With the improved understanding and control of acute diarrheal illnesses, prolonged diarrheal illnesses and now emerging as a leading cause of morbidity and mortality. However, the epidemiology, etiology and pathogenesis of prolonged diarrheal remain very poorly understood. Several investigators have described bacterial overgrowth in the upper small bowel of patients with prolonged diarrhea or malnutrition; however, their specific nature and role in causing disease remain unknown. Based on studies with colonizing, non-toxigenic E. coli in piglets (19) and in human volunteers (20), we have recently demonstrated that the non-toxigenic, human colonizing E. coli strain 1392+ (CFA/II) but not the CFA/II negative derivative, colonizes the small intestine in large numbers and causes prolonged diarrhea in a rabbit model (17), establishing that colonization per se can cause prolonged small intestinal net secretion and diarrhea. We postulate that prolonged diarrhea is more common than generally recognized, has significant predisposing risk factors, and that combinations of specific infections (such as C. pylori gastritis with achlorhydria, and small bowel colonization with specific colonizing bacteria) derange small bowel electrolyte and nutrient absorption in susceptible hosts to cause prolonged diarrhea. Our overall objective is to determine the epidemiology, predisposing factors, etiologies, and pathogenesis of prolonged diarrhea in a highly endemic area, the tropical, developing Northeast of Brazil. We shall follow a cohort of infants born in an urban favela (slum) in Fortaleza, Ceara for frequency, risk factors, potential etiologies and the sequence of events leading to prolonged diarrhea (>14d). We shall conduct detailed fecal studies of 500 cases of all diarrhea and 100 cases of prolonged illness (to include 50 cases of sequential sampling of cases that become prolonged), then conduct intubation and balance studies of 50 children and 30 adults with prolonged diarrhea (>14, <30 days) and controls to examine potential etiologies (including quantitative cultures of adherent flora), host differences, and functional derangements. We shall determine the role and mechanisms by which colonizing Enterobacteriaciae either alone or in concert with other agents such as C. pylori or rotaviruses may contribute to prolonged intestinal dysfunction and malnourishing diarrhea. These studies will define potential risk factors and the sequence of events that lead to prolonged diarrhea, its etiologies and the key host factors and functional derangements that must be considered in controlling this important problem.
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