Environmental, Metabolic, and Inflammatory Factors Converge in the Pathogenesis of Moderate Acute Malnutrition in Children: An Observational Cohort Study

Abstract

Acute malnutrition affects more than 50 million children worldwide. These children are at an increased risk of morbidity and mortality from infectious disease. However, the pathogenesis of acute malnutrition and mechanisms underlying the increased risk and poor outcomes from infection are not well understood. Our objective was to identify differences in inflammation and inflammatory responses between children with moderate acute malnutrition (MAM) and healthy controls (HCs), and search for environmental, pathophysiological, and metabolic factors that may influence this response. Sixteen children with MAM and 16 HCs aged 18-36 months were studied in Nairobi, Kenya. None of the children had symptoms of an infectious disease (fever, diarrhea, or cough) in the 2 weeks before enrollment and sample collection. Demographic and health data were provided by their primary caregivers. Blood samples were collected to measure various biomarkers and the response to an inflammatory stimulus. Children with MAM were more frequently from households with contaminated water, crowding, and unstable income sources. They also had increases in basal inflammation, circulating bacterial lipopolysaccharide (LPS), markers of intestinal damage, and an exaggerated whole blood inflammatory response to LPS. Metabolic changes in children with MAM led to increased plasma levels of long-chain fatty acids, which were found to contribute to the pro-inflammatory state. These exploratory findings suggest convergence of multiple factors to promote dysregulated inflammatory responses and prompt several mechanistic hypotheses that can be pursued to better understand the pathogenesis of MAM.

Figure 1.

Concentrations of markers of intestinal health, bacterial translocation, and inflammation in naive plasma from children with MAM (n = 16) and healthy controls (HCs) (n = 16). Data missing for lipopolysaccharide value for one child with MAM. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. MAM = moderate acute malnutrition. This figure appears in color at www.ajtmh.org.

Figure 2.

Concentration of inflammatory cytokines (A) and acute-phase response proteins (B) in naive plasma from children with MAM (n = 16) and healthy controls (HCs) (n = 16). Data missing for LPS-binding protein (LBP) value for two children with MAM and two HCs. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001. MAM = moderate acute malnutrition. This figure appears in color at www.ajtmh.org.

Figure 3.

Concentrations of metabolites (A) and metabolic regulators (B) in naive plasma from children with moderate acute malnutrition (MAM) (n = 16) and healthy controls (HCs) (n = 16). Glycolysis rate is estimated from amino acid concentrations ([alanine + glycine + serine]/hexose). *P < 0.05 and **P < 0.01. This figure appears in color at www.ajtmh.org.

Figure 4.

Correlations between variables associated with malnutrition. Correlations that were not significant (P > 0.05) are shown as empty boxes. Size of dot indicates the level of statistical significance; a larger dot indicates a smaller P-value. Color indicates correlation coefficient as indicated by the range given on the side of the graphic. Variables are grouped by hierarchical clustering. Glycolysis is defined as the ratio of the concentrations of specific amino acids or the concentration of hexoses (ala + gly + ser)/hexose.

Figure 5.

Cytokine production by human PBMCs on exposure to free fatty acids and/or lipopolysaccharide. PBMCs were isolated from a healthy adult volunteer and exposed to albumin-bound saturated long-chain fatty acids or vehicle control (con) (A), or to albumin-bound saturated long-chain fatty acid or a vehicle control plus 10 ng/mL Lipopolysaccharide (B). Long-chain fatty acids included myristic acid (C14), palmitic acid (C16), and steric acid (C18). After 24 hours, cytokines were measured in supernatant by Bio-Plex. Data representative of two independent experiments. *P < 0.05 and **P < 0.01. PBMC = peripheral blood mononuclear cell.

Figure 6.

Cytokine production by peripheral blood mononuclear cells (PBMCs) from a healthy adult volunteer following exposure to plasma from children with MAM or healthy controls (HCs) with or without simultaneous exposure to LPS. Cytokine concentration was measured in cell supernatants by Bio-Plex. The Mann–Whitney U test was used to compare cells exposed to plasma from MAM subjects and HCs, with or without LPS. *P < 0.05 and **P < 0.01. MAM = moderate acute malnutrition; LPS = lipopolysaccharide.