Impact of Microbiota-Generated Metabolites on Campylobacter jejuni Colonization

微生物群产生的代谢物对空肠弯曲菌定殖的影响

基本信息

批准号：
10179434
负责人：
DAVID R HENDRIXSON
金额：
$ 41.38万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-07 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179434
关键词：
Acetates Affect Agriculture Animals Bacteria Birds Butyrates Campylobacter jejuni Cells Chick Chick model Chickens Colon Consumption Cues Data Disease Domestic Fowls Event Gene Expression Generations Genes Genetic Screening Genetic Transcription Growth Human Incidence Infection Intervention Intestines Large Intestine Lead Meat Meat Products Mediating Metabolic Monitor Mucous body substance Mutagenesis Nutrient Pathogenesis Pathway interactions Poultry Diseases Production Rectum Regulon Research Severities Symbiosis System Therapeutic United States Virulence Virulence Factors Volatile Fatty Acids Work c new commensal bacteria diarrheal disease experimental study gut colonization gut microbiota host colonization in vivo in vivo monitoring insight intestinal crypt intestinal epithelium member microbiota microbiota metabolites organic acid prevent residence transcriptome sequencing

项目摘要

Project Summary To infect a host, bacteria must recognize niches that support growth and interact or compete with members of the microbiota to establish residence in a niche to promote disease or persistence. Campylobacter jejuni is a leading cause of bacterial diarrheal disease in the United States and throughout the world. C. jejuni is also a commensal bacterium of the intestinal tracts of many animals in the wild and agriculture, especially avian species. Sporadic cases of C. jejuni diarrheal disease are most often associated with consumption or handling of contaminated chicken meats. Thus, understanding mechanisms for how C. jejuni senses and responds to avian or human intestinal components during initial events in infection are useful for developing therapeutic strategies that may reduce the burden of C. jejuni diarrheal disease in humans and the presence of the bacterium in agriculture and meats for human consumption. We discovered that C. jejuni senses and responds to metabolites generated by the intestinal microbiota of chickens to influence expression of genes essential for commensal colonization of avian hosts, with some genes also functioning in pathogenesis of diarrheal disease in humans. We found that short-chain fatty acids (SCFAs) such as butyrate and acetate that are abundant in the lower intestinal tract, stimulated expression of many genes required for colonization of chicks. In contrast, the organic acid lactate, which is produced at higher levels in the upper intestinal tract, repressed expression of these same genes. We propose that C. jejuni senses SCFAs and organic acids produced by the resident microbiota to discriminate between different intestinal regions and identify lower intestinal niches that are ideal to support in vivo growth to establish a persistent, commensal colonization of the intestines of poultry. Since the metabolites and microbiota species that produce them are similarly spatially organized in the human intestines, we propose that C. jejuni monitors the same metabolites to identify ideal human colonic niches that support growth to establish an infection for diarrheal disease. In Aim 1, we will explore the C. jejuni SCFA- and lactate-modulated regulon and identify new colonization determinants of C. jejuni. In Aim 2, we will employ multiple approaches to identify pathways in C. jejuni involved in sensing SCFAs and lactate and mediating expression of colonization and virulence genes. In Aim 3, we will explore how in vivo manipulation of SCFAs and lactate levels or the microbiota that generate them impacts C. jejuni for commensal colonization of the avian intestines. Accomplishment of these aims will promote new insights for: 1) how C. jejuni senses and responds to in vivo metabolites and factors to recognize ideal niches for establishing infection; 2) factors required for C. jejuni colonization and virulence; 3) regulatory mechanisms for C. jejuni gene expression; 4) how manipulation of the human or avian intestinal metabolites and the microbiota impacts interactions of C. jejuni with hosts; and 5) strategies to reduce the burden of C. jejuni diarrheal disease and its presence in agriculture to create safer meat products for human consumption.

项目摘要要感染宿主，细菌必须识别支持增长并互动或与成员互动或竞争在利基市场中建立住所以促进疾病或持久性的菌群。弯曲杆菌空肠是一个在美国和世界各地的细菌性腹泻病的主要原因。 C. Jejuni也是野生和农业中许多动物的肠道的共生细菌，尤其是禽类物种。零星腹膜内疾病的零星病例最常与消费或处理有关被污染的鸡肉肉。因此，理解旋转梭菌的感觉和响应的机制在感染中初次事件中，鸟类或人肠部成分对于发展治疗很有用可能减轻人类腹泻性腹泻疾病负担的策略以及存在农业中的细菌和肉类供人类食用。我们发现C. jejuni感官并做出回应由鸡肠菌产生的代谢产物，影响基因的表达鸟类宿主的共生定殖，一些基因在腹泻病的发病机理中也起作用在人类中。我们发现短链脂肪酸（SCFA），例如丁酸酯和乙酸下肠道的下部，刺激了雏鸡定植所需的许多基因的表达。相比之下，有机酸乳酸是在上肠道上以较高水平产生的，抑制的表达这些相同的基因。我们提出，空肠C. c。c。c。c。SCFAS和居民产生的有机酸微生物群以区分不同的肠道区域并识别理想的下肠壁ni 支持体内生长以建立禽类肠道的持久，共同的殖民化。自从产生它们的代谢产物和微生物群类似地在人类中组织肠道，我们提出，空肠梭菌监测相同的代谢产物，以识别理想的人类结肠壁ni 支持生长建立腹泻病的感染。在AIM 1中，我们将探索C. jejuni scfa-和乳酸调节的调节并鉴定了空肠梭状芽孢杆菌的新定植决定因素。在AIM 2中，我们将雇用多种方法来识别参与感应SCFA和乳酸和介导的Jejuni中的途径定植和毒力基因的表达。在AIM 3中，我们将探讨如何在体内操纵SCFA 和乳酸水平或产生它们的微生物群会影响空肠梭菌的共同定植鸟类肠道。这些目标的实现将促进新见解：1）C。Jejuni的感官和对体内代谢产物的反应和因素，以识别建立感染的理想壁nir； 2）因素空肠梭状芽孢杆菌的定植和毒力所必需的； 3）旋转梭菌基因表达的调节机制； 4）人类或禽肠的代谢产物和微生物群的操纵如何影响C的相互作用。 Jejuni与主持人； 5）减轻腹泻腹泻疾病负担及其在其中的存在的策略农业生产更安全的肉类产品供人类消费。