title: Stunting is characterized by chronic inflammation in Zimbabwean infants.
abstract: BACKGROUND
  Stunting affects one-third of children in developing countries, but the causes remain unclear. We hypothesized that enteropathy leads to low-grade inflammation, which suppresses the growth hormone-IGF axis and mediates stunting.
  
  
  METHODS
  We conducted a case-control study of 202 HIV-unexposed Zimbabwean infants who were stunted (height-for-age Z-score (HAZ) <-2; cases) or non-stunted (HAZ >-0.5; controls) at 18 months. We measured biomarkers of intestinal damage (I-FABP), inflammation (CRP, AGP, IL-6) and growth hormone-IGF axis (IGF-1, IGFBP3) in infant plasma at 6 weeks and 3, 6, 12 and 18 months, and in paired maternal-infant plasma at birth. Adjusted mean differences between biomarkers were estimated using regression models. Multivariate odds ratios of stunting were estimated by logistic regression.
  
  
  RESULTS
  At birth, cases were shorter (median (IQR) HAZ -1.00 (-1.53, -0.08) vs 0.03 (-0.57, 0.62,); P<0.001) than controls and their mothers had lower levels of IGF-1 (adjusted mean difference (95%CI) -21.4 (-39.8, -3.1) ng/mL). From 6 weeks to 12 months of age, levels of CRP and AGP were consistently higher and IGF-1 and IGFBP3 lower in cases versus controls; IGF-1 correlated inversely with inflammatory markers at all time-points. I-FABP increased between 3-12 months, indicating extensive intestinal damage during infancy, which was similar in cases and controls. In multivariate analysis, higher log10 levels of CRP (aOR 3.06 (95%CI 1.34, 6.99); P = 0.008) and AGP (aOR 7.87 (95%CI 0.74, 83.74); P = 0.087) during infancy were associated with stunting. There were no associations between levels of I-FABP, IL-6, sCD14 or EndoCAb and stunting.
  
  
  CONCLUSIONS
  Stunting began in utero and was associated with low maternal IGF-1 levels at birth. Inflammatory markers were higher in cases than controls from 6 weeks of age and were associated with lower levels of IGF-1 throughout infancy. Higher levels of CRP and AGP during infancy were associated with stunting. These findings suggest that an extensive enteropathy occurs during infancy and that low-grade chronic inflammation may impair infant growth.
authors.affiliation: Centre for Paediatrics, Blizard Institute, Queen Mary University of London, London, United Kingdom ; Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe ; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Prendergast
authors.affiliation: Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rukobo
authors.affiliation: Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe.
authors.forename: Bernard
authors.initials: B
authors.lastname: Chasekwa
authors.affiliation: Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe.
authors.forename: Kuda
authors.initials: K
authors.lastname: Mutasa
authors.affiliation: Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe.
authors.forename: Robert
authors.initials: R
authors.lastname: Ntozini
authors.affiliation: Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe ; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Mduduzi N N
authors.initials: MN
authors.lastname: Mbuya
authors.affiliation: University of Michigan, School of Public Health, Ann Arbor, Michigan, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Moulton
authors.affiliation: Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States of America.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Stoltzfus
authors.affiliation: Zvitambo Institute for Maternal Child Health Research, Harare, Zimbabwe ; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
authors.forename: Jean H
authors.initials: JH
authors.lastname: Humphrey
mesh_terms: D000886:Anthropometry; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002097:C-Reactive Protein / Q000378:metabolism; D016022:Case-Control Studies; D002675:Child, Preschool; D005260:Female; D006130:Growth Disorders / Q000453:epidemiology*; D015658:HIV Infections / Q000097:blood / Q000175:diagnosis; D019382:Human Growth Hormone / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000453:epidemiology / Q000503:physiopathology*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D015233:Models, Statistical; D015999:Multivariate Analysis; D016017:Odds Ratio; D015030:Zimbabwe / Q000453:epidemiology
chemical_list: D015415:Biomarkers; C583557:IGF1 protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D015850:Interleukin-6; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D002097:C-Reactive Protein