The intestine performs many functions, including the processes of digestion, absorption, and secretion. Yet, in addition, the intestine also serves as a barrier which prevents bacteria contained within the gut from invading systemic organs. Based on clinical studies, the mucosal barrier to bacteria appears to be lost under certain circumstances resulting in systemic sepsis. In fact, life-threatening infections with gut-associated bacteria, in which no infective focus can be found even at autopsy, is a major clinical problem in burn and trauma victims, ICU patients and patients developing multiple organ failure. We have previously established that bacteria can translocate across the mucosal barrier and spread systemically under a variety of experimental conditions. Most recently, we have observed that parenteral and certain enteral diets promote bacterial translocation and that protein-malnourished animals are more susceptible to lethal gut origin sepsis than normally-nourished animals. Since the mechanisms underlying these observations are not well understood, the central goal of this proposal is to investigate the physiology of normal intestinal barrier function and to determine how these defenses are altered by nutritional perturbations that promote or prevent bacterial translocation. Since the initial event in translocation is the crossing of the mucosal barrier by bacteria, this proposal will focus an the early stages of the translocation process. Specifically, AIM I will focus on the physiology of the intestinal barrier under normal and nutritionally perturbed circumstances, while AIM II will concentrate on the bacterial arm of the translocation process. To achieve these AIMS, the translocation process will be investigated in three distinct experimental systems, since in no one system is it possible to adequately characterize or elucidate the various potential mechanisms involved in normal intestinal barrier function or how these defenses are altered under conditions associated with bacterial translocation. The three experimental systems are; 1) in vivo animal models, 2) a cultured epithelial monolayer model (Caco-2 cells), and 3) the Ussing chamber system, in which the barrier function of intestinal mucosa harvested from animals subjected to various nutritional regimens is tested in vitro. The investigations outlined in this proposal will help clarify the mechanisms that promote bacterial translocation from the gut and thus provide information for developing therapeutic strategies to prevent systemic infections by organisms colonizing the patient's GI tract.
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