Impact of Microbiota-Generated Metabolites on Campylobacter jejuni Colonization

项目摘要 为了感染宿主，细菌必须识别支持生长的小生境，并与宿主的成员相互作用或竞争。 微生物群在一个小生境中建立居所，以促进疾病或持久性。空肠弯曲杆菌是一种 在美国和全世界细菌性尿道炎的主要原因。C.空肠也是一种 野生和农业中许多动物肠道中的寄生菌，特别是鸟类 物种散发C.空肠弯曲症最常与食用或处理有关 受污染的鸡肉因此，理解C.空肠感觉并响应 在感染的初始事件期间，禽类或人类的肠组分可用于开发治疗性药物。 可能减轻C.人类空肠弯曲病和存在的 农业和人类食用肉类中的细菌。我们发现C.空肠感觉和反应 鸡肠道微生物群产生的代谢物，以影响 鸟类宿主的肠道定殖，一些基因也在肠道疾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（SCFAs），如丁酸和乙酸，丰富的， 下肠道，刺激了许多基因的表达，这些基因是小鸡定居所必需的。与此相反， 有机酸乳酸盐在上肠道中以较高水平产生，抑制了 同样的基因。我们建议C.空肠感觉到由居民产生的SCFAs和有机酸 微生物群来区分不同的肠道区域，并确定理想的下肠道生态位 支持体内生长，以建立家禽肠道的持久共生定植。以来 代谢物和产生它们的微生物群物种在人体内的空间组织相似 肠，我们建议C。空肠监测相同的代谢物，以确定理想的人类结肠小生境， 支持生长，以建立一个感染的疟疾疾病。在目标1中，我们将探索C。空肠SCFA-和 乳酸调节调节子和鉴定新的C.空肠。在目标2中，我们将采用 多种方法来识别C.空肠参与感知SCFAs和乳酸，并介导 定植和毒力基因的表达。在目标3中，我们将探索如何在体内操作SCFAs 乳酸水平或产生乳酸的微生物群会影响C。空肠的空肠定植 鸟的肠子这些目标的实现将促进对以下问题的新认识：1）C。空肠感觉和 响应于体内代谢物和因子以识别用于建立感染的理想小生境; 2）因子 需要C。空肠定殖和毒力; 3）C.空肠基因表达; 4） 人类或鸟类肠道代谢物和微生物群的操纵如何影响C. jejuni与宿主的关系; 5）减少C.空肠弯曲病及其在 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.