The Impact of Environmental Enteropathy and Systemic Inflammation on Infant Growth Failure

Abstract

Malnutrition affects 20% of children under 5 years of age, with a particularly large burden in south Asia and Africa. Inadequate nutrition is responsible for some of this malnutrition, but the frequently observed poor response to nutritional therapy suggests that other factors are contributing to growth failure. Environmental enteropathy (EE), a subclinical inflammation of the intestinal tract, has been hypothesized to contribute to malnutrition. This study tested the hypothesis that EE early in life was associated with poor growth. 700 infants from an urban slum in Dhaka, Bangladesh were followed for two years from birth. Anthropometry and stool, serum, and urine samples were collected during this time. Using the change in HAZ from birth to one year of life as an outcome for growth, univariate and multivariable statistical methods were used to detect correlations between growth and a comprehensive panel of biomarkers measured in the first 18 weeks of life. The biomarkers included those representing intestinal inflammation and EE, systemic inflammation and indicators of maternal health.Biomarkers of EE Reg1B, myeloperoxidase, and calprotectin, measured in the stool at 12 weeks of age negatively correlated with growth. Systemic inflammation was also observed to have strong negative correlations with growth, with particular emphasis on C‐reactive protein, ferritin, and soluble CD14. Finally, maternal health had strong positive correlations on growth. Using a restricted set of biomarkers identified by multivariable SCAD analysis that included Reg1b, myeloperoxidase, ferritin, sCD14, CRP, maternal education, and maternal height, we found that these biomarkers could explain 46.3% of variance observed for change in HAZ.In addition to analyzing the biomarkers for correlation with change in HAZ, we performed a cluster analysis on the complete biomarker set. This analysis revealed three dominant clusters of biomarkers. Cluster 1 was defined by the presence of the systemic inflammatory markers, including all but one of the cytokines, as well as ferritin. Cluster 2 contained the EE markers, as well as CRP and sCD14. Cluster 3 represented maternal health and socioeconomic status markers. This triple clustering suggested that there are three pathways leading to poor growth: systemic inflammation, enteric inflammation, and maternal health.We conclude that both systemic and enteric inflammation early in life had a negative on growth, and that these two sets of biomarkers could represent distinct pathways leading to malnutrition. It is possible that there are distinct drivers for each pathway. Diarrheal burden was located on Cluster 1, suggesting that diarrheal disease drives an acute systemic response, while enteric inflammation is driven by a different challenge, possibly subclinical infections. The smaller panel of biomarkers identified could also be used to identify young children at risk for future malnutrition, allowing early intervention.Support or Funding InformationThe Bill and Melinda Gates Foundation