Exploiting commensal-pathogen competition to treat mucosal infection

最近，引起疾病的细菌数量急剧增加，这些细菌对通常用于治疗疾病的抗生素产生了耐药性。这些细菌被称为抗微生物药物耐药性（AMR），它们携带介导对这些药物不敏感、降解或排出的基因。在不久的将来，我们将面临这样一种情况：曾经微不足道、容易治疗的感染可能会致命。目前，大肠杆菌是一种构成正常肠道菌群重要组成部分的细菌，是欧洲和英国最常见的AMR医院获得性感染之一，也是血液中毒、腹泻和复发性尿路感染的主要原因。滥用和过度使用抗生素（例如在化疗期间或在重症监护病房）是抗生素耐药性问题的核心。然而，迄今为止，很少有研究在相关动物模型中阐明抗菌素耐药性的体内后果。在过去的20年里，我的实验室一直在用老鼠的致病性大肠杆菌来模拟人类肠道感染，使用老鼠的病原体啮齿柠檬酸杆菌。啮齿鼠感染是一种很好的细菌定植模型，因为它不会引起小鼠的严重疾病。最近，我们发现，当治疗感染了对抗生素卡那霉素（Kan）具有耐药性的啮齿C.的小鼠时，高水平的Kan会导致一种我们称为抗生素诱导细菌持久性（AIBP）的现象。AIBP状态下的啮齿c在胃肠道内持续多日，并与宿主形成新的关系，这与典型的病原体-宿主相互作用不同。特别是，在AIBP状态下，毒力基因在啮齿鼠中被关闭，病原体是非传染性的。相比之下，用低水平的Kan治疗具有Kan抗性的C. rodentium感染会导致病原体的清除延迟，这与共生肠道细菌的生长相吻合，而共生肠道细菌可能会竞争或杀死C. rodentium。在这项研究中，我们将表征在AIBP状态下的啮齿鼠及其与共生细菌的关系。虽然我们意识到小鼠肠道微生物群与人类肠道微生物群不相同，但该项目将揭示抗生素治疗期间肠道细菌竞争和适应的共同可转移原则，使用错误的抗生素治疗AR感染的后果，并导致鉴定微生物组表达的影响病原体-宿主相互作用的新型天然产物。这些原则可能适用于在定植过程中必须与肠道微生物群竞争的其他肠道病原体。

Recently, there has been a dramatic rise in the number of bacteria that cause disease acquiring resistance to antibiotics that are commonly used to treat them. These bacteria are known as antimicrobial resistant (AMR) and carry gene/s that mediate insensitivity to, degradation of, or expulsion of, these drugs. In the not too distant future, we are facing a situation where once trivial, easily treatable, infections could potentially prove fatal. Currently, E. coli, a bacterium that constitutes an important part of the normal gut flora, is one of the most frequently isolated AMR hospital acquired infections in Europe and the UK and is a major cause of blood poisoning, diarrhoea and recurrent urinary tract infections. Misuse and overuse of antibiotics (e.g. during chemotherapy or in intensive care units) is at the heart of the AMR problem. However, little research has been performed to date to elucidate the in vivo consequences of AMR in relevant animal models. For the last 20 years my lab has been modelling human intestinal infections with pathogenic E. coli in mice, using the mouse pathogen Citrobacter rodentium. C. rodentium infection is an excellent bacterial colonisation model as it does not cause severe disease in mice. Recently, we found that when treatment of mice infected with C. rodentium that is resistant to the antibiotic kanamycin (Kan), with high level of Kan leads to a phenomenon we termed antibiotic induced bacterial persistence (AIBP). C. rodentium in the AIBP state persists within the gastrointestinal tract for many days and develops a new relationship with the host, which is different from a typical pathogen-host interaction. In particular, virulence genes are turned off in C. rodentium in the AIBP state and the pathogen is non-infectious. In contrast, treating infections with Kan resistant C. rodentium with low levels of Kan leads to delay clearance of the pathogen, which coincided with growth of commensal gut bacteria, which could potentially outcompete or kill C. rodentium.In this study we will characterise C. rodentium in the AIBP state and its relationship with commensal bacteria. Although we appreciate that the mouse intestinal microbiota is not identical to that in humans, this project will reveal common transferable principles underpinning bacterial competition and adaptation in the intestine during antibiotic treatment, the consequences of using the wrong antibiotics to treat AR infections and lead to the identification of novel new natural products expressed by the microbiome that impact on pathogen-host interactions. These principles are likely to be applicable to other enteric pathogens that have to compete with the gut microbiota during colonisation.