Diet transformation by the microbiome and its impact on bacterial infection

项目摘要 食物中含有大量的生物活性小分子， 胃肠道中的微生物。据报道，微生物组代谢在饮食中 然而，代谢膳食小分子的微生物酶可以是高浓度的。 底物特异性，这些活性在个体之间可以有很大的差异。饮食对 微生物组也已建立。因此，肠道微生物组很可能是一个人的决定性因素， 饮食代谢物暴露，与感染、癌症、炎症性疾病、心血管疾病 疾病和其他受饮食影响的疾病。微生物和饮食在感染的背景下直接交叉 由食源性肠道病原体沙门氏菌血清型鼠伤寒和弯曲杆菌引起 空肠，每年造成数千万例食源性疾病，主要是通过食用 鸡肉和其他家禽产品。了解这些相互作用的进展将改变我们的能力， 管理这一重大公共卫生挑战，使人类和我们的食物链， 可以直接开处方。该提案将检验以下假设： 肠道微生物群，以及饮食化合物对微生物群的破坏，决定了这些微生物群的功能。 调节定殖抗性（微生物组对病原体的排斥），病原体生长， 和毒力。在目标1中，我们将生成代谢的系统图 来自两个人类队列的100多种肠道微生物和微生物组的100多种膳食化合物， 鸡在社区，物种，酶和代谢产物的水平。在目标2中，我们将确定如何 这些化合物调节沙门氏菌的无菌小鼠和无菌鸡模型中的定殖抗性。 Typhimurium和C.空肠感染在目标3中，我们将测量膳食化合物及其微生物 代谢物在体外影响病原体生长和毒力，在来源于肠类器官的2D单层中， 和非生物性动物。总之，这些研究将确定饮食和饮食之间的相互作用， 微生物组决定了食源性感染的结果，这是一个重大的公共卫生风险。

Project Summary Food contains a vast collection of bioactive small molecules that encounter enormous populations of commensal microbes in the gastrointestinal tract. Microbiome metabolism has been reported across dietary compound classes; however, the microbial enzymes that metabolize dietary small molecules can be highly substrate specific and these activities can vary widely between individuals. The impact of diet on the microbiome is also well established. Thus, the gut microbiome is likely a determining factor in an individual's dietary metabolite exposure, with implications for infection, cancer, inflammatory diseases, cardiovascular diseases, and other diseases impacted by diet. Microbes and diet directly intersect in the context of infections caused by the food-borne enteropathogens Salmonella enterica serovar Typhimurium and Campylobacter jejuni, which cause tens of millions of cases of food-borne illness every year, largely through consumption of chicken and other poultry products. Progress understanding these interactions would transform our ability to manage this major public health challenge, enabling interventions in humans and in our food chain where diet can be directly prescribed. This proposal will test the hypothesis that modification of dietary compounds by the gut microbiota, and disruption of the microbiota by dietary compounds, determines the function of these molecules in modulating colonization resistance (pathogen exclusion by the microbiome), pathogen growth, and virulence in humans and in our food chain. In Aim 1, we will generate a systematic map of the metabolism of over 100 dietary compounds by over 100 gut microbes and microbiomes from two human cohorts and chickens at the level of communities, species, enzymes, and metabolites. In Aim 2, we will determine how these compounds modulate colonization resistance in gnotobiotic mouse and gnotobiotic chicken models of S. Typhimurium and C. jejuni infections. In Aim 3, we will measure how dietary compounds and their microbial metabolites impact pathogen growth and virulence in vitro, in 2D monolayers derived from intestinal organoids, and in gnotobiotic animals. Together, these studies will define how the reciprocal interactions between diet and the microbiome determine the outcome of food-borne infections, a major public health risk.