Immune - Microbiota Interaction in defense against Clostridium difficile

Sloan-Kettering Inst Can Research, New York NY

Investigators

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Abstract

Project Summary 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