Lessons from Diarrheal Diseases: Demography to Molecular Pharmacology

Abstract

From diarrheal diseases come profound lessons about health and population growth, microbial pathogenesis, and the molecular pharmacology of signal transduction. Epidemics such as cholera, hemorrhagic colitis, salmonellosis, and cryptosporidiosis remind us of how interdependent we are, sharing enteric microbial flora on a global scale. Diarrhea morbidity and mortality teach us that disease and poverty do not control but are associated with population overgrowth. Great advances are being made in understanding new bacterial, viral, and parasitic causes and treatment of diarrhea, especially persistent diarrhea. In addition, microbial toxins provide unique pharmacologic tools to probe cell signaling pathways. The mechanism of action of cholera toxin, once thought so clear, now appears to involve additional pathways such as platelet-activating factor and prostaglandin synthesis. Escherichia coli ST has opened a whole family of activators of guanylate cyclase, including new mammalian products that regulate sodium transport. Clostridium difficile toxin A provides a novel tool to dissect mediators involved in inflammatory diarrhea. These lessons have both basic implications for science and practical applications for medicine and society.

Management and prevention of Clostridium difficile-associated diarrhea

“…Platelet-activating factor antagonists, various nonsteroidal anti-inflammatory agents, and COX-2 inhibitors all have been shown to attenuate toxin A-related effects in animal models [36,37]. While none of these compounds have been studied in humans with CDAD, such agents remain a promising avenue of research as adjunctive therapy to antibiotics.…”

Secretory diarrhea

“…Several mechanisms by which diarrhea is produced by microorganisms have been discovered by researchers [5][6][7][8][9]. These mechanisms include enterotoxins that subvert mucosal transport, invasion of the mucosa, bacterial adhesion to the enterocytes, and production of cytotoxins that destroy enterocytes.…”

Why America must care about tropical medicine: threats to global health and security from tropical infectious diseases.

“…Not only has cholera toxin, like E. coli heat-stable toxin, enlightened us about basic cell signaling, 7 but perhaps the most important medical discovery of our century has been the finding that glucose, sugars, or simple starches can drive absorption of water and electrolytes and reduce this mortality to less than 1%. We are now excited about glutamine, and new, more stable derivatives, doing potentially even better at rehydration while also rebuilding the damaged gut mucosa, as a new oral rehydration and nutrition therapy (ORNT) for acute or persistent diarrhea.…”

“…While some like to blame the Pope, even Italy has a lower fertility rate than the United States, Japan, or Sweden (Figure 4). 7,27 Furthermore, there has been a consistent decrease in the period required for the ''demographic transition;'' the time over which infant mortality and fertility decline. This interval has progressively shortened from more than 60 years for western Europe from 1870 to the 1930s, to less than 12-20 years in rapidly developing countries such as Thailand, Botswana, Kenya, and Zimbabwe (1980-1990s).…”