Serum Adipokines, Growth Factors, and Cytokines Are Independently Associated with Stunting in Bangladeshi Children

Muttaquina Hossain, Baitun Nahar, Md Ahshanul Haque, Dinesh Mondal, Mustafa Mahfuz, Nurun Nahar Naila, Md Amran Gazi, Md Mehedi Hasan, Nur Muhammad Shahedul Haque, Rashidul Haque, Michael B Arndt, Judd L Walson, Tahmeed Ahmed, Muttaquina Hossain, Baitun Nahar, Md Ahshanul Haque, Dinesh Mondal, Mustafa Mahfuz, Nurun Nahar Naila, Md Amran Gazi, Md Mehedi Hasan, Nur Muhammad Shahedul Haque, Rashidul Haque, Michael B Arndt, Judd L Walson, Tahmeed Ahmed

Abstract

Growth in young children is controlled through the release of several hormonal signals, which are affected by diet, infection, and other exposures. Stunting is clearly a growth disorder, yet limited evidence exists documenting the association of different growth biomarkers with child stunting. This study explored the association between different growth biomarkers and stunting in Bangladeshi children. A quasi-experimental study was conducted among 50 stunted (length-for-age Z-score (LAZ) < -2 SD) and 50 control (LAZ ≥ -2 SD) children, aged 12-18 months, residing in a Bangladeshi slum. The enrolled stunted children received an intervention package, which included food supplementation for three months, psychosocial stimulation for six months, and routine clinical care on community nutrition center at the study field site. The controls received routine clinical care only. All children were clinically screened over the study period. Length, weight, fasting blood and fecal biomarkers were measured. All biomarkers levels were similar in both groups except for oxyntomodulin at enrolment. Leptin (adjusted odds ratio, AOR: 4.0, p < 0.01), leptin-adiponectin ratio (AOR 5.07 × 108, p < 0.01), insulin-like growth factor-1 (IGF-1) (AOR 1.02, p < 0.05), and gamma interferon (IFN-γ) (AOR 0.92, p < 0.05) levels were independently associated with stunting at enrolment. Serum leptin, leptin-adiponectin ratio, interleukin-6 (IL-6), IL-10, tumor necrosis factor-alpha (TNF-α), and fecal alpha-1-antitrypsin (AAT) levels increased significantly (p < 0.001), while IFN-γ levels significantly decreased among stunted children after six months of intervention. Leptin, leptin-adiponectin ratio, IGF-1, and IFN-γ are independently associated with stunting in Bangladeshi children. This trial was registered at clinicaltrials.gov as NCT02839148.

Keywords: Bangladesh; adipokines; children; peptides; stunting.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cohorts, participants, and analyses flow chart.

References

    1. De Onis M., Branca F. Childhood stunting: A global perspective. Matern. Child Nutr. 2016;12(Suppl. 1):12–26. doi: 10.1111/mcn.12231.
    1. United Nations Children’s Fund (Unicef) The World Health Organization. The International Bank for Reconstruction and Development/The World Bank . Levels and Trends in Child Malnutrition: Key Findings of the 2018 Edition of the Joint Child Malnutrition Estimates. Unicef; New York, NY, USA: Department of Nutrition for Health and Development, WHO; Geneva, Switzerland: Development Data Group of the World Bank; Washington, DC, USA: 2018. Data and Analytics Section of the Division of Data, Research and Policy.
    1. National Institute Of Population Research Training—Niport/Bangladesh. Mitra Associates. Icf International . Bangladesh Demographic and Health Survey 2014. Niport/Mitra Associates/Icf International; Dhaka, Bangladesh: 2016.
    1. Islam M.M., Sanin K.I., Mahfuz M., Ahmed A.M.S., Mondal D., Haque R., Ahmed T. Risk factors of stunting among children living in an urban slum of Bangladesh: Findings of a prospective cohort study. BMC Public Health. 2018;18:197. doi: 10.1186/s12889-018-5101-x.
