Gut microbiome-mediated small-molecule signaling and resistance to invading microorganisms

霍乱弧菌引起霍乱，这是一种影响数百万人的毁灭性腹泻疾病 每年在全球范围内。霍乱在许多卫生条件差的地区流行， 在死亡率和疾病方面的巨大负担，往往落在最无力负担的国家身上。 尽管对霍乱弧菌如何引起疾病的理解有所进展，但仍然缺乏预防霍乱弧菌的机制。 霍乱的传播。我们以前的研究发现，肠道微生物组的特定结构，或 所有人类胃肠道中的常驻细菌群落介导对霍乱弧菌的易感性 感染我们推测，个体差异在肠道微生物可能是一个危险因素霍乱。 该提案旨在确定肠道微生物组的结构与肠道微生物的能力之间的关系。 诉霍乱菌定植并引起疾病。病原体-微生物组相互作用的研究受到缺乏 合适的动物模型，一个问题，这是特别严重的霍乱研究，作为行为的 病原体在许多动物模型和人类之间是不同的，而其他模型受到成本和 空房的我们已经开始采用一种流行的、容易获得的霍乱弧菌动物模型 发病机制，乳鼠模型，允许建立人类微生物组之前， 感染使用这些和gnotobiotic成人殖民模型，我们将确定如何人类肠道 微生物组驱使肠道的生物化学环境进入病原体抗性或易感状态。这些 机制可能决定成年肠道微生物群落的建立和组成， 确定个性化的传染病风险。这些研究将提高模型的可及性， 研究肠道微生物组如何影响肠道细菌感染，并确定预防的新目标 以及肠道微生物组的治疗性操作以对抗霍乱弧菌。

The bacterium Vibrio cholerae causes cholera, a devastating diarrhea disease that affects millions of people worldwide each year. Cholera is endemic in many areas that suffer from poor sanitation, and imposes an immense burden in terms of mortality and illness, often on those countries least able to afford it. Despite advances in understanding how V. cholerae causes disease, there is still a lack of mechanisms to prevent the spread of cholera. Our previous studies have found that specific configurations of the gut microbiome, or the community of resident bacteria in the gastrointestinal tract of all humans, mediate susceptibility to V. cholerae infection. We hypothesize that individual differences in commensal microbes may be a risk factor for cholera. This proposal aims to determine the relationship between the structure of the gut microbiome and the ability of V. cholerae to colonize and cause disease. Studies of pathogen-microbiome interactions are limited by a lack of suitable animal models, a problem that is particularly acute for cholera research, as the behavior of the pathogen differs between many animal models and humans, while other models are limited by cost and availability. We have begun to adapt a popular and readily accessible animal model of V. cholerae pathogenesis, the suckling mouse model, to allow for the establishment of human microbiomes prior to infection. Using these and gnotobiotic adult colonization models, we will determine how human gut microbiomes drive the biochemical milieu of the gut into pathogen-resistant or susceptible states. These mechanisms may determine the establishment and composition of the adult gut microbial community, and thus determine personalized infectious disease risk. These studies will improve the accessibility of models for studying how gut microbiomes influence bacterial infections of the gut, and identify new targets for prophylactic and therapeutic manipulations of the gut microbiome to combat V. cholerae.