C. difficile is a hospital-acquired infection that causes severe diarrhoea and was a contributing factor to more than 2000 deaths in the UK in 2011. It lives naturally in the body of some people, where other bacteria in the gut suppress its numbers and prevent it from spreading.
If a person has been treated with a broad-spectrum antibiotic such as clindamycin, however, our bodies’ natural bacteria can be destroyed and the gut can become overrun by C. difficile.
The team studied mice that were infected with an aggressive strain of C. difficile, known as O27, which has been responsible for epidemics in Europe, North America and Australia. This strain is known as a ‘supershedder’ because it releases highly resistant spores of bacteria for a prolonged period that are very difficult to eradicate from the environment, a scenario that is likely to occur in hospitals.
It establishes a persistent infection with an extended contagious period that is difficult to treat with antibiotics. The researchers first tried treating the infected mice with a range of antibiotics, but they found that they consistently relapsed to a high level of shedding or contagiousness.
Dr Trevor Lawley, lead author from the Wellcome Trust Sanger Institute, explains: “We then attempted treating the mice using faecal transplantation – homogenised faeces from a healthy mouse. This quickly and effectively supressed the disease and supershedding state with no reoccurrence in the vast majority of cases.”
The team wanted to take this research one step further and isolate the precise bacteria that supressed C. difficile and restored microbial balance of the gut. They cultured a large number of bacteria naturally found in the gut of mice, all from one of four main groups of bacteria found in mammals, and tested many combinations of these bacteria until they isolated a cocktail of six that worked best to suppress the infection.
“The mixture of six bacterial species effectively and reproducibly suppressed the C. difficile supershedder state in mice, restoring the healthy bacterial diversity of the gut,” said Professor Harry Flint, senior author from the University of Aberdeen.
The team then sequenced the genomes of the six bacteria and compared their genetic family tree to more precisely define them. Based on this analysis, the team found that the mixture of six bacteria contained three that have been previously described and three novel species. This mix is genetically diverse and comes from all four main groups of bacteria found in mammals.
These results illustrate the effectiveness of displacing C. difficile and the supershedder microbiota with a defined mix of bacteria, found naturally in the gut.
“Our results open the way to reducing the overuse of antibiotic treatment and harnessing the potential of naturally occurring microbial communities to treat C. difficile infection and transmission, and potentially other diseases associated with microbial imbalances,” explains Professor Gordon Dougan, senior author from the Wellcome Trust Sanger Institute.
“Faecal transplantation is viewed as an alternative treatment, but it is not widely used because of the risk of introducing harmful pathogens, as well as general patient aversion. This model encapsulates some of the features of faecal therapy and acts as a basis to develop standardised treatment mixture.”
Image: Clostridium difficile. Credit: Genome Research Ltd.
Lawley TD et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLOS Pathogens 2012 (epub ahead of print).