The link between malnutrition and chronic diarrhea is particularly strong early in life. ^13,14 It has been shown that intestinal permeability is exacerbated by zinc deficiency. A 5mg/day zinc supplement suffices to improve that condition,¹⁵ although protein losses cannot be fully controlled, even with a higher dose.¹⁶ More recently it has been shown that zinc supplements improve the speed of recovery and diminish week long diarrhea episodes.⁵ Zinc supplements (20 mg/day) with multivitamins reduced 33% illness duration in Bangladeshi children ⁶ Equally encouraging results were obtained in Pakistan with doses of 3mg/kg/day ¹⁷ and in Peru, with 20 mg/day ⁷ Of even greater significance appears to be the fact that zinc supplementation, even in modest doses, not only reduced diarrheal disease duration and prevalence, but also diminished the incidence of pneumonia. ¹⁸

A general feature of these trials is that infants and children who were growth retarded and malnourished improved better than others with zinc supplementation. Two mechanisms have been proposed to account for the interaction between zinc deficiency and diarrhea. The expression of nitric oxide synthase, the enzyme involved in the formation of nitric oxide from L-arginine, is greater in the intestine of zinc deficient rats, especially after induction of the enzyme by interleukin (IL-1a). ¹⁹ Alternatively, it has been reported that in zinc deficiency there is over expression or uroguanylin, a peptide related to the cellular receptor of thermostable E. coli toxin. ²⁰ This would present a greater number of receptor sites for toxin attachment and thus trigger the chain of reactions leading to diarrhea.²¹ A potential benefit of the presence of zinc salts in the intestinal lumen may be that they could act as nitric oxide scavengers and reduce its intracellular biologic effects.²²

A number of randomized controlled trials carried out in developing countries explored the efficacy of zinc in preventing intestinal infections. The incidence and duration of acute and persistent diarrhea were significantly lower in zinc supplemented children versus placebo-treated counterparts ^23,24 Moreover, in children younger than 5 years, zinc treatment during acute diarrhea illness resulted in fewer subsequent diarrhea episodes and in a concomitant reduction in the use of antibiotics .25,26 The preventive and therapeutic effects of zinc in reducing diarrhea morbidity have relevant economic implications in terms of hospitalization and antibiotic use .²⁷



Given the benefits of zinc supplementation in a large number of studies, in May 2004, the United Nations Children's Fund (UNICEF) and the WHO issued a statement recommending that all children with diarrhea in developing countries be treated with zinc. ²⁷ The new WHO/UNICEF recommendation to incorporate zinc supplementation into diarrhea management is based on a substantial body of scientific evidence of benefits emerging from 17 efficacy studies - 12 on acute and 5 on persistent diarrhea.28,29 Together these studies have demonstrated that zinc in addition to ORS reduces both the duration and severity of acute diarrhea relative to treatment with ORS alone^28,29.These benefits are significant both statistically and clinically. Treatment of diarrhea for 10-14 days with zinc supplements also reduces the incidence of diarrhea and pneumonia in the 2-3 months after the treatment with zinc supplements .30A large community-based study in Bangladesh demonstrated the feasibility of incorporating zinc into diarrhea treatment with ORS into a program setting .26 This effectiveness study recorded a reduction in duration of diarrhea in those given zinc that was comparable to the efficacy studies. The study also noted significant reductions in hospitalizations from diarrhea and overall mortality among children living in villages where zinc in addition to ORS was available relative to those living in areas where only ORS was available. Additionally, the use of zinc was associated with important indirect benefits. For example, inappropriate use of antibiotics and other medicines was reduced, visits to pharmacies and village drug sellers were also reduced, and the use of ORS was increased .²⁶ Available evidence also indicates that zinc for diarrhea treatment is highly cost-effective.