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

基本信息

批准号：
10684849
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
项目类别：
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/10684849
关键词：
Address Animal Model Animals Antibiotics Area Bacteria Bacterial Infections Biological Markers Campylobacter jejuni Cardiovascular Diseases Chicken Model Chickens Circulation Clinical Research Collection Communities Consumption Custom Diet Diet Modification Dietary Component Disease Drug Kinetics Eating Enzymes Exclusion Food Food Chain 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 absorption bacterial community biomarker identification 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 medical examination metabolomics microbial microbiome microbiome composition microbiota monolayer pathogen predictive marker repository small molecule

项目摘要

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.

项目概要食物中含有大量的生物活性小分子，它们会遇到大量的生物活性物质。胃肠道中的共生微生物。据报道，膳食中的微生物组代谢复合类；然而，代谢膳食小分子的微生物酶可能高度底物特异性和这些活性在个体之间可能存在很大差异。饮食对身体的影响微生物组也已很成熟。因此，肠道微生物组可能是个体健康状况的决定因素。饮食代谢物暴露，对感染、癌症、炎症性疾病、心血管疾病有影响疾病，以及受饮食影响的其他疾病。微生物和饮食在感染中直接交叉由食源性肠道病原体鼠伤寒沙门氏菌和弯曲杆菌引起空肠弯曲菌，每年导致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。进一步理解这些相互作用将改变我们的能力应对这一重大公共卫生挑战，对人类和我们的食物链进行干预，其中饮食可以直接开处方。该提案将检验以下假设：通过改变膳食化合物肠道微生物群以及膳食化合物对微生物群的破坏决定了这些微生物的功能调节定植抗性（微生物群排除病原体）、病原体生长的分子，以及对人类和食物链的毒力。在目标 1 中，我们将生成一个系统的新陈代谢图来自两个人类队列的 100 多种肠道微生物和微生物组对 100 多种膳食化合物进行了研究，鸡群落、物种、酶和代谢物水平。在目标 2 中，我们将确定如何这些化合物可调节金黄色葡萄球菌限生小鼠和限生鸡模型中的定植抗性。鼠伤寒杆菌和空肠弯曲菌感染。在目标 3 中，我们将测量膳食化合物及其微生物如何代谢物在体外影响来自肠道类器官的二维单层病原体的生长和毒力，以及在限生动物中。这些研究将共同定义饮食和饮食之间的相互作用。微生物群决定食源性感染的结果，食源性感染是一项主要的公共卫生风险。