EMBARGOED UNTIL: Monday 5/20, 3 PM MDT

(Symposium Session 140, Paper )

Casey Theriot
The University of Michigan
Ann Arbor, MI, United States
Phone: 919-757-6006
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Clostridium difficile infection following the administration of antibiotics is the most common hospital-acquired infectious disease. There has been a recent increase in deaths and healthcare costs associated with C. difficile infection. This infection produces a range of disease from mild diarrhea to severe inflammation of the colon. Major risk factors for getting this infection include staying in the hospital and taking antibiotics. We know that antibiotics change the makeup of the “good” bacteria in the gut, but we do not know how this allows “bad” bacteria to flourish. In this study, we show how antibiotics not only change the bacterial makeup of the gut but also shape the nutrients there. Furthermore, we show that C. difficile uses many of these nutrients as a food source boosting growth. This is the first study to examine how bacteria in the gut shape the nutrient environment and foster the growth of this persistent pathogen. We hope that new treatments to combat this infection will arise from these findings.

This research was performed by Casey M. Theriot, PhD at the University of Michigan in Ann Arbor, Michigan in the laboratory of Vincent B. Young, MD/PhD. Conceived/designed the experiments: CMT, MJK, PEC, GBH, and VBY. Performed the experiments: CMT, MJK, PEC, and GEH. Performed the analysis: CMT, AMN, BL, and JL. This work was funded by NIH grant U19 (1U19AI090871-01) (PEC, JL, GBH and VBY). AMN and CMT were funded by training grant NHLBI T32 HL007749 and others included MJK (5T32 AI007528). These data were presented at the American Society of Microbiology General Meeting in Denver, CO on Monday May 20, 2013. 

We found that antibiotic administration resulted in distinct changes in the gastrointestinal microbiome and metabolome. We correlated specific alterations of the microbiome and metabolome to identify multiple states of the gastrointestinal ecosystem that were resistant to C. difficile infection (CDI). These states had distinct microbial community structures, but similar metabolic function. The metabolic environment of the murine gastrointestinal tract after antibiotic treatment was enriched in primary bile acids and carbohydrates that supported germination and growth of C. difficile in vitro. This is the first report to illustrate how the structure of the gut microbiome can shape function and, ultimately, influence disease outcome. Understanding how the structure of the indigenous gut microbiota shapes pathogen and host metabolism is vital for the development of novel therapies for CDI.

To link microbiome community structure to function, we characterized both the murine gut microbiome and metabolome following antibiotic administration. We found two distinct community structures that both exhibited complete colonization resistance against the C. difficile. Although these two resistant community structures had observable differences with regards to the total metabolome, they were indistinguishable with respect to primary and secondary bile acids, carbohydrates, and fatty acids. Our in vitro data further supports the concept that the changes immediately following antibiotic administration were sufficient to substantially induce germination and growth, thus could act as a key mechanistic link between antibiotic use and C. difficile susceptibility.

This study also indicates that multiple community structures of the microbiome can share identical function. This is compatible with the findings that humans may possess one of several “enterotypes” (specific communities that are distinguished by particular dominant bacterial members), but all have normal gastrointestinal health. We determined that the ability to metabolize bile acids and ferment carbohydrates into SCFAs could be carried out both by a community with an equal abundance of Firmicutes and Bacteroidetes as well as one that dominated by Firmicutes alone. These results underscore the importance of looking beyond microbiome community structure and measuring functional aspects when determining the relationship between the microbiome and human health and disease. Our ability to gain insight into the metabolic function of the microbiome, beyond just the structure of the community, should lead to diagnostic and therapeutic modalities targeting the microbiome in response to C. difficile infection and other diseases.