Role of Cytokines in Persistent Diarrhea

Despite advances in the diagnosis and control of acute diarrhea, persistent diarrhea has emerged as a major cause of morbidity and mortality that is poorly understood. In our studies in Fortaleza amidst Brazil's impoverished Northeast, we find that persistent diarrhea causes over 30% of all diarrhea morbidity and over 50% of all diarrhea mortality. Furthermore, we have recently found that persistent diarrhea severely disrupts intestinal barrier function, is caused by emerging pathogens including Cryptosporidium and enteroaggregative E. coli, and predisposes to a prolonged, 2-3-fold increase in post illness diarrhea burden over several months after the persistent diarrheal illness. Yet little is known about the pathogenesis or therapy of this quietly devastating disease. New methods now enable the study of inflammatory markers and cytokines which are found in a growing range of enteric infections and may be involved in the disruption of intestinal barrier function and in the prolonged post illness increased diarrhea burden. In addition, recently developed noninvasive methods to assess disrupted intestinal barrier function now enable us to study the role of cytokines in this barrier disruption and its repair by novel, functionally directed glutamine derivatives and micronutrients. We postulate that the major causes of persistent diarrhea are associated with increased enteric proinflammatory cytokines that may disrupt intestinal epithelial barrier function, that disease expression with persistent diarrhea is determined by cellular immunity, and that a new, stable glutamine derivative and micronutrients will speed the repair of disrupted intestinal barrier function. We therefore propose to build upon the unique strengths in this TMRC Consortium to (A) characterize the role of cytokines in the immunopathogenesis of major enteric protozoal and bacterial infections that cause persistent diarrhea in children and in patients with AIDS, (B) define the cellular immunologic determinants of persistent diarrhea in a population of children at a high risk for Cryptosporidium, enteroaggregative E. coli and other enteric infections and (C) to evaluate the immediate and long-term benefits of the new stable tripeptide alanyl- glutaminyl-glutamine and vitamin A and zinc in the repair of disrupted epithelial function. These areas opened by our new TMRC consortium uniquely address the roles of cytokines and cellular immunity in the immunopathogenesis of as well as novel approaches to intestinal repair in cryptosporidial, enteroaggregative E. coli and other persistent diarrheal illnesses. In addition to bridging outstanding institutions in the highly endemic Northeast of Brazil for heavy tropical disease burdens, these studies hold great promise for improving the control of this major global threat to health and its potentially devastating nutritional impact throughout developing, tropical areas.