    1. Alam M.A., Mahfuz M., Islam M.M., Mondal D., Ahmed A.M.S., Haque R., Ahmed T., Hossain M.I. Contextual factors for stunting among children of age 6 to 24 months in an under-privileged community of Dhaka, Bangladesh. Indian Pediatr. 2017;54:373–376. doi: 10.1007/s13312-017-1109-z.
    1. Bozzola E., Meazza C., Arvigo M., Travaglino P., Pagani S., Stronati M., Gasparoni A., Bianco C., Bozzola M. Role of adiponectin and leptin on body development in infants during the first year of life. Italian J. Pediatr. 2010;36:26. doi: 10.1186/1824-7288-36-26.
    1. Laron Z. Insulin-like growth factor 1 (Igf-1): A growth hormone. Mol. Pathol. 2001;54:311–316. doi: 10.1136/mp.54.5.311.
    1. Pittas A.G., Joseph N.A., Greenberg A.S. Adipocytokines and insulin resistance. J. Clin. Endocrinol. Metab. 2004;89:447–452. doi: 10.1210/jc.2003-031005.
    1. Mather K.J., Goldberg R.B. Clinical Use of Adiponectin as a Marker of Metabolic Dysregulation. Best Pract. Res. Clin. Endocrinol. Metab. 2014;28:107–117. doi: 10.1016/j.beem.2013.06.008.
    1. Gat-Yablonski G., Phillip M. Leptin and regulation of linear growth. Curr. Opin. Clin. Nutr. Metab. Care. 2008;11:303–308. doi: 10.1097/MCO.0b013e3282f795cf.
    1. Tsuji K., Maeda T., Kawane T., Matsunuma A., Horiuchi N. Leptin Stimulates fibroblast growth factor 23 expression in bone and suppresses renal 1alpha,25-dihydroxyvitamin d3 synthesis in leptin-deficient mice. J. Bone Mineral Res. 2010;25:1711–1723. doi: 10.1002/jbmr.65.
    1. Stofkova A. Leptin and adiponectin: From energy and metabolic dysbalance to inflammation and autoimmunity. Endocr. Regul. 2009;43:157–168.
    1. Perry B., Wang Y. Appetite regulation and weight control: The Role of gut hormones. Nutr. Diabetes. 2012;2:E26. doi: 10.1038/nutd.2011.21.
    1. Ickes S.B., Hossain M., Ritter G., Lazarus M., Reynolds K., Nahar B., Ahmed T., Walson J., Denno D.M. Systematic Review of tools and methods to measure appetite in undernourished children in the context of low- and middle-income countries. Adv. Nutr. 2018;9:789–812. doi: 10.1093/advances/nmy042.
    1. Bourke C.D., Berkley J.A., Prendergast A.J. Immune dysfunction as a cause and consequence of malnutrition. Trends Immunol. 2016;37:386–398. doi: 10.1016/j.it.2016.04.003.
    1. Arango Duque G., Descoteaux A. Macrophage cytokines: Involvement in immunity and infectious diseases. Front. Immunol. 2014;5:491. doi: 10.3389/fimmu.2014.00491.
    1. Dewey K.G., Mayers D.R. Early child growth: How do nutrition and infection interact? Mater. Child Nutr. 2011;7:129–142. doi: 10.1111/j.1740-8709.2011.00357.x.
    1. Wong S.C., Dobie R., Altowati M.A., Werther G.A., Farquharson C., Ahmed S.F. Growth and the growth hormone-insulin like growth factor 1 axis in children with chronic inflammation: Current evidence, gaps in knowledge, and future directions. Endocr. Rev. 2016;37:62–110. doi: 10.1210/er.2015-1026.
    1. Mccormick B.J.J., Lee G.O., Seidman J.C., Haque R., Mondal D., Quetz J., Lima A.A.M., Babji S., Kang G., Shrestha S.K., et al. Dynamics and Trends in Fecal Biomarkers of Gut Function in Children from 1-24 Months in the Mal-Ed Study. Am. J. Trop. Med. Hyg. 2017;96:465–472. doi: 10.4269/ajtmh.16-0496.
