Impact of Microbiota-Generated Metabolites on Campylobacter jejuni Colonization

项目摘要 要感染宿主，细菌必须识别支持生长的生态位，并与 微生物区系在一个利基中建立栖息地，以促进疾病或持久性。空肠弯曲杆菌是一种 细菌性腹泻病在美国和全世界都是主要原因。空肠弯曲菌也是一种 野生和农业中许多动物肠道的共生细菌，特别是禽类 物种。零星的空肠弯曲菌腹泻病例最常与摄入或处理有关 受污染的鸡肉。因此，了解空肠弯曲菌如何感知和反应的机制 感染初期的禽类或人类肠道成分对开发治疗方法很有用 可减轻人类空肠弯曲菌腹泻疾病负担和存在的战略 农业和供人食用的肉类中的细菌。我们发现空肠弯曲菌能够感知和反应 影响鸡肠道微生物区系所产生的代谢产物，从而影响必需基因的表达 禽类宿主的共生定植，一些基因也在腹泻病的发病机制中发挥作用 在人类身上。我们发现，短链脂肪酸(SCFA)，如丁酸盐和醋酸酯，在 肠道下部，刺激许多小鸡定植所需基因的表达。相比之下， 在上肠道中产生的有机酸乳酸水平较高，抑制了 这些相同的基因。我们推测空肠弯曲菌能感知居民体产生的单链脂肪酸和有机酸。 微生物区系，以区分不同的肠道区域，并确定理想的较低肠道生态位 支持体内生长，以建立家禽肠道的持久共生定植。自.以来 产生它们的代谢物和微生物区系物种在空间上与人类相似。 肠道，我们认为空肠弯曲菌监测相同的代谢物，以确定理想的人类结肠生态位 支持生长，以确定腹泻疾病的感染。在目标1中，我们将探索空肠弯曲菌SCFA-和 空肠弯曲菌乳酸调节调节基因和鉴定新的定植决定因素。在目标2中，我们将使用 多种方法识别空肠弯曲菌中参与感知SCFAs和乳酸及其调节的途径 定殖和毒力基因的表达。在目标3中，我们将探索如何在体内操作SCFA 而乳酸水平或产生乳酸的微生物区系会影响空肠弯曲菌的共生定植 禽类肠道。这些目标的实现将促进对以下方面的新见解：1)空肠弯曲菌如何感觉和 对体内代谢物和因素作出反应，以识别确定感染的理想环境；2)因素 空肠弯曲菌定植和毒力所必需的；3)空肠弯曲菌基因表达的调控机制；4) 人类或禽类肠道代谢物和微生物区系的操作如何影响C. 空肠与宿主；5)减少空肠弯曲菌腹泻疾病负担及其在 农业为人类消费创造更安全的肉类产品。

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.