Impact of Daily Preventive Zinc or Therapeutic Zinc Supplementation for Diarrhea on Plasma Biomarkers of Environmental Enteric Dysfunction among Rural Laotian Children: A Randomized Controlled Trial

K Ryan Wessells, Guy-Marino Hinnouho, Maxwell A Barffour, Charles D Arnold, Sengchanh Kounnavong, Chidchamai Kewcharoenwong, Ganjana Lertmemongkolchai, Gertrud U Schuster, Charles B Stephensen, Sonja Y Hess, K Ryan Wessells, Guy-Marino Hinnouho, Maxwell A Barffour, Charles D Arnold, Sengchanh Kounnavong, Chidchamai Kewcharoenwong, Ganjana Lertmemongkolchai, Gertrud U Schuster, Charles B Stephensen, Sonja Y Hess

Abstract

Environmental enteric dysfunction (EED) may be ameliorated by zinc supplementation. The objective of this study was to investigate the impact of different forms of zinc supplementation on biomarkers of EED (i.e., plasma citrulline, kynurenine, and tryptophan concentrations and the kynurenine:tryptophan [KT] ratio) among young Laotian children. In a double-blind randomized controlled trial, 3,407 children aged 6-23 months were randomized into one of four groups: daily preventive zinc dispersible tablets (PZ; 7 mg zinc), daily multiple micronutrient powders (MNP; 10 mg zinc, 6 mg iron, and 13 other micronutrients), therapeutic zinc supplements for diarrhea treatment (TZ; 20 mg/day for 10 days), or daily placebo powder, and followed up for ∼36 weeks. Plasma samples at baseline and endline for 359 children were analyzed for citrulline, kynurenine, and tryptophan concentrations. At baseline, the prevalence of stunting and zinc deficiency was 37% and 76.5%, respectively. The mean plasma citrulline, kynurenine, and tryptophan concentrations were 24.6 ± 5.4 µmol/L, 3.27 ± 0.83 µmol/L, and 72.3 ± 12.9 µmol/L, respectively; the mean KT ratio (×1,000) was 45.9 ± 12.0. At endline, neither plasma citrulline, kynurenine, or tryptophan concentrations, nor the KT ratio differed among intervention groups (P > 0.05). In this population, PZ, MNP, and TZ had no overall effect on plasma concentrations of citrulline, kynurenine, and tryptophan, or the KT ratio. The need remains to better understand the etiology of EED, and the development of biomarkers to diagnose EED and evaluate the impact of interventions.

Conflict of interest statement

Disclosures: The sponsors had no involvement in the study implementation, data analyses, and manuscript writing.

Figures

Figure 1.
Figure 1.
Flowchart of participant progression through the randomized controlled trial.

