May 2007: 218 –232 Special Article The Comparative Impact of Iron, the B-Complex Vitamins, Vitamins C and E, and Selenium on Diarrheal Pathogen Outcomes Relative to the Impact Produced by Vitamin A and Zinc Kurt Z. Long, PhD, Jorge L. Rosado, PhD, and Wafaie Fawzi, MBBS, DrPH Micronutrient supplementation offers one of the most cost-effective means of improving the health and sur- vival of children in developing countries. However, the effects of supplementation with single micronutri- ents on diarrhea are not always consistent, and sup- plementation with multi-micronutrient supplements can have negative effects. These inconsistencies may result from the failure to consider the diverse etiolog- ical agents that cause diarrhea and the unique effects each micronutrient has on the immune response to each of these agents. This review examines the sepa- rate effects that supplementation with the B-complex vitamins, vitamin C, vitamin E, selenium, and iron have on diarrheal disease-related outcomes. Supple- mentation with iron may increase the risk of infection by invasive diarrheal pathogens, while supplementa- tion with the remaining micronutrients may reduce this risk. These differences may be due to distinct regulatory effects each micronutrient has on the pathogen-specific immune response, as well as on the virulence of specific pathogens. The findings of these studies suggest that micronutrient supplementation of children must take into account the pathogens preva- lent within communities as reflected by their diarrheal disease burdens. The effectiveness of combining mul- tiple micronutrients into one supplement must also be reconsidered. Key words: B-complex vitamins, diarrhea pathogens, iron, selenium, vitamin C, vitamin E © 2007 International Life Sciences Institute doi: 10.1301/nr.2007.may.218 –232 INTRODUCTION An extensive literature now exists reporting the association between specific micronutrient deficiencies among children in developing countries and an increased risk of diarrheal disease morbidity and related mortality. 1 However, clinical trials testing the effectiveness of sup- plementation with single micronutrients or combined multiple micronutrients have not produced consistent results. 2 The failure to find a clear effect of micronutrient supplementation may reflect an underlying heterogeneity in the etiology of this disease group. Diarrheal disease is caused by an extensive and diverse group of patho- gens. 3,4 The prevalence of these pathogens can vary within and between communities due to differences in the implementation of hygiene and sanitation measures that play a role in their transmission. 5-7 The inconsistent effects reported in previous trials may partly be due to the analysis of diarrheal disease as one single disease, which ignores this etiological diversity. The heterogeneity of the immune response elicited during specific pathogen infections and the regulatory effect individual micronutrients have on these responses may also be responsible for these inconsistent findings. Each pathogen carries distinct sets of antigenic epitopes that can induce unique immune responses in the host. These responses can lead to the resolution of the infec- tion or can lead to pathogenesis if the response is inad- equate or inappropriate. Specific micronutrients have different regulatory effects on these pathogen-specific immune responses and so differ in their ability to up- or Dr. Long is with the Department of Nutrition, Har- vard School of Public Health, Boston, Massachusetts; Dr. Rosado is with the School of Natural Sciences, Universidad Auto ´ noma de Quere ´ taro, Quere ´ taro, Me ´ x- ico; Dr. Fawzi is with the Department of Nutrition, Harvard School of Public Health and the Department of Epidemiology, Harvard School of Public Health. Please address all correspondence to: Dr. Kurt Long, Harvard School of Public Health, Department of Nutrition, Harvard School of Public Health, 1663 Tremont Street, Boston MA, 02115; Phone: 617- 432-1222; Fax: 617-432-1355; E-mail: klong@ hsph.harvard.edu. Supported by grants from the National Council of Science and Technology of Mexico and National In- stitutes of Health grant no. K01 DK06142-02. 218 Nutrition Reviews, Vol. 65, No. 5