Nutrient competition and metabolite production by the gut microbiota to reduce carbapenem-resistant Enterobacteriaceae growth in the human intestine

抗菌素耐药性严重威胁人类健康，导致治疗失败、感染复发、住院时间延长和临床结果不佳。治疗选择有限，往往效果较差，并涉及到使用毒性更大的抗生素。抗菌素耐药感染每年导致全球70万人死亡，如果不开发新的治疗方法，到2050年，这一数字估计将上升到每年1000万人。抗菌素耐药感染的爆发对NHS来说也是非常昂贵的。因此，迫切需要开发新的方法来预防和治疗耐药感染。肠道是称为碳青霉烯类耐药肠杆菌科(Cre)的病原体的主要定植场所和储存库。CRE肠道定植先于其他严重的CRE感染，如血液感染。患者将受益于在他们继续发展为这些严重感染之前从他们的肠道中移除CRE。然而，目前还没有针对肠道Cre定植患者的临床指南、护理标准或管理指南。研究表明，粪便微生物区系移植(FMT)可以将Cre从肠道中移除，来自健康捐赠者的粪便被输送到Cre定植患者的肠道。然而，我们并不了解FMT用于从肠道中移除Cre的机制，而且FMT并不是一个无风险的过程。FMT的缺点包括担心治疗免疫功能低下的患者、传播感染的风险以及侵入性给药途径。此外，对FMT的监管有限，协议也不标准化。FMT需要被更有效、更安全、设计合理、剂量更大的新疗法所取代。健康的肠道被一系列不同的微生物定居，这些微生物统称为肠道微生物区系。健康的肠道微生物区系可提供保护，防止CRE在肠道内定植。肠道中的营养物质是有限的，微生物必须相互竞争才能利用这些营养物质来支持自己的生长。健康的肠道微生物群对这些营养物质的竞争超过了Cre，并产生了一种称为代谢物的化合物，可以抑制Cre的生长。然而，抗生素介导的对肠道微生物区系成员的杀灭允许Cre在肠道中定居并占据主导地位。抗生素增加了可用于支持Cre生长的营养物质的浓度，同时降低了可以抑制Cre生长的代谢物的浓度。这项建议的目标是开发由合成微生物联盟(肠道微生物区系的特定成员)和抑制代谢物组成的新的微生物组疗法。抑制代谢产物将导致Cre生长的最初减慢。合成的微生物联合体将在肠道内定居，在营养方面胜过Cre，并通过产生抑制代谢物来抑制Cre的生长，导致Cre的生长长期减少。将使用Cre肠道定植的人工肠道模型来确定抗生素和FMT对营养竞争、代谢物产生、肠道微生物区系组成和Cre生长的影响。将设计由肠道微生物群成员组成的合成微生物联合体，这些微生物群成员在营养方面与Cre竞争，并产生抑制Cre生长的代谢物。这种新的治疗方法将在人工肠道模型中进行测试，以证明其抑制Cre生长的有效性。这项研究有可能通过开发一种新的治疗方法来显著影响临床实践，这种新方法可用于预防或治疗Cre肠道定植，从而预防其他严重感染，如Cre血流感染。

Antimicrobial resistance is a serious threat to human health, resulting in treatment failures, infection relapses, longer hospitalisations, and poor clinical outcomes. Treatment options are limited, frequently less effective, and involve administration of more toxic antibiotics. Antimicrobial-resistant infections are responsible for 700,000 deaths globally each year, and without the development of new treatments this figure is estimated to rise to 10 million deaths per year by 2050. Outbreaks of antimicrobial-resistant infections are also very costly to the NHS. Therefore, there is an urgent need to develop new approaches to prevent and treat antimicrobial-resistant infections.The intestine is the primary colonisation site and reservoir for pathogens called carbapenem-resistant Enterobacteriaceae (CRE). CRE intestinal colonisation precedes the development of other serious CRE infections, such as bloodstream infections. Patients would benefit from the removal of CRE from their intestines before they go on to develop these serious infections. However, currently there are no clinical guidelines, standard of care, or management guidance for patients with intestinal CRE colonisation.Studies have demonstrated that faecal microbiota transplantation (FMT) can remove CRE from the intestine, where faeces from a healthy donor are administered to the intestine of a CRE colonised patient. However, we do not understand the mechanisms that FMT uses to remove CRE from the intestine, and FMT is not a risk-free procedure. Examples of disadvantages of FMT include concerns treating immunocompromised patients, the risk of transmitting infections, and invasive administration routes. Moreover, regulatory oversight is limited for FMT and protocols are not standardised. FMT needs to be replaced with new therapies that are more effective, safe, rationally designed, and doseable.The healthy gut is colonised by a diverse collection of microbes collectively referred to as the gut microbiota. A healthy gut microbiota provides protection against intestinal colonisation with CRE. Nutrients are limited in the intestine and microbes must compete with each other to use these nutrients to support their growth. A healthy gut microbiota outcompetes CRE for these nutrients and also produces compounds called metabolites that can inhibit CRE growth. However, antibiotic-mediated killing of gut microbiota members allows CRE to colonise and dominate the intestine. Antibiotics increase the concentration of nutrients available to support CRE growth coupled with a reduction in the concentration of metabolites that can inhibit CRE growth.The goal of this proposal is to develop new microbiome therapeutics consisting of a synthetic microbial consortium (specific members of the gut microbiota) and inhibitory metabolites. The inhibitory metabolites will cause an initial reduction in CRE growth. The synthetic microbial consortium will colonise the intestine, outcompete CRE for nutrients, and inhibit CRE growth by producing inhibitory metabolites, resulting in a long-term reduction in CRE growth. An artificial gut model of CRE intestinal colonisation will be used to determine the effects of antibiotics and FMT on nutrient competition, metabolite production, gut microbiota composition, and CRE growth. Synthetic microbial consortia will be designed consisting of gut microbiota members that outcompete CRE for nutrients and produce metabolites that inhibit CRE growth. This new therapeutic will be tested in the artificial gut model to demonstrate its efficacy to inhibit CRE growth.This study has the potential to significantly impact clinical practice by developing a new treatment that could be used to prevent or treat CRE intestinal colonisation, and therefore prevent other serious infections such as CRE bloodstream infections.