Inflammation-derived sugars lower resistance against Salmonella

 描述(申请人提供)：栖息在大肠内的微生物群落提供了对肠道病原体的保护，这种特性被称为“耐定殖性”。抗生素治疗对微生物群落的破坏伴随着对肠道病原体感染的敏感性增加，如肠道沙门氏菌。然而，抗生素治疗后降低“定植抗性”的机制仍然知之甚少，这是这一应用中将解决的一个关键知识缺口。我们的中心假设是，抗生素治疗诱导了与产生活性氧和氮物种相关的轻微炎症反应，这些反应反过来又与碳水化合物反应，产生炎症衍生的营养物质，促进肠球菌的腔内生长。我们将通过确定氧化碳水化合物在抗生素治疗后是否降低对鼠伤寒沙门氏菌的“定植抵抗力”来检验我们的假设的关键方面(目标1)。我们期望拟议实验的成功完成将建立一个创新的新概念，即局部炎症反应创造了一个独特的营养环境，有利于能够利用炎症衍生营养的肠道病原体的大量繁殖。这项工作的成功完成将具有重大意义，因为这项工作的结果将与理解对肠道病原体的“定植抗性”的潜在机制、肠道炎症条件下微生物群落的变化(例如炎症性肠病)以及与抗生素相关的肠道疾病(例如肠易激综合征)的发病机制具有广泛的相关性。

 DESCRIPTION (provided by applicant): The microbial community inhabiting the large intestine confers protection against enteric pathogens, a property known as "colonization resistance". A disruption of the microbial community by antibiotic treatment is accompanied with increased susceptibility to infections with enteric pathogens, such as Salmonella enterica. However, the mechanisms lowering "colonization resistance" after antibiotic treatment remain poorly understood, which represents a key gap in knowledge that will be addressed in this application. Our central hypothesis is that antibiotic treatment induces a mild inflammatory response associated with the generation of reactive oxygen and nitrogen species, which in turn react with carbohydrates to generate inflammation-derived nutrients that fuel luminal growth of S. enterica. We will test key aspects of our hypothesis by determining whether oxidized carbohydrates reduce "colonization resistance" against S. Typhimurium after antibiotic treatment (Aim 1). It is our expectation that successful completion of the proposed experiments will establish the innovative new concept that the local inflammatory response creates a unique nutritional environment that is conducive to a bloom of enteric pathogens capable of utilizing inflammation-derived nutrients. Successful completion will be significant because results from this work will have broad relevance for understanding the mechanisms underlying "colonization resistance" against enteric pathogens, changes in microbial communities during conditions of intestinal inflammation (e.g. inflammatory bowel disease), and the pathogenesis of antibiotic-related intestinal disorders (e.g. irritable bowel syndrome).