Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Minerals, trace elements, Vit. D and bone health

Vitamin-D status is not a confounder of the relationship between zinc and diarrhoea: a study in 6–24-month-old underweight and normal-weight children of urban Bangladesh

European Journal of Clinical Nutrition volume 70, pages 620–628 (2016)Cite this article

Subjects

Abstract

Background/Objective:

The role of micronutrients particularly zinc in childhood diarrhoea is well established. Immunomodulatory functions of vitamin-D in diarrhoea and its role in the effect of other micronutrients are not well understood. This study aimed to investigate whether vitamin-D directly associated or confounded the association between other micronutrient status and diarrhoeal incidence and severity in 6–24-month underweight and normal-weight children in urban Bangladesh.

Subjects/Methods:

Multivariable generalised estimating equations were used to estimate incidence rate ratios for incidence (Poisson) and severity (binomial) of diarrhoea on cohorts of 446 normal-weight and 466 underweight children. Outcomes of interest included incidence and severity of diarrhoea, measured daily during a follow-up period of 5 months. The exposure of interest was vitamin-D status at enrolment.

Results:

Normal-weight and underweight children contributed 62 117 and 62 967 day observation, with 14.2 and 12.8 days/child/year of diarrhoea, respectively. None of the models showed significant associations of vitamin-D status with diarrhoeal morbidity. In the final model, zinc-insufficient normal-weight children had 1.3 times more days of diarrhoea than sufficient children (P<0.05). Again zinc insufficiency and mother's education (1–5 and >5 years) had 1.8 and 2.3 times more risk of severe diarrhoea. In underweight children, older age and female had 24–63 and 17% fewer days of diarrhoea and 52–54 and 31% fewer chances of severe diarrhoea.

Conclusion:

Vitamin-D status was not associated with incidence and severity of diarrhoea in study children. Role of zinc in diarrhoea was only evident in normal-weight children. Our findings demonstrate that vitamin-D is not a confounder of the relationship between zinc and diarrhoea.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

Similar content being viewed by others

References

  1. Liu L, Johnson HL, Cousens S, Perin J, Scott S, Lawn JE et al. Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000. Lancet 2012; 379: 2151–2161.

    Article  Google Scholar 

  2. Walker CL, Rudan I, Liu L, Nair H, Theodoratou E, Bhutta ZA et al. Global burden of childhood pneumonia and diarrhoea. Lancet 2013; 381: 1405–1416.

    Article  Google Scholar 

  3. WHO. Global Health Observatory Data Repository. Available at: http://apps.who.int/gho/data/view.main.gbdc-BGD (last accessed 15 March 2013).

  4. Mayo-Wilson E, Imdad A, Herzer K, Yakoob MY, Bhutta ZA . Vitamin A supplements for preventing mortality, illness, and blindness in children aged under 5: systematic review and meta-analysis. BMJ 2011; 343: d5094.

    Article  Google Scholar 

  5. Mayo-Wilson E, Junior JA, Imdad A, Dean S, Chan XH, Chan ES et al. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. Cochrane Database Syst Rev 2014; 5: Cd009384.

    Google Scholar 

  6. Hewison M . An update on vitamin D and human immunity. Clin Endocrinol (Oxf) 2012; 76: 315–325.

    Article  CAS  Google Scholar 

  7. Liu PT, Stenger S, Li H, Wenzel L, Tan BH, Krutzik SR et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006; 311: 1770–1773.

    Article  CAS  Google Scholar 

  8. Hewison M . Vitamin D and the immune system: new perspectives on an old theme. Rheum Dis Clin N Am 2012; 38: 125–139.

    Article  Google Scholar 

  9. Adams JS, Hewison M . Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008; 4: 80–90.

    Article  CAS  Google Scholar 

  10. Yamshchikov AV, Desai NS, Blumberg HM, Ziegler TR, Tangpricha V . Vitamin D for treatment and prevention of infectious diseases: a systematic review of randomized controlled trials. Endocr Pract 2009; 15: 438–449.