    1. Owino V., Ahmed T., Freemark M., Kelly P., Loy A., Manary M., Loechl C. Environmental enteric dysfunction and growth failure/stunting in global child health. Pediatrics. 2016;138:e20160641. doi: 10.1542/peds.2016-0641.
    1. Prendergast A.J., Rukobo S., Chasekwa B., Mutasa K., Ntozini R., Mbuya M.N., Jones A., Moulton L.H., Stoltzfus R.J., Humphrey J.H. Stunting is characterized by chronic inflammation in Zimbabwean infants. PLoS ONE. 2014;9:E86928. doi: 10.1371/journal.pone.0086928.
    1. Kosek M., Haque R., Lima A., Babji S., Shrestha S., Qureshi S., Amidou S., Mduma E., Lee G., Yori P.P., et al. Fecal markers of intestinal inflammation and permeability associated with the subsequent acquisition of linear growth deficits in infants. Am. J. Trop. Med. Hyg. 2013;88:390–396. doi: 10.4269/ajtmh.2012.12-0549.
    1. Gicquel C., Le Bouc Y. Hormonal regulation of fetal growth. Hormone Res. Paediatr. 2006;65(Suppl. 3):28–33. doi: 10.1159/000091503.
    1. Karakosta P., Roumeliotaki T., Chalkiadaki G., Sarri K., Vassilaki M., Venihaki M., Malliaraki N., Kampa M., Castanas E., Kogevinas M., et al. Cord blood leptin levels in relation to child growth trajectories. Metabolism. 2016;65:874–882. doi: 10.1016/j.metabol.2016.03.003.
    1. Moher D., Schulz K.F., Altman D.G. The consort statement: Revised recommendations for improving the quality of reports of parallel-group randomised trials. Lancet. 2001;357:1191–1194. doi: 10.1016/S0140-6736(00)04337-3.
    1. Von Elm E., Altman D.G., Egger M., Pocock S.J., Gotzsche P.C., Vandenbroucke J.P. The strengthening the reporting of observational studies in epidemiology (strobe) statement: Guidelines for reporting observational studies. Lancet. 2007;370:1453–1457. doi: 10.1016/S0140-6736(07)61602-X.
    1. Ahmed T., Mahfuz M., Islam M.M., Mondal D., Hossain M.I., Ahmed A.S., Tofail F., Gaffar S.A., Haque R., Guerrant R.L., et al. The mal-ed cohort study in Mirpur, Bangladesh. Clin. Infect. Dis. Off. Publicat. Infect. Dis. Soc. Am. 2014;59(Suppl. 4):S280–S286. doi: 10.1093/cid/ciu458.
    1. Nahar B., Hossain M.I., Hamadani J.D., Ahmed T., Huda S.N., Grantham-McGregor S.M., Persson L.A. effects of a community-based approach of food and psychosocial stimulation on growth and development of severely malnourished children in Bangladesh: A randomised trial. Eur. J. Clin. Nutr. 2012;66:701. doi: 10.1038/ejcn.2012.13.
    1. De A.B.E.S., Gill M.S., De Freitas M.E., Magalhaes M.M., Souza A.H., Aguiar-Oliveira M.H., Clayton P.E. Serum leptin and body composition in children with familial gh deficiency (ghd) due to a mutation in the growth hormone-releasing hormone (ghrh) receptor. Clin. Endocrinol. 1999;51:559–564.
    1. Arguelles B., Barrios V., Buno M., Madero L., Argente J. Anthropometric parameters and their relationship to serum growth hormone-binding protein and leptin levels in children with acute lymphoblastic leukemia: A prospective study. Eur. J. Endocrinol. 2000;143:243–250. doi: 10.1530/eje.0.1430243.
    1. Karakosta P., Georgiou V., Fthenou E., Papadopoulou E., Roumeliotaki T., Margioris A., Castanas E., Kampa M., Kogevinas M., Chatzi L. Maternal weight status, cord blood leptin and fetal growth: A prospective mother-child cohort study (rhea study) Paediatr. Perinat. Epidemiol. 2013;27:461–471. doi: 10.1111/ppe.12074.
