Metabolomic Profiles Associated with Mortality of Children with Complicated Severe Malnutrition: A Nested Case-Control Study

Abstract

Abstract Objectives Children hospitalized with complicated severe malnutrition (CSM) have unacceptably high mortality rates despite receiving standard nutritional and medical treatment. The underlying pathology of the poor prognosis is not well understood. Growing evidence indicates presence of metabolic dysfunction in CSM. Yet, it is unclear whether and how metabolic dysfunction contributes the poor prognosis. This study aimed to identify metabolic signatures and pathways associated with CSM mortality. Methods A case-control study was performed on CSM patients enrolled to a multicenter (one Malawi and two Kenya hospitals) randomized control trial (NCT02246296). A total of 90 death cases and 90 discharged controls that were propensity score matched by age, HIV and mid-upper arm circumferences were included in the study. Targeted metabolomics was performed on their serum samples collected at admission and on day 3 of hospitalization. In particular, 206 metabolites, including amino acids, acylcarnitines, lipids and organic acids were quantified by LC-MS/MS. Results Discriminant analysis (PLS-DA) showed that metabolomic signatures at admission could differentiate cases from controls, with a cross-validated classification error rate of 21.8%. An increase of homovanillic, isobutyric and propionic acids, and decrease of lipids lysoPC a C18:2, lysoPC a C20:4, PC ae C42:2, SM C26:0, and SM C26:1 were the top 8 significant features characterizing the admission metabolomes of cases. Notably, cases with higher levels of isobutyrate, a microbial fermentation product, had significantly shorter survival time, implying a role of gut integrity in mortality. Pathway analysis revealed that metabolites of the tricarboxylic acid (TCA) cycle pathway differentiated cases from controls. Analysis of day 3 samples showed metabolic differences in response to treatment, especially in the recovery rate of lipids, between cases and controls. Conclusions CSM non-survivors have metabolomes distinct from survivors indicating perturbations in mitochondrial function and nutrition utilization. Perturbed metabolites identified shed light on biological mechanisms of mortality and may serve as targets of nutritional or therapeutic interventions to improve CSM survival. Funding Sources Bill and Melinda Gates Foundation, Thrasher Research Fund, and RESTRACOMP Graduate Scholarship.