Clostridium difficile Infection

One major long-term goal of our program is to develop new and better treatments for C. difficile infection. Intestinal microbiota transplantation is remarkably successful in treating patients with this infection even when it cannot be cleared with any other standard treatments. Somehow our own microbiota can keep C. difficile in check. Therefore, we hope to harness the power of our own microbiome to solve this problem. We are actively working in these areas:

  1. Develop intestinal microbiota therapeutics that can be ultimately introduced into widespread clinical practice. Our group was first to publish a protocol for standardized preparation of intestinal microbiota, including its cryopreservation for long-term storage (Hamilton et al., 2012). We are currently working on next-generation preparations that will be easier to store and deliver to patients. As we learn more about mechanisms of how intestinal microbiota transplants work, we hope to develop preparations that will have even higher treatment potency.
  2. Identify the mechanisms of how intestinal microbiota control C. difficile infection. Our group was the first to demonstrate that donor microbial communities engraft into patients with multiply recurrent C. difficile infections (Khoruts et al., 2010). We have since further built on this initial finding and demonstrated that the procedure leads to restoration of the normal distal gut microbial community structure (Hamilton et al., 2013; Shankar et al., 2014; Weingarden et al., 2014). In addition, we found that patients with multiply recurrent C. difficile infection become deficient in secondary bile acid metabolism, and the remaining (primary) bile acids in their intestines actually promote germination and growth of C. difficile bacteria. IMT restores the secondary bile acid metabolism, and the secondary bile acids are inhibitory to C. difficile (Weingarden et al., 2014). This mechanistic insight is now the foundation of a number of new initiatives in developing treatments for C. difficile infection.

Selected References
Hamilton, M.J., A.R. Weingarden, M.J. Sadowsky, and A. Khoruts. 2012. Standardized frozen preparation for transplantation of fecal microbiota for recurrent Clostridium difficile infection. The American journal of gastroenterology 107:761-767.

Hamilton, M.J., A.R. Weingarden, T. Unno, A. Khoruts, and M.J. Sadowsky. 2013. High-throughput DNA sequence analysis reveals stable engraftment of gut microbiota following transplantation of previously frozen fecal bacteria. Gut microbes 4:125-135.

Khoruts, A., J. Dicksved, J.K. Jansson, and M.J. Sadowsky. 2010. Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. Journal of clinical gastroenterology 44:354-360.

Shankar, V., M.J. Hamilton, A. Khoruts, A. Kilburn, T. Unno, O. Paliy, and M.J. Sadowsky. 2014. Species and genus level resolution analysis of gut microbiota in Clostridium difficile patients following fecal microbiota transplantation. Microbiome 2:13.

Weingarden, A.R., C. Chen, A. Bobr, D. Yao, Y. Lu, V.M. Nelson, M.J. Sadowsky, and A. Khoruts. 2014. Microbiota transplantation restores normal fecal bile acid composition in recurrent Clostridium difficile infection. American journal of physiology. Gastrointestinal and liver physiology 306:G310-319.

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