播和定居， 并将限制促炎性微生物群成员的传播，有效地赋予牛群 对肠道炎症的免疫力我们使用斑马鱼和它们的肠道微生物群作为一种可访问的 监测和操纵宿主微生物系统的实验平台将提供重要的新技术， 如果我们希望使用类似的智能益生菌策略来改变其他多物种， 系统，如人类。

PROJECT SUMMARY/ABSTRACT (OVERALL) The overall research goal of this Program Project Grant is to develop the knowledge base and the experimental and theoretical framework for engineering transmissible health. Since the establishment of the germ theory of disease in the late 1800s, a major public health goal has been to limit the transmission of disease-causing microbes. Microbes normally resident in hosts, in contrast, are increasingly appreciated for their health- promoting roles, which include fostering normal development, establishing appropriate immunological tone, and preventing invasion of pathogens. The potential for resident microbes to be used as therapeutic probiotics holds great promise, but current probiotic design strategies focus exclusively on administering probiotics to individual hosts, neglecting the possibility of transmission except as a threat that needs to be prevented. However, just as for pathogens, transmission of commensal microbiota between individuals and within social groups is likely to occur and may even contribute to the health benefits associated with social connectivity. In contrast, microbial isolation is a defining feature of modernized societies, which are experiencing alarming increases in autoimmune disorders and other diseases of microbiota dysbiosis. The interactions between commensal microbes and their environments both within and outside of hosts, and the ways in which these interactions shape dispersal, transmission, and host health, remain opaque, preventing design of community- level strategies to exploit the beneficial potential of our intestinal microbiota. We propose to explore the parameters of inter-host transmission of host-associated bacteria and bacterial communities that could be harnessed for therapeutic purposes. We imagine that the properties of resident bacteria can be tuned to promote health on both an individual and a population level. In particular, we propose to design smart probiotics that would sense and treat inflammation. At a local level, in individual host intestines, these microbes would be engineered to inhibit features of the host environment that favor pro-inflammatory strains. At a population level, these microbes would be engineered to successfully spread between and colonize hosts, and would limit the transmission of pro-inflammatory microbiota members, effectively conferring herd immunity to intestinal inflammation. Our use of zebrafish and their commensal microbiota as an accessible experimental platform for monitoring and manipulating host-microbe systems will provide important new insights that are crucial if we hope to use similar smart probiotic strategies to transform other multi-species systems, such as humans.