Engineering microbiota to optimize population-level health

项目摘要/摘要(项目3) 越来越多的人类疾病，包括炎症性肠病(IBD)、代谢综合征、 和糖尿病，已经被认为与居民微生物群落的紊乱有关。在这些疾病中，没有一个 感染性有机体是牵连的，但却是异常的，也称为非生物微生物群落，通常 以促炎类群过多和抗炎类群代表性不足为特征的 炎症性类群，与引起疾病症状有关。越来越多的证据表明，亲- 发炎的微生物区系可以自我延续，因为发炎的宿主环境选择了微生物 在使炎症持续存在的条件下促进并茁壮成长。我们假设PRO的传播- 炎症性微生物区系成员增加了发生疾病的可能性，这种传播是 由于缺乏通常会抑制慢性炎症宿主的抗炎类群而得到加强 环境。我们假设，可传播的抗炎菌株不仅对 减轻单个宿主的炎症，但传播对促炎菌株的耐药性，从而 创造对致病菌株的群体免疫力，类似于疫苗接种。我们建议设计微生物区系 作为“智能益生菌”发挥作用的成员，在调节和局部的 时尚。我们将决定如何调整这些智能益生菌的治疗和传播特性 优化他们治疗单个宿主炎症的能力，并在 宿主产生保护，防止促炎菌株在人口规模上传播。这些 实验将确立工程传播健康的设计原则。

PROJECT SUMMARY/ABSTRACT (PROJECT 3) Increasing numbers of human ailments, including inflammatory bowel disease (IBD), metabolic syndrome, and diabetes, have been linked to disturbances in resident microbial communities. In these diseases, no single infectious organism is implicated, but instead abnormal, also called dysbiotic microbial communities, often characterized by an overabundance of pro-inflammatory taxa and an underrepresentation of anti- inflammatory taxa, are implicated in causing disease symptoms. Mounting evidence suggests that pro- inflammatory microbiota can be self-perpetuating because the inflamed host environment selects for microbes that promote and thrive on conditions that perpetuate inflammation. We hypothesize that transmission of pro- inflammatory microbiota members increases the likelihood of developing disease, and that this transmission is enhanced by the absence of anti-inflammatory taxa that would normally curtail a chronically inflamed host environment. We hypothesize that transmissible anti-inflammatory strains would be useful not only for alleviating inflammation in individual hosts, but for spreading resistance to pro-inflammatory strains, thereby creating herd immunity to disease-causing strains similar to vaccination. We propose to engineer microbiota members that function as “smart probiotics” to sense and alleviate host inflammation in a modulated and local fashion. We will determine how to tune the therapeutic and transmission properties of these smart probiotics to optimize their capacity to treat inflammation in individual hosts and to disseminate sufficiently between hosts to generate protection against the spread of pro-inflammatory strains on a population scale. These experiments will establish the design principles for engineering transmissible health.