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The role of bile-metabolising enzymes in the pathogenesis of Clostridium difficile infection, and the impact of faecal microbiota transplantation.

胆汁代谢酶在艰难梭菌感染发病机制中的作用以及粪便微生物群移植的影响。

基本信息

批准号：
MR/R000875/1
负责人：
Benjamin Harvey Mullish
金额：
$ 18.26万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR000875%2F1
关键词：
role bile metabolising enzymes pathogenesis

项目摘要

Our gut is full of billions of bacteria; whilst some may be harmful, many of these live there without problem, and actually perform important roles in keeping us healthy. Some of these 'good' gut bacteria in fact appear to act to stop other bacteria that could cause harmful gut infections from growing within the gut. Whilst antibiotics help us overcome chest, urine and other infections, doctors now realise that an unintended effect of their use is that they may also destroy some of the gut's 'good' bacteria, meaning that we lose the benefit of their protective roles. One example of this occurs in Clostridium difficile infection (CDI). Clostridium difficile is a form of bacteria that can grow within the human gut and cause disease ranging from mild diarrhoea up to severe bowel inflammation and even death. CDI is responsible for many hospital admissions and deaths worldwide every year. Whilst this infection rarely happens in healthy people, it occurs much more frequently in people who have had recent antibiotics. Doctors believe that this is because antibiotics destroy the 'good' bacteria in the gut that protect against CDI, and therefore allows Clostridium difficile bacteria to grow within the gut and cause disease. However, exactly which beneficial bacteria they destroy - and how these bacteria protect us normally - is not properly understood.CDI is becoming more difficult to treat; the main reason for this is that the usual antibiotics used as treatment do not work as well as they used to. One unusual treatment that has been recently introduced is faecal microbiota transplantation (FMT), i.e. taking faeces from a healthy person (containing normal healthy gut bacteria), processing this in a laboratory to create a liquid suspension, and delivering this (via a tube up the nose and into the stomach, or via a colonoscopy) into the gut of people with CDI. Trials show that this appears to be a much more effective treatment for recurrent CDI than conventional antibiotic treatment. However, FMT is not without drawbacks; for instance, it may be unpleasant for a person with CDI to receive this, it can be difficult to administer, and there is a theoretical risk of transmitting infections from the donor to the recipient. Furthermore, exactly which 'good' bacteria in the transplant lead to treatment of CDI (and the means by which they do this) is still unknown.We intend to identify which 'good' bacteria are killed by antibiotics with CDI; in addition, we will find which bacteria replaced into the gut by FMT cause people to get better from the infection, and how they do this. Recent research shows that certain components of bile (a liquid made by our livers and secreted into our guts) help Clostridium difficile grow under the microscope, whilst other components prevent it growing. Based on this, we suspect that FMT may work by replacing the gut bacteria that produce enzymes that alter the composition of bile (called bile salt hydrolases (BSH)). We think that FMT restoring BSH-producing bacteria may result in an increase in bile components that stop C. difficile growing, and reduction in those that help the bacteria divide. To investigate this, we will take samples from healthy people and those with CDI (both pre- and post-FMT, both from people where FMT has worked and where it has not) to compare which bacteria and which bile components are present in the gut in these different situations, and to investigate how much BSH enzyme is present in all cases. We will then test adding bacteria that produce BSH to a simulated model of a gut suffering from CDI, to see if this is as effective as FMT, and also assess how these bacteria affect C difficile's survival. If our data support this hypothesis, we may in the future be able to move on from FMT and instead treat CDI (or people at risk of the condition) by giving a drink or pill specifically containing bacteria that produce BSH, or that just contain BSH alone.

我们的肠道充满了数十亿的细菌;虽然有些可能是有害的，但其中许多细菌生活在那里没有问题，实际上在保持我们的健康方面发挥着重要作用。事实上，这些“好”的肠道细菌中的一些似乎可以阻止其他可能导致有害肠道感染的细菌在肠道内生长。虽然抗生素可以帮助我们克服胸部、尿液和其他感染，但医生现在意识到，使用抗生素的一个意想不到的效果是，它们也可能会破坏肠道中的一些“好”细菌，这意味着我们失去了它们的保护作用。其中一个例子发生在艰难梭菌感染（CDI）中。艰难梭菌是一种细菌，可以在人体肠道内生长，引起从轻度腹泻到严重肠道炎症甚至死亡的疾病。CDI每年在全世界造成许多住院和死亡。虽然这种感染很少发生在健康人身上，但它更经常发生在最近使用抗生素的人身上。医生认为，这是因为抗生素破坏了肠道中保护免受CDI的“好”细菌，因此允许艰难梭菌细菌在肠道内生长并引起疾病。然而，它们究竟破坏了哪些有益细菌，以及这些细菌通常如何保护我们，目前还没有得到正确的理解。CDI变得越来越难以治疗;主要原因是通常用于治疗的抗生素不像以前那样有效。最近引入的一种不寻常的治疗方法是粪便微生物群移植（FMT），即从健康人（含有正常健康的肠道细菌）中取出粪便，在实验室中处理以产生液体悬浮液，并将其（通过鼻子和胃的管子，或通过结肠镜检查）输送到CDI患者的肠道中。试验表明，这似乎是一个更有效的治疗复发性CDI比传统的抗生素治疗。然而，FMT并非没有缺点;例如，对于CDI患者来说，接受它可能是不愉快的，它可能难以管理，并且理论上存在将感染从供体传播到受体的风险。此外，移植物中的哪些"好"细菌导致了CDI的治疗（以及它们实现这一点的方式）仍然是未知的。我们打算确定哪些"好"细菌被CDI的抗生素杀死;此外，我们将发现哪些细菌被FMT替换到肠道中使人们从感染中好转，以及它们是如何做到这一点的。最近的研究表明，胆汁的某些成分（由我们的肝脏产生并分泌到我们的肠道中的液体）有助于艰难梭菌在显微镜下生长，而其他成分则阻止其生长。基于此，我们怀疑FMT可能通过取代产生改变胆汁组成的酶（称为胆盐水解酶（BSH））的肠道细菌而起作用。我们认为，FMT恢复产生BSH的细菌可能会导致胆汁成分的增加，阻止C。艰难生长，减少那些帮助细菌分裂。为了研究这一点，我们将从健康人和CDI患者（FMT前后，FMT有效和无效的人）中采集样本，以比较在这些不同情况下肠道中存在哪些细菌和哪些胆汁成分，并研究在所有情况下存在多少BSH酶。然后，我们将测试将产生BSH的细菌添加到患有CDI的肠道模拟模型中，看看这是否与FMT一样有效，并评估这些细菌如何影响艰难梭菌的存活。如果我们的数据支持这一假设，我们可能在未来能够从FMT继续前进，而是通过提供含有产生BSH的细菌或仅含有BSH的饮料或药丸来治疗CDI（或有这种情况风险的人）。