References

    1. Lindenmayer GW, Stoltzfus RJ, Prendergast AJ, 2014. Interactions between zinc deficiency and environmental enteropathy in developing countries. Adv Nutr 5: 1–6.
    1. Sanitation Hygiene Infant Nutrition Efficacy Trial Team, Humphrey JH, et al. 2015. The Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial: rationale, design, and methods. Clin Infect Dis 61 (Suppl 7): S685–S702.
    1. Lindenbaum J, Harmon JW, Gerson CD, 1972. Subclinical malabsorption in developing countries. Am J Clin Nutr 25: 1056–1061.
    1. Harper KM, Mutasa M, Prendergast AJ, Humphrey J, Manges AR, 2018. Environmental enteric dysfunction pathways and child stunting: a systematic review. PLoS Negl Trop Dis 12: e0006205.
    1. Crane RJ, Jones KD, Berkley JA, 2015. Environmental enteric dysfunction: an overview. Food Nutr Bull 36 (Suppl 1): S76–S87.
    1. Oria RB, Murray-Kolb LE, Scharf RJ, Pendergast LL, Lang DR, Kolling GL, Guerrant RL, 2016. Early-life enteric infections: relation between chronic systemic inflammation and poor cognition in children. Nutr Rev 74: 374–386.
    1. Brown KH, Peerson JM, Baker SK, Hess SY, 2009. Preventive zinc supplementation among infants, preschoolers, and older prepubertal children. Food Nutr Bull 30 (Suppl 1): S12–S40.
    1. Mayo-Wilson E, Junior JA, Imdad A, Dean S, Chan XH, Chan ES, Jaswal A, Bhutta ZA, 2014. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. Cochrane Database Syst Rev 5: 1 CD009384.
    1. Liu E, Pimpin L, Shulkin M, Kranz S, Duggan CP, Mozaffarian D, Fawzi WW, 2018. Effect of zinc supplementation on growth outcomes in children under 5 years of age. Nutrients 10: E377.
    1. Lazzerini M, Ronfani L, 2013. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 12: CD005436.
    1. Bates CJ, et al. 1993. A trial of zinc supplementation in young rural Gambian children. Br J Nutr 69: 243–255.
    1. Roy SK, Behrens RH, Haider R, Akramuzzaman SM, Mahalanabis D, Wahed MA, Tomkins AM, 1992. Impact of zinc supplementation on intestinal permeability in Bangladeshi children with acute diarrhoea and persistent diarrhoea syndrome. J Pediatr Gastroenterol Nutr 15: 289–296.
    1. Alam AN, Sarker SA, Wahed MA, Khatun M, Rahaman MM, 1994. Enteric protein loss and intestinal permeability changes in children during acute shigellosis and after recovery: effect of zinc supplementation. Gut 35: 1707–1711.
    1. Ryan KN, Stephenson KB, Trehan I, Shulman RJ, Thakwalakwa C, Murray E, Maleta K, Manary MJ, 2014. Zinc or albendazole attenuates the progression of environmental enteropathy: a randomized controlled trial. Clin Gastroenterol Hepatol 12: 1507.e1–1513.e1.
    1. De-Regil LM, Suchdev PS, Vist GE, Walleser S, Pena-Rosas JP, 2011. Home fortification of foods with multiple micronutrient powders for health and nutrition in children under two years of age. Cochrane Database Syst Rev 9: CD008959.
    1. Lamberti LM, Fischer Walker CL, Black RE, 2016. Zinc deficiency in childhood and pregnancy: evidence for intervention effects and program responses. World Rev Nutr Diet 115: 125–133.
    1. Wang AZ, Shulman RJ, Crocker AH, Thakwalakwa C, Maleta KM, Devaraj S, Manary MJ, Trehan I, 2017. A combined intervention of zinc, multiple micronutrients, and albendazole does not ameliorate environmental enteric dysfunction or stunting in rural Malawian children in a double-blind randomized controlled trial. J Nutr 147: 97–103.
    1. Smith HE, et al. 2014. Multiple micronutrient supplementation transiently ameliorates environmental enteropathy in Malawian children aged 12-35 months in a randomized controlled clinical trial. J Nutr 144: 2059–2065.
    1. Kelly P, Shawa T, Mwanamakondo S, Soko R, Smith G, Barclay GR, Sanderson IR, 2010. Gastric and intestinal barrier impairment in tropical enteropathy and HIV: limited impact of micronutrient supplementation during a randomised controlled trial. BMC Gastroenterol 10: 72.
    1. Soofi S, Cousens S, Iqbal SP, Akhund T, Khan J, Ahmed I, Zaidi AK, Bhutta ZA, 2013. Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial. Lancet 382: 29–40.
    1. Jaeggi T, et al. 2015. Iron fortification adversely affects the gut microbiome, increases pathogen abundance and induces intestinal inflammation in Kenyan infants. Gut 64: 731–742.
    1. Crenn P, Vahedi K, Lavergne-Slove A, Cynober L, Matuchansky C, Messing B, 2003. Plasma citrulline: a marker of enterocyte mass in villous atrophy-associated small bowel disease. Gastroenterology 124: 1210–1219.
    1. DeBoer MD, et al. 2018. Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT): a protocol for a randomised factorial, double-blind, placebo-controlled trial of azithromycin, nitazoxanide and nicotinamide. BMJ Open 8: e021817.
