Early-Life Iron Deficiency and Its Natural Resolution Are Associated with Altered Serum Metabolomic Profiles in Infant Rhesus Monkeys

Brian J. Sandri, Gabriele R. Lubach, Eric F. Lock, Michael K. Georgieff, Pamela J. Kling, Christopher L. Coe, Raghavendra B. Rao

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: Iron deficiency is the most common nutrient deficiency in human infants aged 6 to 24 mo, and negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. There can be persistent influences on long-term metabolic health beyond its acute effects. Objectives: The objective was to determine how iron deficiency in infancy alters the serum metabolomic profile and to test whether these effects persist after the resolution of iron deficiency in a nonhuman primate model of spontaneous iron deficiency. Methods: Blood was collected from naturally iron-sufficient (IS; n = 10) and iron-deficient (ID; n = 10) male and female infant rhesus monkeys (Macaca mulatta) at 6 mo of age. Iron deficiency resolved without intervention upon feeding of solid foods, and iron status was re-evaluated at 12 mo of age from the IS and formerly ID monkeys using hematological and other indices; sera were metabolically profiled using HPLC/MS and GC/MS with isobaric standards for identification and quantification at both time points. Results: A total of 413 metabolites were measured, with differences in 40 metabolites identified between IS and ID monkeys at 6 mo (P$\le $ 0.05). At 12 mo, iron-related hematological parameters had returned to normal, but the formerly ID infants remained metabolically distinct from the age-matched IS infants, with 48 metabolites differentially expressed between the groups. Metabolomic profiling indicated altered liver metabolites, differential fatty acid production, increased serum uridine release, and atypical bile acid production in the ID monkeys. Conclusions: Pathway analyses of serum metabolites provided evidence of a hypometabolic state, altered liver function, differential essential fatty acid production, irregular uracil metabolism, and atypical bile acid production in ID infants. Many metabolites remained altered after the resolution of ID, suggesting long-term effects on metabolic health.

Original languageEnglish (US)
Pages (from-to)685-693
Number of pages9
JournalJournal of Nutrition
Volume150
Issue number4
DOIs
StatePublished - Apr 1 2020

Bibliographical note

Funding Information:
This work was supported by grants NIH R01HD089989, NIH R01HD080201, NIH R01HD057064, and NIH R01HD39386. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Author disclosures: The authors report no conflicts of interest. Supplemental Tables 1 and 2 and Supplemental Figures 1 and 2 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/. Address correspondence to RBR (e-mail: raghurao@umn.edu). Abbreviations used: CCA, canonical correlation analysis; CSF, cerebrospinal fluid; HCT, hematocrit; Hgb, hemoglobin; ID, iron-deficient; IPA, Ingenuity Pathway Analysis; IS, iron-sufficient; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RDW, red blood cell distribution width; TSAT, transferrin saturation; ZnPP/H, zinc protoporphyrin/heme; 3-HBA, 3-hydroxybutyrate; 7-HOCA, 7α-hydroxy-3-oxo-4-cholestenoic acid.

Keywords

  • Altered liver function
  • Infant
  • Iron
  • Iron deficiency
  • Metabolomics
  • Rhesus

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