    1. Mellati A.A., Mazloomzadeh S., Anjomshoaa A., Alipour M., Karimi F., Mazloomi S., Naghi Kazemi S.A. Multiple correlations between cord blood leptin concentration and indices of neonatal growth. Arch. Med. Res. 2010;41:26–32. doi: 10.1016/j.arcmed.2009.12.001.
    1. Sadownik B., Lukas W., Behrendt J., Stojewska M., Kwiatkowska-Gruca M., Rygiel K., Adamik K., Godula-Stuglik U. An Analysis of factors determining serum leptin concentration in healthy and infected newborns. Neurol. Endocrinol. Lett. 2010;31:221–228.
    1. Lopez-Siguero J.P., Lopez-Canti L.F., Espino R., Caro E., Fernandez-Garcia J.M., Gutierrez-Macias A., Rial J.M., Lechuga J.L., Macias F., Martinez-Aedo M.J., et al. Effect of recombinant growth hormone on leptin, adiponectin, resistin, interleukin-6, tumor necrosis factor-alpha and ghrelin levels in growth hormone-deficient children. J. Endocrinol. Invest. 2011;34:300–306. doi: 10.1007/BF03347090.
    1. Flexeder C., Thiering E., Kratzsch J., Klumper C., Koletzko B., Muller M.J., Koletzko S., Heinrich J., GINIplus and LISAplus Study Group6 Is a child’s growth pattern early in life related to serum adipokines at the age of 10 years? Eur. J. Clin. Nutr. 2014;68:25–31. doi: 10.1038/ejcn.2013.213.
    1. Soliman A.T., Elzalabany M.M., Salama M., Ansari B.M. Serum leptin concentrations during severe protein-energy malnutrition: Correlation with growth parameters and endocrine function. Metabolism. 2000;49:819–825. doi: 10.1053/meta.2000.6745.
    1. Wilasco M.I.A., Goldani H.A.S., Dornelles C.T.L., Maurer R.L., Kieling C.O., Porowski M., Silveira T.R. Ghrelin, leptin and insulin in healthy children: Relationship with anthropometry, gender, and age distribution. Regulat. Peptid. 2012;173:21–26. doi: 10.1016/j.regpep.2011.08.013.
    1. Frühbeck G., Catalán V., Rodríguez A., Gómez-Ambrosi J. Adiponectin-leptin ratio: A promising index to estimate adipose tissue dysfunction. relation with obesity-associated cardiometabolic risk. Adipocyte. 2018;7:57–62. doi: 10.1080/21623945.2017.1402151.
    1. Soliman A.T., Yasin M., Kassem A. Leptin in pediatrics: A hormone from adipocyte that wheels several functions in children. Indian J. Endocrinol. Metab. 2012;16:S577–S587. doi: 10.4103/2230-8210.105575.
    1. Gat-Yablonski G., Ben-Ari T., Shtaif B., Potievsky O., Moran O., Eshet R., Maor G., Segev Y., Phillip M. Leptin reverses the inhibitory effect of caloric restriction on longitudinal growth. Endocrinology. 2004;145:343–350. doi: 10.1210/en.2003-0910.
    1. Gomez J.M., Maravall F.J., Gomez N., Navarro M.A., Casamitjana R., Soler J. Interactions between serum leptin, the insulin-like growth factor-i system, and sex, age, anthropometric and body composition variables in a healthy population randomly selected. Clin. Endocrinol. 2003;58:213–219. doi: 10.1046/j.1365-2265.2003.01698.x.
    1. Abo-Shousha S.A., Hussein M.Z., Rashwan I.A., Salama M. Production of proinflammatory cytokines: Granulocyte-macrophage colony stimulating factor, interleukin-8 and interleukin-6 by peripheral blood mononuclear cells of protein energy malnourished children. Egypt. J. Immunol. 2005;12:125–131.
