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

项目概要/摘要： 克罗恩病（CD）是一种慢性胃肠道疾病，影响约70万人， 美国的微生物群的潜在致病性成员的异常积累，称为 致病菌，被认为有助于CD的发病机制。例如，粘附性侵袭性埃希氏菌 大肠杆菌（AIEC），一种与CD相关的潜在致病菌，从超过35%的 CD患者，但低于6%的健康人。然而致病菌使用的精确机制 包括AIEC在CD患者的肠道中茁壮成长仍然是未知的。长期目标是 应用是要解开机制，其中CD相关的致病菌积累在肠道， 患者在稳态条件下，大多数肠道细菌是专性厌氧菌。突出 兼性厌氧菌如肠杆菌科仅构成微生物群的一小部分。肠 已知CD患者的炎症促进肠杆菌科（例如，E. coli）。然而，在这方面， 炎症本身不能解释致病性E.大肠杆菌，如AIEC，能够竞争其他，非- 致病性大肠杆菌大肠杆菌菌株。因此，可以设想致病性E.大肠杆菌有策略， 处置，以克服其自己的物种在发炎的肠道成员。我们的初步结果表明， 致病性大肠大肠杆菌可以在大肠杆菌上生长。大肠杆菌菌株。有趣的是，这种增长 优势，与致病性E.大肠杆菌，是钝化时，膳食氨基酸的可用性， 特别是丝氨酸被耗尽。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E.大肠杆菌在 炎症我们计划通过追求以下三个具体目标来测试我们的中心假设：1。识别 致病性E.大肠杆菌利用饮食中的氨基酸， 在发炎的肠道中保持健康。我们将确定参与氨基酸利用的机制为炎症 在肠道中诱导E.大肠杆菌优先降解氨基酸。2确定丝氨酸摄取的作用，因为它 与致病性大肠杆菌的竞争适合度有关。大肠杆菌感染我们将揭开 丝氨酸摄取和致病性E.大肠杆菌菌株在肠道中茁壮成长。此外，我们将评估 与选择性预防丝氨酸摄取相关的治疗潜力。总的来说，这项建议是 预计将导致开发新的疗法，目标是专门利用的营养素， 致病性大肠大肠杆菌，以获得优势，超过其商业竞争对手

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