Zinc for Infectious Diarrhea in Developed Countries: Should We Be Sprinkling Our Own Lawns?

Canani and Ruotolo reviewed the data supporting the use of zinc in acute gastroenteritis in developing countries in the Journal in 2006 (1) and opined that a new “zinc era” in enteric infections may be at hand. That evidence prompted the United Nations Children's Fund and the World Health Organization to issue statements endorsing the use of zinc for treatment of acute diarrhea in all children in developing countries. The US Centers for Disease Control and Prevention also endorsed the use of supplemental zinc in acute gastroenteritis in children in developing countries but stopped short of recommending zinc in the US population, stating that “The role of zinc supplements in developed countries needs further evaluation” (2). Since the endorsements were issued by health authorities, several additional reports on the effects of zinc have appeared. One emerging theme among the clinical studies is that the beneficial effects of zinc apparently are not restricted to children who are zinc deficient (3,4). An emerging theme of basic studies on the action of zinc is that the effects of zinc may be pathogen specific, or in the case of toxin-producing organisms, toxin specific. For example, Canani et al found that zinc blocked the secretory effects of cholera toxin and the Escherichia coli heat-labile enterotoxin, LT, which act via cyclic adenosine monophosphate, but not the effects of the E coli heat-stable toxin, ST, which acts via cyclic guanosine monophosphate (5). Those findings were supported by a separate report from one of the present authors [K.M.H., (6)]. Other articles suggesting that zinc may have pathogen-specific effects have also appeared (7). One of us (J.K.C.) recently reported that zinc has direct inhibitory effects on another common pathogen in pediatric diarrhea, enteropathogenic E coli [EPEC, (8)]. In vitro zinc inhibited the expression of several important adhesins and virulence factors in EPEC, including the bundle-forming pilus, intimin, and several EPEC-secreted proteins. In cultured cells zinc inhibited EPEC adherence and EPEC-induced adenosine triphosphate release. In vivo zinc reduced EPEC adherence and blocked EPEC-induced fluid secretion into ligated intestinal loops in zinc-replete rabbits. In ligated ileal loops the protective effect of zinc was limited to the actual loops receiving the zinc, without any cross-protection of neighboring infected loops. This demonstrated that zinc can act locally, possibly in the lumen of the gastrointestinal tract, and that not all of its effects require systemic absorption, at least not with EPEC, which behaves as a noninvasive pathogen. Zinc has been tested in field trials of childhood diarrhea in many countries around the world. The prevailing view at the time those trials were planned and conducted was that zinc acted by correcting zinc deficiency or by stimulating the immune system (9). Perhaps as a result of that view, many of the early field trials of zinc in diarrhea included only cursory diagnostic microbiology or no diagnostic microbiology at all. As a result of the lack of data on infectious etiologies, it is unclear whether zinc is equally effective against all types of infectious diarrhea or whether zinc is particularly active against some pathogens. There are hints that the latter is true. For example, Bhatnagar et al noted that the effect of zinc was greater in children testing positive for rotavirus than those who tested rotavirus negative (4). Our finding that zinc can have effects on the pathogen as well as on the host makes the notion that zinc may act in a pathogen-specific manner even more plausible. Another emerging theme in the basic science studies of zinc is that zinc can act in a drug-like manner rather than strictly as a micronutrient, an idea that has been reflected in recent editorials as well (10). If this is the case, then a short course of zinc at or slightly above the recommended daily value may be better than prolonged, low-dose treatment for specific indications. If zinc has beneficial effects that are independent of zinc deficiency in the host, and if zinc has activity against ubiquitous pathogens such as rotavirus, then should zinc not also be studied in the types of infectious diarrhea common in developed countries? The incidence and severity of diarrhea due to Clostridium difficile is on the increase in the United States, Canada, the United Kingdom, European countries, and Australia (11–15). Norovirus infections and Norovirus outbreaks also appear to be increasing worldwide (16–19). If zinc has beneficial effects (antisecretory, antipathogen, immune-stimulating, or other effects), then this would be welcome news to the patients with these infections and the health care providers who care for them. One popular zinc and mineral supplement is called Sprinkles and has been tested in developing countries around the world (20). Perhaps it is time for us in industrialized countries to study the effects of sprinkling our own backyards.

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