Dietary amino acids control the competition between pathogenic and commensal E. coli in inflamed gut

项目摘要/摘要： 克罗恩病(CD)是一种慢性胃肠道疾病，在美国约有70万人受到影响。 美国。微生物区系潜在致病成员的异常积累，称为 致病因子，被认为与CD的发病机制有关。例如，粘附性侵袭性埃希氏菌 大肠杆菌(AIEC)是一种与Cd相关的潜在致病菌，从超过35%的人的回肠粘膜中分离出来 CD患者，但不到6%的健康人。然而，病原体使用的精确机制 包括在CD患者的肠道中蓬勃发展的AIEC在很大程度上仍然是未知的。这样做的长期目标是 应用是解开Cd相关致病离子在肠道中积聚的机制。 病人。在动态平衡条件下，大多数共生细菌是专性厌氧菌。突出 兼性厌氧菌，如肠杆菌科，只占微生物区系的一小部分。肠道 众所周知，CD患者的炎症可以促进肠杆菌科细菌(如大肠杆菌)的蓬勃发展。然而， 炎症本身不能解释为什么致病性大肠杆菌，如AIEC，能够胜过其他非致病性 致病性共生大肠杆菌菌株。因此，可以想见，致病性大肠杆菌在其 处理以克服其自身物种在肠道发炎的成员。我们的初步结果表明 致病性大肠杆菌可以在发炎的肠道中生长超过共生的大肠杆菌菌株。有趣的是，这种增长 与致病性大肠杆菌相关的优势，当饮食中氨基酸的可获得性， 尤其是丝氨酸，已经耗尽。基于这些结果，我们对这一应用的中心假设是饮食- 衍生的氨基酸，特别是丝氨酸，选择性地控制致病性大肠杆菌在 发炎。我们计划通过追求以下三个具体目标来检验我们的中心假设：1.确定 致病性大肠埃希氏菌利用膳食氨基酸提高竞争力的机制 在发炎的肠道中健康。我们将确定氨基酸利用的机制是炎症。 在肠道中诱导大肠杆菌优先分解氨基酸。2确定丝氨酸摄取的作用 与致病性大肠杆菌在发炎的肠道中的竞争适合性有关。我们将解开两者之间的联系 丝氨酸摄取和致病性大肠杆菌菌株在肠道中茁壮成长的能力。此外，我们会评估 选择性预防丝氨酸摄取的治疗潜力。总而言之，这项提案是 有望导致新疗法的开发，这些疗法针对的是 致病性大肠杆菌将获得相对于其共生竞争对手的优势

Project Summary/Abstract: Crohn's disease (CD) is a chronic gastrointestinal disorder that affects approximately 0.7 million people in the United States. Abnormal accumulation of potentially pathogenic members of the microbiota, referred to as pathobionts, is thought to contribute to the pathogenesis of CD. For example, adherent invasive Escherichia coli (AIEC), a potential pathobiont associated with CD, is isolated from the ileal mucosa of more than 35% of CD patients, but fewer than 6% of healthy individuals. However, the precise mechanism used by pathobionts including AIEC to thrive in the gut in CD patients remains largely unknown. The long-term goal of this application is to unravel the mechanism whereby CD-associated pathobionts accumulate in the intestine of patients. Under homeostatic conditions, the majority of commensal bacteria are obligate anaerobes. Prominent facultative anaerobes, such as Enterobacteriaceae, constitute only a minor fraction of the microbiota. Intestinal inflammation in patients with CD is known to promote thrive of Enterobacteriaceae (e.g. E. coli). However, inflammation alone does not explain why pathogenic E. coli, such as AIEC, is able to out-compete other, non- pathogenic commensal E. coli strains. Thus, it is conceivable that pathogenic E. coli has strategies at its disposal to overcome members of its own species in inflamed intestine. Our preliminary results suggest that pathogenic E. coli can outgrow over commensal E. coli strains in the inflamed gut. Interestingly, this growth advantage, associated with pathogenic E. coli, is blunted when the availability of dietary amino acids, particularly serine, is depleted. Based on these results, our central hypothesis for this application is that diet- derived amino acids, particularly serine, selectively control the competitive fitness of pathogenic E. coli during inflammation. We plan to test our central hypothesis by pursing the following three specific aims: 1. Identify the mechanisms by which pathogenic E. coli utilizes dietary amino acids to increase its competitive fitness in the inflamed gut. We will identify the mechanisms involved in amino acid utilization as inflammation in the gut induces E. coli to preferentially catabolize amino acids. 2 Determine the role of serine uptake as it relates to competitive fitness of pathogenic E. coli in the inflamed gut. We will unravel the link between serine uptake and the ability of pathogenic E. coli strains to thrive in the gut. Furthermore, we will assess the therapeutic potential associated with selective prevention of serine uptake. Collectively, this proposal is expected to result in the development of novel therapies that target the nutrients specifically utilized by pathogenic E. coli to gain an edge over its commensal competitors