RESUMEN
BACKGROUND: The efficacy of vitamin A supplementation on diarrheal disease morbidity may reflect the divergent effects that supplementation has on pathogen-specific immune responses and pathogen-specific outcomes. OBJECTIVE: We examined how vitamin A supplementation modified associations between gut-cytokine immune responses and the resolution of different diarrheal pathogen infections. DESIGN: Stools collected from 127 Mexican children who were 5-15 mo old and enrolled in a randomized, placebo-controlled vitamin A supplementation trial were screened for enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), and Giardia lamblia. Fecal concentrations of interleukin (IL)-6, IL-8, IL-4, IL-5, IL-10, monocyte chemoattractant protein 1 (MCP-1), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) were measured by using an enzyme-linked immunosorbent assay. Hazard models that incorporated categorized cytokine variables (ie, nondetectable, less than the median of detectable concentrations, and at least the median of detectable concentrations) were fit to the length of pathogen infections stratified by treatment group. RESULTS: Vitamin A-supplemented children with fecal MCP-1 or IL-8 concentrations less than the median of detectable concentrations and IL-10 concentrations of at least median concentrations had longer durations of EPEC infection than did children in the placebo group. In supplemented children, detectable fecal TNF-α or IL-6 concentrations were associated with shorter ETEC infection durations, whereas MCP-1 concentrations of at least the median were associated with longer infection durations. Children in this group who had IL-4, IL-5, or IFN-γ concentrations of at least median detectable concentrations had shorter durations of G. lamblia infection. CONCLUSION: The effect of supplementation on associations between fecal cytokine concentrations and pathogen infection resolution depends on the role of inflammatory immune responses in resolving specific pathogen infections.
Asunto(s)
Diarrea Infantil/tratamiento farmacológico , Diarrea Infantil/inmunología , Suplementos Dietéticos , Infecciones por Enterobacteriaceae/tratamiento farmacológico , Enterobacteriaceae/aislamiento & purificación , Inmunidad/efectos de los fármacos , Vitamina A/uso terapéutico , Inmunidad Adaptativa/efectos de los fármacos , Citocinas/análisis , Enterobacteriaceae/efectos de los fármacos , Infecciones por Enterobacteriaceae/microbiología , Escherichia coli Enteropatógena/efectos de los fármacos , Escherichia coli Enteropatógena/aislamiento & purificación , Escherichia coli Enterotoxigénica/efectos de los fármacos , Escherichia coli Enterotoxigénica/aislamiento & purificación , Heces/química , Heces/microbiología , Femenino , Giardia lamblia/efectos de los fármacos , Giardia lamblia/aislamiento & purificación , Humanos , Inmunidad Innata/efectos de los fármacos , Inmunidad Mucosa/efectos de los fármacos , Lactante , Masculino , México , Modelos de Riesgos ProporcionalesRESUMEN
The identification of immune response mechanisms that contribute to the control of diarrheal disease in developing countries remains an important priority. We addressed the role of fecal chemokines and cytokines in the resolution of diarrheal Escherichia coli and Giardia lamblia infections. Stools collected from 127 Mexican children 5 to 15 months of age enrolled in a randomized, double-blind, placebo-controlled, vitamin A supplementation trial were screened for enteropathogenic Escherichia coli (EPEC), enterotoxigenic E. coli (ETEC), and Giardia lamblia. Fecal concentrations of tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein-1 (MCP-1), interleukin-4 (IL-4), IL-5, IL-6, IL-8, IL-10, and interferon-gamma (IFN-gamma) were determined. Hazard models incorporating cytokine variables were fit to durations of asymptomatic and symptomatic pathogen infections, controlling for treatment group. Increased levels of TNF-alpha and IL-6 were associated with decreased durations of EPEC infection and increased ETEC durations. Increased IL-4 and IFN-gamma levels were associated with decreased and increased durations, respectively, of both EPEC and ETEC infections. Increased IL-10 levels were associated with increased and decreased durations of asymptomatic and symptomatic EPEC infections, respectively, and increased durations of both asymptomatic and symptomatic ETEC infections. Increased levels of MCP-1, IFN-gamma, IL-4, and IL-5 were associated with increased G. lamblia infection duration, while increased IL-8 levels were associated with decreased durations. Differences in proinflammatory and Treg cytokine levels are associated with differences in the resolution of inflammatory and noninflammatory pathogen infections.
Asunto(s)
Diarrea/inmunología , Enteritis/inmunología , Infecciones por Escherichia coli/inmunología , Escherichia coli/inmunología , Giardia lamblia/inmunología , Giardiasis/inmunología , Inmunidad Mucosa , Inmunidad Adaptativa , Animales , Citocinas/análisis , Heces/química , Humanos , Inmunidad Innata , Lactante , México , Ensayos Clínicos Controlados Aleatorios como Asunto , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Vitamina A/administración & dosificaciónRESUMEN
The impact of vitamin A supplementation on childhood diarrhea may be determined by the regulatory effect supplementation has on the mucosal immune response in the gut. Previous studies have not addressed the impact of vitamin A supplementation on the production of monocyte chemoattractant protein 1 (MCP-1), an essential chemokine involved in pathogen-specific mucosal immune response. Fecal MCP-1 concentrations, determined by an enzyme-linked immuno absorption assay, were compared among 127 Mexican children 5-15 mo of age randomized to receive a vitamin A supplement (<12 mo of age, 20,000 IU of retinol; > or =12 mo, 45,000 iu) every 2 mo or a placebo as part of a larger vitamin A supplementation trial. Stools collected during the summer months were screened for MCP-1 and gastrointestinal pathogens. Values of MCP-1 were categorized into 3 levels (nondetectable,
Asunto(s)
Quimiocina CCL2/análisis , Quimiocina CCL2/inmunología , Diarrea/inmunología , Intestinos/inmunología , Vitamina A/administración & dosificación , Animales , Antiinflamatorios/administración & dosificación , Ascariasis/inmunología , Ascaris lumbricoides , Quimiocina CCL2/biosíntesis , Diarrea/microbiología , Diarrea/parasitología , Suplementos Dietéticos , Ensayo de Inmunoadsorción Enzimática , Infecciones por Escherichia coli/inmunología , Heces/química , Heces/microbiología , Heces/parasitología , Giardia lamblia , Giardiasis/inmunología , Humanos , Lactante , Intestinos/química , Modelos Logísticos , México , PlacebosRESUMEN
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-gamma (IFN-gamma), and gastrointestinal pathogens. Fecal cytokine values were categorized into 3 levels (undetectable,