Hospitalized patients receiving antibiotic treatment experience a disruption in the intestinal microbiota enabling opportunistic pathogens, such as Clostridium difficile to colonize the intestinal tract (1-3). Complications resulting from C. difficile associated disease are a major burden on the health care system costing $4.8 billion and resulting in 15,000 ? 20,000 deaths per year (5-7). Current antibiotic treatment options yield a high recurrence rate emphasizing the need to develop alternative treatment strategies (8-10). Recently, fecal microbiota transplantation (FMT) has proven to be a remarkable effective strategy for resolving chronic C. difficile infection (13). The inability to fully define the host and microbial factors that mediate clearance of C. difficile and recently discovered associations of fecal microbiota composition with a range of metabolic and inflammatory diseases raise concerns about the long-term impact of fecal transplantation from heterologous donors (18). The murine model of antibiotic-induced C. difficile infection offers insights into the mechanism of action of FMT and preliminary data presented in this proposal suggests an important role for the host's immune system in supporting FMT efficacy. The K99 phase of this proposal will develop techniques to analyze shifts in bacterial communities, bacterial gene transcription, and metabolic profiles in the intestines following FMT of C. difficile infected mice using high-throughput deep sequencing technology and Gas or Liquid Chromatography- Mass Spectrometry. Having developed these techniques, I will then probe immune mechanisms that influence intestinal microbial communities and FMT-mediated resolution of C. difficile infection.
These aims will expand our knowledge of the role of host's immune sistem in successful FMT therapy of intestinal disorders and potentially identify novel therapeutic targets in treating C. difficile associated disease. 1

Public Health Relevance

The intestinal pathogen Clostridium difficile has become the most common hospital-acquired infection in the United States, and the inefficacy of current antibiotic treatment regimens highlight the need to develop alternative treatment strategies. Fecal transplantation of healthy bacteria into an infected patient's intestinal tract has emerged as a remarkably effective and promising therapy, however, the mechanism through which beneficial bacteria act to clear C. difficile is not well understood. This proposal seeks to understand how the body's own immune defenses work with the fecal transplant to support clearance of C. difficile infection. 1

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Career Transition Award (K99)
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Study Section
Microbiology and Infectious Diseases B Subcommittee (MID-B)
Program Officer
Ranallo, Ryan
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Sloan-Kettering Institute for Cancer Research
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New York
United States
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Abt, Michael C; McKenney, Peter T; Pamer, Eric G (2016) Clostridium difficile colitis: pathogenesis and host defence. Nat Rev Microbiol 14:609-20
Abt, Michael C; Buffie, Charlie G; Sušac, Bože et al. (2016) TLR-7 activation enhances IL-22-mediated colonization resistance against vancomycin-resistant enterococcus. Sci Transl Med 8:327ra25