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.

Pathologic Inflammation in Malnutrition Is Driven by Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, and Translocation of Bacterial Lipopolysaccharide

“…The hyper-inflammatory phenotype we observed in malnourished mice recapitulates our findings and those of others in children with MAM (25,36). It contrasts with findings in children with SAM, who typically display decreased circulating levels of inflammatory cytokines at baseline and a reduced inflammatory response to infection (3,7).…”

“…The inflammatory response is energetically costly for malnourished children and diverts already scarce nutrients to acute phase and immune protein production (23). Observational studies in children with SAM (24) and MAM (25) have linked malnutrition, intestinal damage, and elevated circulating LPS. However, the mechanisms that underpin these findings are obscure.…”

Inflammatory stimuli alter bone marrow composition and compromise bone health in the malnourished host

“…Inflammasomes can be activated in a low-grade inflammation typical of non-infectious insults such as aging, promoting osteoclast differentiation, bone loss, and osteolysis ( 89 ). Our finding of high inflammasome activation in the bone marrow of naïve malnourished mice supports the notion that malnutrition promotes a state of sustained inflammation ( 10 , 90 ) that favors bone resorption. Despite the inflammasome activation and IL-1ß production being dependent on inflammatory monocytes in DT malnourished mice, TNF and IL-6 were not abrogated suggesting that inflammatory monocytes are not the sole source of inflammatory cytokines in this model.…”

“…There is a growing body of evidence that changes in the intestinal microbiota and intestinal and systemic inflammation, with or without overt bacterial infection, underpin pathophysiological processes in the malnourished host. Recently, we demonstrated an increase in basal inflammatory cytokines, impaired intestinal barrier function, circulating endotoxin, and an exaggerated response to inflammatory stimuli in children with MAM ( 10 ). Similar features are reported in our studies in a mouse model that mimics the features of MAM ( 11 ).…”

“…The mechanisms responsible for impaired host defense in childhood malnutrition are not fully understood. One source of susceptibility to infections linked with nutritional deficiencies is the disruption of enteric barrier function that promotes the systemic translocation of bacteria and bacterial products such as LPS ( 9 , 10 ). The metabolic cost of the activated immune response and the consequent intestinal or systemic inflammation during the infection support the vicious cycle of nutritional deficiency and impaired host defense.…”