Engineering Transmissible Health

项目摘要/摘要(总体) 本计划项目资助的总体研究目标是开发知识库和实验 和工程可传播健康的理论框架。自细菌理论建立以来， 19世纪末，一个主要的公共卫生目标是限制致病的传播 微生物。相比之下，通常居住在宿主中的微生物越来越受到重视，因为它们的健康-- 促进作用，包括促进正常发育，建立适当的免疫基调， 和防止病原体的入侵。驻留微生物作为治疗益生菌的潜力 拥有巨大的希望，但目前的益生菌设计策略仅专注于将益生菌用于 个别主机，忽略传播的可能性，除非是需要预防的威胁。 然而，就像病原体一样，共生微生物群在个人之间和社会内部的传播 群体很可能发生，甚至可能有助于与社会联系相关的健康益处。在……里面 相比之下，微生物隔离是正在经历令人震惊的现代化社会的一个决定性特征 自身免疫性疾病和其他微生物区系失调疾病的增加。两国之间的相互作用 寄主内外的共生微生物及其环境，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- 水平战略，以开发我们的肠道微生物区系的有益潜力。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可能是 出于治疗目的而佩带的。我们设想，寄生细菌的特性可以被调节到 在个人和人群层面上促进健康。特别是，我们建议设计智能 可以感知和治疗炎症的益生菌。在地方层面上，在单个宿主肠道中，这些 微生物将被改造成抑制宿主环境中有利于促炎菌株的特征。 在种群水平上，这些微生物将被改造成在宿主之间成功传播并定居， 并将限制促炎微生物区系成员的传播，有效地赋予牛群 对肠道炎症免疫。我们利用斑马鱼及其共生微生物群作为可获得的 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造其他多物种，洞察力是至关重要的 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.