    1. Kosek MN, et al. 2016. Plasma tryptophan and the kynurenine-tryptophan ratio are associated with the acquisition of statural growth deficits and oral vaccine underperformance in populations with environmental enteropathy. Am J Trop Med Hyg 95: 928–937.
    1. Le Floc’h N, Otten W, Merlot E, 2011. Tryptophan metabolism, from nutrition to potential therapeutic applications. Amino Acids 41: 1195–1205.
    1. Cervenka I, Agudelo LZ, Ruas JL, 2017. Kynurenines: tryptophan’s metabolites in exercise, inflammation, and mental health. Science 357: eaaf9794.
    1. Wessells KR, et al. 2018. Comparison of two forms of daily preventive zinc supplementation versus therapeutic zinc supplementation for diarrhea on young children's physical growth and risk of infection: study design and rationale for a randomized controlled trial. BMC Nutr 4: 39.
    1. Barffour MA, et al. 2019. Effects of daily zinc, daily multiple micronutrient powder, or therapeutic zinc supplementation for diarrhea prevention on physical growth, anemia, and micronutrient status in rural Laotian children: a randomized controlled trial. J Pediatr 207: 80.e2–89.e2.
    1. de Onis M; World Health Organization Multicentre Growth Reference Study Group , 2007. WHO Child Growth Standards based on length/height, weight and age. Acta Paediatr 95: 76–85.
    1. Adu-Afarwuah S, Lartey A, Brown KH, Zlotkin S, Briend A, Dewey KG, 2008. Home fortification of complementary foods with micronutrient supplements is well accepted and has positive effects on infant iron status in Ghana. Am J Clin Nutr 87: 929–938.
    1. Wuehler SE, Sempertegui F, Brown KH, 2008. Dose-response trial of prophylactic zinc supplements, with or without copper, in young Ecuadorian children at risk of zinc deficiency. Am J Clin Nutr 87: 723–733.
    1. World Health Organization 2008. Indicators for Assessing Infant and Young Child Feeding Practices: Part 1 Definitions. Geneva, Switzerland: WHO.
    1. Vyas S, Kumaranayake L, 2006. Constructing socio-economic status indices: how to use principal components analysis. Health Policy Plan 21: 459–468.
    1. World Health Organization 2010. Indicators for Assessing Infant and Young Child Feeding Practices: Part 2 Measurement. Geneva, Switzerland: WHO.
    1. Coates J, Swindale A, Bilinksky P. Household Food Insecurity Access Scale (HFIAS) for Measurement of Household Food Access: Indicator Guide (V. 3). Washington, DC: FHI 360/FANTA, 2007. Available at: . Accessed November 7, 2013.
    1. Cogill B, 2003. Anthropometric Indicators Measurement Guide. Washington, DC: Food and Nutrition Technical Assistance Project, Academy for Educational Development.
    1. International Zinc Nutrition Consultative Group , 2012. Assessing Population Zinc Status with Serum Zinc Concentration. IZiNCG technical brief no. 2 Available at: . Accessed March 26, 2014.
    1. Erhardt JG, Estes JE, Pfeiffer CM, Biesalski HK, Craft NE, 2004. Combined measurement of ferritin, soluble transferrin receptor, retinol binding protein, and C-reactive protein by an inexpensive, sensitive, and simple sandwich enzyme-linked immunosorbent assay technique. J Nutr 134: 3127–3132.
    1. Killilea DW, Ames BN, 2008. Magnesium deficiency accelerates cellular senescence in cultured human fibroblasts. Proc Natl Acad Sci USA 105: 5768–5773.
    1. Namaste SM, Aaron GJ, Varadhan R, Peerson JM, Suchdev PS; BRINDA Working Group , 2017. Methodologic approach for the biomarkers reflecting inflammation and nutritional determinants of anemia (BRINDA) project. Am J Clin Nutr 106 (Suppl 1): 333S–347S.
    1. Vaghri Z, Guhn M, Weinberg J, Grunau RE, Yu W, Hertzman C, 2013. Hair cortisol reflects socio-economic factors and hair zinc in preschoolers. Psychoneuroendocrinology 38: 331–340.
    1. Hinnouho GM, Bernstein RM, Barffour MA, Arnold CD, Wessells KR, Ratsavong K, Bounheuang B, Kounnavong S, Hess SY, 2018. Impact of two forms of daily preventive zinc or therapeutic zinc supplementation for diarrhea on hair cortisol concentrations among rural Laotian children: a randomized controlled trial. Nutrients 11: E47.
    1. Matyash V, Liebisch G, Kurzchalia TV, Shevchenko A, Schwudke D, 2008. Lipid extraction by methyl-tert-butyl ether for high-throughput lipidomics. J Lipid Res 49: 1137–1146.
    1. Hess SY, Barffour MA, Hinnouho GM, 2019. Lao Zinc Study. Open Science Framework. Available at: Accessed May 13, 2019.
    1. Johnston BC, Guyatt GH, 2016. Best (but oft-forgotten) practices: intention-to-treat, treatment adherence, and missing participant outcome data in the nutrition literature. Am J Clin Nutr 104: 1197–1201.
    1. Tsugawa H, Cajka T, Kind T, Ma Y, Higgins B, Ikeda K, Kanazawa M, VanderGheynst J, Fiehn O, Arita M, 2015. MS-DIAL: data-independent MS/MS deconvolution for comprehensive metabolome analysis. Nat Methods 12: 523–526.
