Sunday, November 9, 2014

Using Specific Bacteria to Treat Antibiotic-Induced Diarrheal Disease (C. difficile)

Clostridium difficile establishes infections following
antibiotic treatment and causes diarrheal disease.
There has been a lot of talk about the microbiome and Clostridium difficile infections.  This is because patient antibiotic or chemotherapeutic exposure (both of which can destroy your commensal bacterial communities) increases the risk of C. difficile infection.  This observation suggests a role for commensal bacteria in mediating infection resistance.  The exact commensal bacteria that mediate protection against C. difficile infection are not known, but luckily for us, scientists are working on it.  A paper, recently published in Nature, describes a study that sheds light on what bacteria might be offering protection against C. difficile infection.

Before we dive into the paper, it is important that we understand the basics of C. difficile infections.  As I mentioned above, C. difficile infections are often brought on by heavy exposure to antibiotics or chemotherapeutics, which can both disrupt your commensal gut bacterial communities.  The idea is that the destruction of your commensal gut bacteria opens up an ecological niche which can be filled by the opportunistic C. difficile.  This occupation is what leads to infection, which can result in a nasty diarrheal disease that is a bit of a nightmare to deal with.  One therapy that has been showing promise is the fecal microbiome transplant therapy.

The fecal microbiome transplant is a procedure that does just what it says.  This is a procedure in which a healthy fecal donor sample is prepared and transplanted to the gut of the C. difficile infected patient.  This is a promising approach and is gaining momentum in C. difficile treatment.  While the commensal gut bacterial community provides increased resistance to C. difficile infection, the specific bacteria that mediate the resistance phenotype remain unknown.  Understanding the specific bacteria that promote resistance, and how they promote resistance, could allow for more targeted and fine tuned approaches to treating C. difficile infection.

Electron microscopy image of C. difficile. <Source>
A group led by Charlie Buffie et al, who recently reported their study in Nature, investigated what bacteria may specifically provide protection against C. difficile infection.  The group started by using 16S rRNA gene sequencing to show that administration of different antibiotics in mice have different impacts on bacterial communities and C. difficile infection susceptibility (this confirms previous findings).  The group exposed mice to these different antibiotics and observed that, in some cases, the gut bacterial diversity was low in both C. difficile susceptible and resistant groups.  This observation suggested that there are specific bacteria mediating infection resistance, since diversity alone could not predict susceptibility.  From here they used a combination of murine and human 16S rRNA microbiome data to predict which bacteria are most likely the important mediators of infection resistance.  C. scindens was their strongest candidate from both the human and murine datasets.

To get at functionality and causality, the group administered a cocktail of four bacteria that were correlated with increased infection resistance, and also administered C. scindens alone.  This was done after the mice were treated with antibiotics, and before they were infected with C. difficile.  Surprisingly, the cocktail and C. scindens alone both promoted resistance against C. difficile infection, and the individual cocktail bacteria alone did not improve resistance.  This is a really cool result, and to make things better, they followed up on this by evaluating what specific C. scindens functionality was promoting infection resistance.

Fecal transplants are currently being investigated as
treatments for C. difficile infections. <Source>
Even though they only had 16S rRNA sequence data, the group was able to predict the functionality of the bacterial communities using the program PICRUSt.  PICRUSt uses 16S rRNA gene sequences, along with the functional knowledge of the bacteria they belong to, to predict the functional potential of a bacterial community.  This analysis revealed that levels of secondary bile acid biosynthesis were correlated with C. difficile infection.  In short, the group's analyses suggest that their bacterial cocktail and C. scindens alone restore secondary bile acid biosynthesis, which may explain their ability to promote resistance to C. difficile infection.  They further support this functional dependence of C. scindens mediated infection resistance on bile acids by showing that cholestyramine treatment (a bile acid sequestering agent) prevents C. scindens mediated protection.

Overall this paper was a really cool read and I would suggest you check it out.  And what can we say about the paper?  We can say that, despite a loss in bacterial diversity previously being associated with C. difficile infection, it appears specific bacteria are primarily involved in mediating infection resistance.  C. scindens was the best candidate for mediating C. difficile infection resistance, and its resistance potential was functionally supported.  C. scindens mediated protection is potentially mediated through bile acid synthesis.

Finally, what does this mean in the clinic?  Does this mean you should try to get a pill of C. scindens next time you take antibiotics so that you can prevent a C. difficile infection?  As of now, I think that would be a bit premature.  These are certainly interesting findings, and will be worth watching in the future, but more research will be needed before we can use these bacteria to treat patients in the clinic.

Works Cited

Buffie CG, Bucci V, Stein RR, McKenney PT, Ling L, Gobourne A, No D, Liu H, Kinnebrew M, Viale A, Littmann E, van den Brink MR, Jenq RR, Taur Y, Sander C, Cross J, Toussaint NC, Xavier JB, & Pamer EG (2014). Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature PMID: 25337874

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