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Nutritional Immunology

The Effect of Vitamin A Supplementation on the Intestinal Immune Response in Mexican Children Is Modified by Pathogen Infections and Diarrhea^1,2

Kurt Z. Long^*,3, Teresa Estrada-Garcia, Jorge L. Rosado^**, Jose Ignacio Santos, Meredith Haas, Mathew Firestone, Jui Bhagwat^*, Cheryl Young, Herbert L. DuPont^#, Ellen Hertzmark^* and Nanda N. Nanthakumar

^* Department of Nutrition, Harvard School of Public Health, Boston MA; Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico City, Mexico; ^** Universidad Autonoma de Queretero, Queretero, Mexico; Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico; DePauw University Greencastle, IN; Department of Anthropology, Harvard University, Boston MA; ^# University of Texas Medical School, and School of Public Health, Houston, TX; and Harvard Medical School, Boston, MA

³ To whom correspondence should be addressed. E-mail: klong{at}hsph.harvard.edu.

Vitamin A supplementation has consistently reduced infant mortality and the severity of pathogen-induced diarrhea. The mechanism by which vitamin A modulates the mucosal immune response to produce these effects remains poorly defined. To address this issue, stools collected during the summer months from 127 Mexican children 5–15 mo old enrolled in a larger, randomized, double-blind, placebo-controlled, vitamin A supplementation trial were screened for interleukin (IL)-4, IL-6, interferon- (IFN-), and gastrointestinal pathogens. Fecal cytokine values were categorized into 3 levels (undetectable, <median, median). Multinomial regression models were used to determine the probability that vitamin A–supplemented children had higher categorical values of a cytokine than children in the placebo group. Differences in categorical values were also analyzed after stratification by gastrointestinal pathogen infections and diarrheal symptoms. Overall, fecal cytokine categorical levels did not differ between children randomized to the 2 arms. Vitamin A–supplemented children infected with enteropathogenic E. coli (EPEC) had reduced IL-4 and IFN- levels [odds ratio (OR) = 0.3, 95% CI 0.13–0.67 and OR = 0.34, 95% CI 0.14–0.83, respectively] compared with children in the placebo group. Vitamin A–supplemented children had increased IL-4 levels when infected with A. lumbricoides (OR = 12.06, 95% CI 0.95–153.85). In contrast, IL-4 levels increased (OR = 2.14, 95% CI 0.94–4.87) and IFN- levels decreased (OR = 0.51, 95% CI 0.26–0.99) among vitamin A–supplemented children with diarrhea compared with children in the placebo group. These findings suggest that the regulation of the mucosal immune response by vitamin A may depend on the type of enteric pathogen infecting the child and the presence of clinical symptoms.

KEY WORDS: • Vitamin A • cytokine • diarrheal pathogen • children

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