    Article  Google Scholar 

  11. Youssef DA, Miller CW, El-Abbassi AM, Cutchins DC, Cutchins C, Grant WB et al. Antimicrobial implications of vitamin D. Dermatoendocrinol 2011; 3: 220–229.

    Article  CAS  Google Scholar 

  12. Thornton KA, Marin C, Mora-Plazas M, Villamor E . Vitamin D deficiency associated with increased incidence of gastrointestinal and ear infections in school-age children. Pediatr Infect Dis J 2013; 32: 585–593.

    Article  Google Scholar 

  13. Aluisio AR, Maroof Z, Chandramohan D, Bruce J, Mughal MZ, Bhutta Z et al. Vitamin D(3)supplementation and childhood diarrhea: a randomized controlled trial. Pediatrics 2013; 132: e832–e840.

    Article  Google Scholar 

  14. Craig TA, Benson LM, Naylor S, Kumar R . Modulation effects of zinc on the formation of vitamin D receptor and retinoid X receptor alpha-DNA transcription complexes: analysis by microelectrospray mass spectrometry. Rapid Commun Mass Spectrom 2001; 15: 1011–1016.

    Article  CAS  Google Scholar 

  15. Gudmundsson GH, Bergman P, Andersson J, Raqib R, Agerberth B . Battle and balance at mucosal surfaces—the story of Shigella and antimicrobial peptides. Biochem Biophys Res Commun 2010; 396: 116–119.

    Article  CAS  Google Scholar 

  16. Wehkamp J, Schauber J, Stange EF . Defensins and cathelicidins in gastrointestinal infections. Curr Opin Gastroenterol 2007; 23: 32–38.

    Article  CAS  Google Scholar 

  17. Mora JR, Iwata M, von Andrian UH . Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 2008; 8: 685–698.

    Article  CAS  Google Scholar 

  18. MAL-ED Network Investigators. The MAL-ED study: a multinational and multidisciplinary approach to understand the relationship between enteric pathogens, malnutrition, gut physiology, physical growth, cognitive development, and immune responses in infants and children up to 2 years of age in resource-poor environments. Clin Infect Dis 2014; 59: S193–S206.

    Article  Google Scholar 

  19. Ahmed T, Mahfuz M, Islam MM, Mondal D, Hossain MI, Ahmed AS et al. The MAL-ED Cohort Study in Mirpur, Bangladesh. Clin Infect Dis 2014; 59: S280–S286.

    Article  CAS  Google Scholar 

  20. Lind C, Chen J, Byrjalsen I . Enzyme immunoassay for measuring 25-hydroxyvitamin D3 in serum. Clin Chem 1997; 43: 943–949.

    CAS  PubMed  Google Scholar 

  21. Driskell WJ, Neese JW, Bryant CC, Bashor MM . Measurement of vitamin A and vitamin E in human serum by high-performance liquid chromatography. J Chromatogr 1982; 231: 439–444.

    Article  CAS  Google Scholar 

  22. Brown KH, Rivera JA, Bhutta Z, Gibson RS, King JC, Lonnerdal B et al. International Zinc Nutrition Consultative Group (IZiNCG) technical document #1. Assessment of the risk of zinc deficiency in populations and options for its control. Food Nutr Bull 2004; 25: S99–S203.

    Article  Google Scholar 

  23. Engle-Stone R, Haskell MJ, Ndjebayi AO, Nankap M, Erhardt JG, Gimou MM et al. Plasma retinol-binding protein predicts plasma retinol concentration in both infected and uninfected Cameroonian women and children. J Nutr 2011; 141: 2233–2241.

    Article  CAS  Google Scholar 

  24. Lee G, Penataro Yori P, Paredes Olortegui M, Caulfield LE, Sack DA, Fischer-Walker C et al. An instrument for the assessment of diarrhoeal severity based on a longitudinal community-based study. BMJ Open 2014; 4: e004816.