    1. Fan S, Kind T, Cajka T, Hazen SL, Tang WHW, Kaddurah-Daouk R, Irvin MR, Arnett DK, Barupal DK, Fiehn O, 2019. Systematic error removal using random forest for normalizing large-scale untargeted lipidomics data. Anal Chem 91: 3590–3596.
    1. World Health Organization , 2017. Safely Managed Drinking Water–Thematic Report on Drinking Water 2017. Geneva, Switzerland: World Health Organization; Available at: . Accessed February 27, 2019.
    1. Barffour MA, et al. 2018. Effects of two forms of daily preventive zinc and therapeutic zinc supplementation for diarrhea on diarrhea and acute respiratory tract infections in Laotian children (OR32-05). Curr Dev Nutr 2: nzy039.
    1. Hinnouho GM, Wessells KR, Barffour M, Sayasone S, Arnold C, Kounnavong S, Brown K, Hess S, 2019. Effects of different strategies for delivering supplemental zinc on selected fecal markers of environmental enteric dysfunction among young Laotian children (P04-012-19). Curr Dev Nutr 3: nzz051.
    1. Lepage N, McDonald N, Dallaire L, Lambert M, 1997. Age-specific distribution of plasma amino acid concentrations in a healthy pediatric population. Clin Chem 43: 2397–2402.
    1. Syed S, Ali A, Duggan C, 2016. Environmental enteric dysfunction in children. J Pediatr Gastroenterol Nutr 63: 6–14.
    1. Wessells KR, Hess SY, Rouamba N, Ouedraogo ZP, Kellogg M, Goto R, Duggan C, Ouedraogo JB, Brown KH, 2013. Associations between intestinal mucosal function and changes in plasma zinc concentration following zinc supplementation. J Pediatr Gastroenterol Nutr 57: 348–355.
    1. Louis-Auguste J, Greenwald S, Simuyandi M, Soko R, Banda R, Kelly P, 2014. High dose multiple micronutrient supplementation improves villous morphology in environmental enteropathy without HIV enteropathy: results from a double-blind randomised placebo controlled trial in Zambian adults. BMC Gastroenterol 14: 15.
    1. Kosek M, et al. 2013. Fecal markers of intestinal inflammation and permeability associated with the subsequent acquisition of linear growth deficits in infants. Am J Trop Med Hyg 88: 390–396.
    1. Arndt MB, et al. 2016. Fecal markers of environmental enteropathy and subsequent growth in Bangladeshi children. Am J Trop Med Hyg 95: 694–701.
    1. Kosek MN; Mal-Ed Network Investigators , 2017. Causal pathways from enteropathogens to environmental enteropathy: findings from the MAL-ED birth cohort study. EBioMedicine 18: 109–117.
    1. Guerrant RL, et al. 2016. Biomarkers of environmental enteropathy, inflammation, stunting, and impaired growth in children in northeast Brazil. PLoS One 11: e0158772.
    1. Takikawa O, Yoshida R, Kido R, Hayaishi O, 1986. Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase. J Biol Chem 261: 3648–3653.
    1. Gosselin K, et al. 2015. Serum citrulline does not predict stunting or environmental enteric dysfunction in Tanzanian and Malawian infants. FASEB J 29: 403.5.
    1. Taylor MW, Feng GS, 1991. Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5: 2516–2522.
    1. Van der Leek AP, Yanishevsky Y, Kozyrskyj AL, 2017. The kynurenine pathway as a novel link between allergy and the gut microbiome. Front Immunol 8: 1374.
    1. Serrano-Villar S, et al. 2014. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality. PLoS Pathog 10: e1004078.
    1. Gelpi M, Hartling HJ, Ueland PM, Ullum H, Troseid M, Nielsen SD, 2017. Tryptophan catabolism and immune activation in primary and chronic HIV infection. BMC Infect Dis 17: 349.
    1. Humphrey JH, et al. 2019. Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on child stunting and anaemia in rural Zimbabwe: a cluster-randomised trial. Lancet Glob Health 7: e132–e147.
    1. Prendergast AJ, et al. 2019. Independent and combined effects of improved water, sanitation, and hygiene, and improved complementary feeding, on stunting and anaemia among HIV-exposed children in rural Zimbabwe: a cluster-randomised controlled trial. Lancet Child Adolesc Health 3: 77–90.
    1. Luby SP, et al. 2018. Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Bangladesh: a cluster randomised controlled trial. Lancet Glob Health 6: e302–e315.
    1. Null C, et al. 2018. Effects of water quality, sanitation, handwashing, and nutritional interventions on diarrhoea and child growth in rural Kenya: a cluster-randomised controlled trial. Lancet Glob Health 6: e316–e329.
    1. Lin A, et al. 2019. Effects of water, sanitation, handwashing, and nutritional interventions on environmental enteric dysfunction in young children: a cluster-randomized controlled trial in rural Bangladesh. Clin Infect Dis ciz291, doi:10.1093/cid/ciz291.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren