Assessing the relationship between environmental enteric dysfunction and poor growth via a newly developed 11-plex assay

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Project Summary: Undernutrition remains one of the greatest human development challenges of our time. In 2017, an estimated 151 million children < 5 years of age (i.e., 22.2% of the global population) were stunted, increasing their risk for morbidity and mortality in childhood, suboptimal cognitive development, poorer educational outcomes, and lower economic productivity and earnings in adulthood. It has been increasingly appreciated that growth failure can begin in utero and worsen during early infancy; recently, environmental enteric dysfunction (EED) has been hypothesized as an important causal factor. EED is an acquired, subclinical condition of the small intestine associated with chronic exposure to an unhygienic environment where enteric pathogens persist. Histologic features include mucosal inflammation, villous blunting, altered barrier integrity, and reduced intestinal absorptive capacity. Despite EED’s purported link to poor health and nutrition outcomes in young children in low- and middle- income countries (LMICs), our knowledge of EED is relatively limited. Research gaps include the role of infant EED on subsequent poor growth and development and the possible role of maternal EED on adverse birth outcomes. The Trial of Vitamins-5 (ToV5) is an individually randomized, double-blind, placebo-controlled trial (R01 HD83113; ClinicalTrials.gov: NCT02305927) of maternal vitamin D3 (cholecalciferol) supplementation conducted among 2,300 HIV-infected pregnant women in Dar es Salaam, Tanzania. Following enrollment into the trial, mothers were followed-up at monthly clinic visits during pregnancy, at delivery, and then with their child at monthly postpartum clinic visits. Using data and serum samples collected in the ToV5 study, the main objectives of the current proposal are to assess 1) the relationship between infant EED and linear growth, i.e., length-for-age Z-score (LAZ) at 12 months of age; 2) the relationship between infant EED and development, measured by the Caregiver-Reported Early Development Index (CREDI) at 12 months of age; and 3) the relationship between maternal EED during pregnancy and birth outcomes, primarily infant birth weight and duration of gestation. We also aim to 4) examine relationships between the EED, systemic inflammation, and micronutrient biomarkers from a newly developed 11-plex multi-micronutrient and EED assessment tool (MEEDAT); consisting of intestinal fatty acid–binding protein (I-FABP), soluble CD14 (sCD14), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 21 (FGF21), alpha-1-acid glycoprotein (AGP), C-reactive protein (CRP), ferritin, soluble transferrin receptor (sTfR), retinol binding protein 4 (RBP4), thyroglobulin (Tg), and Plasmodium falciparum exposure (HRP2); and anti-flagellin/anti-LPS Igs. Overall, this proposed research will contribute to our understanding of the consequences of EED in LMICs, specifically related to poor growth and adverse birth outcomes, using two innovative methods for assessing EED, namely anti-flagellin/anti-LPS Igs and MEEDAT.