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

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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.