Diet transformation by the microbiome and its impact on bacterial infection

微生物组的饮食转变及其对细菌感染的影响

• 批准号: 10512774
• 负责人: Jorge E Galan
• 金额: $ 83.48万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512774
• 关键词: Address; Animal Model; Animals; Antibiotics; Area; Bacteria; Bacterial Infections; Biological Markers; Blood Circulation; Campylobacter jejuni; Cardiovascular Diseases; Chicken Model; Chickens; Clinical Research; Collection; Communities; Consumption; Custom; Diet; Diet Modification; Dietary Component; Disease; Drug Kinetics; Eating; Enzymes; Exclusion; Food; Food Chain; Food Interactions; Gastrointestinal tract structure; Gnotobiotic; Growth; Human; Human Microbiome; In Vitro; Individual; Infection; Infection prevention; Inflammatory; Intervention; Intestines; Knowledge; Libraries; Malignant Neoplasms; Maps; Mathematics; Measurement; Measures; Mediating; Medical; Metabolism; Microbe; Modeling; Mus; Organoids; Outcome; Persons; Pharmaceutical Preparations; Physiology; Pilot Projects; Play; Population; Poultry Products; Property; Public Health; Reporting; Risk; Salmonella enterica; Salmonella typhimurium; Series; Shapes; Side; Surveys; Techniques; Testing; Time; Variant; Virulence; Virulence Factors; Xenobiotic Metabolism; Xenobiotics; bacterial community; cohort; colonization resistance; commensal microbes; dietary; drug metabolism; enteric pathogen; foodborne; foodborne illness; foodborne infection; gastrointestinal; gut bacteria; gut microbes; gut microbiome; gut microbiota; human microbiota; human model; liquid chromatography mass spectrometry; metabolomics; microbial; microbiome; microbiome composition; microbiota; monolayer; pathogen; predictive marker; repository; small molecule

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.

项目摘要 食物包含大量的生物活性小分子，这些分子遇到了巨大的种群 胃肠道中的共生微生物。据报道，微生物组代谢在饮食中已有报道 复合类；但是，代谢膳食小分子的微生物酶可能高度 底物的特定于底物，这些活动之间的差异可能很大。饮食对 微生物组也已建立得很好。因此，肠道微生物组可能是个人的决定因素 饮食代谢物暴露，对感染，癌症，炎症性疾病，心血管造成影响 疾病和其他受饮食影响的疾病。在感染的背景下，微生物和饮食直接相交 由食源性肠病毒肠道疾病肠typhimurium和弯曲杆菌造成 空肠，每年都会导致数以千计的食物传播疾病，主要是通过消费 鸡肉和其他家禽产品。了解这些互动将改变我们的能力 管理这一重大公共卫生挑战，使人类干预措施以及我们的食物链中的饮食 可以直接处方。该提议将检验以下假设： 肠道菌群和饮食化合物对微生物群的破坏，确定了这些功能 在调节定植耐药性（微生物组排除病原体）中的分子，病原体生长， 和人类和食物链中的毒力。在AIM 1中，我们将生成新陈代谢的系统地图 来自两个人类同类的100多个肠道微生物和微生物组的100多种饮食化合物和 社区，物种，酶和代谢产物的鸡。在AIM 2中，我们将确定如何 这些化合物调节了gnotobiotic小鼠和gnotobiotic鸡模型的定殖抗性。 伤寒和辉长念珠菌感染。在AIM 3中，我们将衡量饮食化合物及其微生物的方式 代谢产物在体外影响病原体的生长和毒力，在源自肠道器官的2D单层中， 和gnotobiotic动物。这些研究将共同​​定义饮食与饮食与 微生物组决定了粮食传播感染的结果，这是一种主要的公共卫生风险。