    Article  Google Scholar 

  25. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011; 96: 1911–1930.

    Article  CAS  Google Scholar 

  26. WHO Global Prevalence of Vitamin A Deficiency in Populations at Risk 1995–2005. WHO Global Database on Vitamin A Deficiency: Geneva, Switzerland, 2009.

  27. The DHS Program DaHS. Wealth Index. Available at: http://dhsprogram.com/topics/Wealth-Index.cfm (last accessed 25 October 2013).

  28. White JH . Vitamin D signaling, infectious diseases, and regulation of innate immunity. Infect Immun 2008; 76: 3837–3843.

    Article  CAS  Google Scholar 

  29. Schwalfenberg GK . A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency. Mol Nutr Food Res 2011; 55: 96–108.

    Article  CAS  Google Scholar 

  30. Liu PT, Stenger S, Tang DH, Modlin RL . Cutting edge: vitamin D-mediated human antimicrobial activity against Mycobacterium tuberculosis is dependent on the induction of cathelicidin. J Immunol 2007; 179: 2060–2063.

    Article  CAS  Google Scholar 

  31. Rook GA, Steele J, Fraher L, Barker S, Karmali R, O'Riordan J et al. Vitamin D3, gamma interferon, and control of proliferation of Mycobacterium tuberculosis by human monocytes. Immunology 1986; 57: 159–163.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Klotman ME, Chang TL . Defensins in innate antiviral immunity. Nat Rev Immunol 2006; 6: 447–456.

    Article  CAS  Google Scholar 

  33. Komatsuzawa H, Ouhara K, Yamada S, Fujiwara T, Sayama K, Hashimoto K et al. Innate defences against methicillin-resistant Staphylococcus aureus (MRSA) infection. J Pathol 2006; 208: 249–260.

    Article  CAS  Google Scholar 

  34. Lopez-Garcia B, Lee PH, Yamasaki K, Gallo RL . Anti-fungal activity of cathelicidins and their potential role in Candida albicans skin infection. J Invest Dermatol 2005; 125: 108–115.

    Article  CAS  Google Scholar 

  35. Bartley J . Vitamin D: emerging roles in infection and immunity. Expert Rev Anti Infect Ther 2010; 8: 1359–1369.

    Article  CAS  Google Scholar 

  36. Cunliffe RN, Mahida YR . Expression and regulation of antimicrobial peptides in the gastrointestinal tract. J Leukoc Biol 2004; 75: 49–58.

    Article  CAS  Google Scholar 

  37. Motarjemi Y, Kaferstein F, Moy G, Quevedo F . Contaminated weaning food: a major risk factor for diarrhoea and associated malnutrition. Bull World Health Organ 1993; 71: 79–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Marino DD . Water and food safety in the developing world: global implications for health and nutrition of infants and young children. J Am Diet Assoc 2007; 107: 1930–1934.

    Article  Google Scholar 

  39. Veenemans J, Schouten LR, Ottenhof MJ, Mank TG, Uges DR, Mbugi EV et al. Effect of preventive supplementation with zinc and other micronutrients on non-malarial morbidity in Tanzanian pre-school children: a randomized trial. PLoS One 2012; 7: e41630.

    Article  CAS  Google Scholar 

  40. Rodriguez L, Cervantes E, Ortiz R . Malnutrition and gastrointestinal and respiratory infections in children: a public health problem. Int J Environ Res Public Health 2011; 8: 1174–1205.

    Article  Google Scholar 

  41. Black RE, Brown KH, Becker S . Malnutrition is a determining factor in diarrheal duration, but not incidence, among young children in a longitudinal study in rural Bangladesh. Am J Clin Nutr 1984; 39: 87–94.