    1. França T., Ishikawa L., Zorzella-Pezavento S., Chiuso-Minicucci F., Da Cunha M., Sartori A. Impact of malnutrition on immunity and infection. J. Venom. Anim. Toxins Include Tropical Dis. 2009;15:374–390. doi: 10.1590/S1678-91992009000300003.
    1. Briend A., Khara T., Dolan C. Wasting And stunting—Similarities and differences: Policy and programmatic implications. Food Nut. Bull. 2015;36:S15–S23. doi: 10.1177/15648265150361S103.
    1. Azevedo Z.M., Luz R.A., Victal S.H., Kurdian B., Fonseca V.M., Fitting C., Camara F.P., Haeffner-Cavaillon N., Cavaillon J.M., Gaspar Elsas M.I., et al. Increased production of tumor necrosis factor-alpha in whole blood cultures from children with primary malnutrition. Braz. J. Med. Biol. Res. Revista Brasil. Pesquisas Med. Biol. 2005;38:171–183. doi: 10.1590/S0100-879X2005000200005.
    1. Doherty J.F., Golden M.H., Remick D.G., Griffin G.E. Production of interleukin-6 and tumour necrosis factor-alpha in vitro is reduced in whole blood of severely malnourished children. Clin. Sci. 1994;86:347–351. doi: 10.1042/cs0860347.
    1. Gaayeb L., Sarr J.B., Cames C., Pincon C., Hanon J.B., Ndiath M.O., Seck M., Herbert F., Sagna A.B., Schacht A.M., et al. Effects of malnutrition on children’s immunity to bacterial antigens in Northern Senegal. Am. J. Tropical Med. Hyg. 2014;90:566–573. doi: 10.4269/ajtmh.12-0657.
    1. Pepys M.B., Hirschfield G.M. C-reactive protein: A critical update. J. Clin. Invest. 2003;111:1805–1812. doi: 10.1172/JCI200318921.
    1. Platts-Mills J.A., Taniuchi M., Uddin M.J., Sobuz S.U., Mahfuz M., Gaffar S.A., Mondal D., Hossain M.I., Islam M.M., Ahmed A.S., et al. Association between enteropathogens and malnutrition in children aged 6–23 mo in Bangladesh: A case-control study. Am. J. Clin. Nutr. 2017;105:1132–1138. doi: 10.3945/ajcn.116.138800.
    1. Abd El-Maksoud A.M., Khairy S.A., Sharada H.M., Abdalla M.S., Ahmed N.F. Evaluation of pro-inflammatory cytokines in nutritionally stunted Egyptian children. Egypt. Pediatr. Assoc. Gazette. 2017;65:80–84. doi: 10.1016/j.epag.2017.04.003.
    1. Bergman M., Bessler H., Salman H., Siomin D., Straussberg R., Djaldetti M. In vitro cytokine production in patients with iron deficiency anemia. Clin. Immunol. 2004;113:340–344. doi: 10.1016/j.clim.2004.08.011.
    1. Mayer L.S., Uciechowski P., Meyer S., Schwerdtle T., Rink L., Haase H. Differential Impact of zinc deficiency on phagocytosis, oxidative burst, and production of pro-inflammatory cytokines by human monocytes. Metallom. Integr. Biomet. Sci. 2014;6:1288–1295. doi: 10.1039/c4mt00051j.
    1. Harper K.M., Mutasa M., Prendergast A.J., Humphrey J., Manges A.R. Environmental Enteric dysfunction pathways and child stunting: A systematic review. PLoS Neglect. Tropical Dis. 2018;12:E0006205. doi: 10.1371/journal.pntd.0006205.
    1. Campbell R.K., Schulze K.J., Shaikh S., Raqib R., Wu L.S.F., Ali H., Mehra S., West K.P., Christian P. Environmental enteric dysfunction and systemic inflammation predict reduced weight but not length gain in rural Bangladeshi children. Br. J. Nutr. 2018;119:407–414. doi: 10.1017/S0007114517003683.

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