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

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”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，但医生们现在意识到，使用抗生素的一个意想不到的影响是，它们也可能破坏一些肠道的“好”细菌，这意味着我们失去了它们保护作用的好处。艰难梭菌感染（CDI）就是一个例子。艰难梭菌是一种可以在人体肠道内生长的细菌，可引起从轻微腹泻到严重肠道炎症甚至死亡的疾病。CDI每年在世界范围内造成许多住院和死亡。虽然这种感染很少发生在健康人群中，但在最近使用抗生素的人群中发生的频率要高得多。医生认为，这是因为抗生素破坏了肠道中防止CDI的“好”细菌，从而使艰难梭菌在肠道内生长并导致疾病。然而，它们究竟摧毁了哪些有益细菌，以及这些细菌如何在正常情况下保护我们，人们还没有完全了解。CDI正变得越来越难以治疗；造成这种情况的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），即从健康人的粪便（含有正常健康的肠道细菌）中提取粪便，在实验室中进行处理，形成液体悬浮液，然后（通过鼻子上的管子进入胃，或通过结肠镜检查）将其输送到CDI患者的肠道。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，对于患有CDI的人来说，接受这种药物可能会很不愉快，可能很难管理，并且理论上存在从供体向受体传播感染的风险。此外，移植中究竟是哪些“好”细菌导致了CDI的治疗（以及它们是如何做到这一点的）仍然未知。我们打算用CDI确定哪些“好”细菌被抗生素杀死；此外，我们将发现哪些细菌被FMT取代进入肠道，使人们从感染中恢复过来，以及它们是如何做到这一点的。最近的研究表明，胆汁（一种由肝脏产生并分泌到肠道中的液体）的某些成分在显微镜下有助于艰难梭菌的生长，而其他成分则阻止它的生长。基于此，我们怀疑FMT可能通过取代产生改变胆汁组成的酶（称为胆汁盐水解酶（BSH））的肠道细菌而起作用。我们认为，FMT恢复产生bsh的细菌可能会导致阻止艰难梭菌生长的胆汁成分增加，并减少那些帮助细菌分裂的成分。为了调查这一点，我们将从健康人群和患有CDI的人群（包括FMT前和FMT后的人群，包括FMT起作用的人群和没有FMT起作用的人群）中采集样本，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，并调查在所有情况下存在多少BSH酶。然后，我们将测试在患有CDI的肠道模拟模型中添加产生BSH的细菌，看看这是否和FMT一样有效，并评估这些细菌如何影响艰难梭菌的生存。如果我们的数据支持这一假设，我们可能在未来能够从FMT转移到CDI（或有疾病风险的人），而不是通过给予含有产生BSH的细菌的饮料或药丸，或者只含有BSH的细菌。

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.