    Article  CAS  Google Scholar 

  42. Islam MA, Ahmed T, Faruque AS, Rahman S, Das SK, Ahmed D et al. Microbiological quality of complementary foods and its association with diarrhoeal morbidity and nutritional status of Bangladeshi children. Eur J Clin Nutr 2012; 66: 1242–1246.

    Article  CAS  Google Scholar 

  43. Hoffman EL, Bennett FC . Birth weight less than 800 grams: changing outcomes and influences of gender and gestation number. Pediatrics 1990; 86: 27–34.

    CAS  PubMed  Google Scholar 

  44. Stoll BJ, Holman RC, Schuchat A . Decline in sepsis-associated neonatal and infant deaths in the United States, 1979 through 1994. Pediatrics 1998; 102: e18.

    Article  CAS  Google Scholar 

  45. Read JS, Troendle JF, Klebanoff MA . Infectious disease mortality among infants in the United States, 1983 through 1987. Am J Public Health 1997 87: 192–198.

  46. Abrams SA . Vitamin D requirements of children: ‘all my life's a circle’. Nutr Rev 2012; 70: 201–206.

    Article  Google Scholar 

  47. Manesh AO, Sheldon TA, Pickett KE, Carr-Hill R . Accuracy of child morbidity data in demographic and health surveys. Int J Epidemiol 2008; 37: 194–200.

    Article  Google Scholar 

  48. Lee G, Cama V, Gilman RH, Cabrera L, Saito M, Checkley W . Comparison of two types of epidemiological surveys aimed at collecting daily clinical symptoms in community-based longitudinal studies. Ann Epidemiol 2010; 20: 151–158.

    Article  Google Scholar 

  49. Fischer Walker CL, Perin J, Aryee MJ, Boschi-Pinto C, Black RE . Diarrhea incidence in low- and middle-income countries in 1990 and 2010: a systematic review. BMC Public Health 2012; 12: 220.

    Article  Google Scholar 

Download references

Acknowledgements

The Aetiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill and Melinda Gates Foundation, the Foundation for the NIH and the National Institutes of Health, Fogarty International Center.

Author contributions

AMSA, RJSM, TA, KL and AM conceived and designed the study; AMSA, TA, MM, MI, IH, AG, AS, RH, RG and WP oversaw data collection; AMSA, RJSM, KL and AM analysed the data; AMSA, RJSM, TA, KL, MM, MI, IH, AG, AS, RH, RG, WP and AM interpreted the data; AMSA drafted the manuscript; AMSA, RJSM, TA, KL and AM contributed to redrafting the manuscript.

Author information

Authors and Affiliations

  1. School of Public Health, The University of Queensland, Brisbane, QLD, Australia

    A M S Ahmed, K Z Long & A A Mamun

  2. Centre for Nutrition and Food Security, International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh

    A M S Ahmed, T Ahmed, MdI Hossain, M M Islam, M Mahfuz, S M A Gaffar, A Sharmeen, R Haque & A A Mamun

  3. School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia

    R J S Magalhaes

  4. Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia

    R J S Magalhaes

  5. Department of Epidemiology and Public Health, Swiss Tropical and Public Health Institute, Basel, Switzerland

    K Z Long

  6. Division of Infectious Diseases and International Health, Department of Internal Medicine, University of Virginia, Charlottesville, VA, USA

    R L Guerrant & W A Petri Jr

Authors
  1. A M S Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R J S Magalhaes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. K Z Long
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. MdI Hossain
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M M Islam
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Mahfuz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. S M A Gaffar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A Sharmeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R Haque
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. R L Guerrant
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. W A Petri Jr
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A A Mamun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A M S Ahmed.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ahmed, A., Magalhaes, R., Ahmed, T. et al. Vitamin-D status is not a confounder of the relationship between zinc and diarrhoea: a study in 6–24-month-old underweight and normal-weight children of urban Bangladesh. Eur J Clin Nutr 70, 620–628 (2016). https://doi.org/10.1038/ejcn.2016.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ejcn.2016.7

This article is cited by

Search

Advanced search

Quick links