Multiomic profiling of iron-deficient infant monkeys reveals alterations in neurologically important biochemicals in serum and cerebrospinal fluid before the onset of anemia

Abstract

Background: The effects of iron deficiency (ID) during infancy extend beyond the hematologic compartment and include short- and long-term adverse effects on many tissues including the brain. However, sensitive biomarkers of iron-dependent brain health are lacking in humans. Objective: To determine whether serum and CSF biomarkers of ID-induced metabolic dysfunction are concordant in the pre/early anemic stage of ID prior to anemia in a nonhuman primate model of infantile IDA. Methods: Paired serum and CSF specimens were collected from iron-sufficient (IS; n = 12) and ID (n = 7) rhesus infants at 4-months (pre-anemic period) and 6-months of age (anemic). Hematological, metabolomic, and proteomic profiles were generated via HPLC/MS at both time points to discriminate serum bio markers of ID-induced brain metabolic dysfunction. Results: We identified 227 metabolites and 205 proteins in serum. Abnormalities indicating altered liver function, lipid dysregulation, and increased acute phase reactants were present in ID. In CSF, we measured 210 metabolites and 1,560 proteins with changes in ID infants indicative of metabolomic and proteomic differences indexing disrupted synaptogenesis. Systemic and CSF proteomic and metabolomic changes were present and concurrent in the pre-anemic and anemic periods. Conclusions: Multiomic serum and CSF profiling uncovered pathways disrupted by ID in both the pre-anemic and anemic stages of infantile IDA, including evidence for hepatic dysfunction and activation of acute phase response. Parallel changes observed in serum and CSF potentially provide measurable serum biomarkers of ID that reflect at-risk brain processes prior to progression to clinical anemia.

Bayesian predictive modeling of multi-source multi-way data

“…We applied our method of multi-source, multi-way Bayesian probit regression to our motivating data on iron deficiency in an infant rhesus monkey model and assessed our ability to discriminate between ID and iron sufficient (IS) infants based on the serum proteomic and metabolomic profiles measured at two time points (4 and 6 months after birth). In this model, infants destined to develop ID show evidence of ID (changes in serum iron indices and lower reticulocyte hemoglobin content) at 4 months, with iron deficiency anemia (lower hemoglobin and mean corpuscular volume) seen at 6 months (Lubach and Coe, 2006;Coe and others, 2013;Rao and others, 2018;Sandri and others, 2020Sandri and others, , 2021Sandri and others, , 2022. Proteomic and metabolomic changes in serum are seen in the preanemic and anemic periods (Sandri and others, 2022).…”

“…In this model, infants destined to develop ID show evidence of ID (changes in serum iron indices and lower reticulocyte hemoglobin content) at 4 months, with iron deficiency anemia (lower hemoglobin and mean corpuscular volume) seen at 6 months (Lubach and Coe, 2006;Coe and others, 2013;Rao and others, 2018;Sandri and others, 2020Sandri and others, , 2021Sandri and others, , 2022. Proteomic and metabolomic changes in serum are seen in the preanemic and anemic periods (Sandri and others, 2022). After routine pre-processing data were available for 227 metabolites and 205 proteins for 6 ID and 6 IS monkeys.…”

“…In this naturalistic ID model in infant rhesus monkeys, 20 − 30% of infants develop ID and anemia between 4 and 6 months of age due to a combination of lower iron stores at birth and rapid postnatal growth rate (Lubach and Coe, 2006;Coe and others, 2013). Prior studies in this model have shown that the ID infants have metabolomic and proteomic abnormalities in the serum and cerebrospinal fluid in the preanemic and anemic periods with residual changes persisting even after the resolution of anemia with iron treatment (Geguchadze and others, 2008;Coe and others, 2009;Patton and others, 2012;others, 2013, 2018;Sandri and others, 2020Sandri and others, , 2021Sandri and others, , 2022. Data were available from two sources, serum proteomics and serum metabolomics, collected at two time points, 4 and 6 months after birth.…”

“…A growing number of datasets are simultaneously multi-source and multi-way (MSMW). As a motivating example of MSMW data, we consider predictors of early-life iron deficiency (ID) in infant monkeys using data described in Sandri and others (2022). In this naturalistic ID model in infant rhesus monkeys, 20 − 30% of infants develop ID and anemia between 4 and 6 months of age due to a combination of lower iron stores at birth and rapid postnatal growth rate (Lubach and Coe, 2006;Coe and others, 2013).…”

Tandem mass tag proteomic and untargeted metabolomic profiling reveals altered serum and CSF biochemical datasets in iron deficient monkeys

“…We generated quantitative proteomic, metabolomic, and hematological profiles of serum and CSF from rhesus macaques at 4- and 6- months of age. The data were processed as previously described [1] , [2] , [3] , [4] , [5] and canonical correlation analysis (CCA) was performed to examine significant trends ( Fig. 1 ).…”