Biomarkers of Environmental Enteric dDsfunction (EED) Predict Growth and Recovery Among Children with Moderate Acute Malnutrition (MAM) in Sierra Leone

Abstract Objectives The objectives of the study were to 1) develop an EED score using fecal host mRNA transcripts, 2) compare three EED biomarkers, and 3) examine associations between EED biomarkers and growth outcomes and recovery from MAM. Methods In a study nested within a supplementary feeding program for children 6–59 months of age with MAM in Sierra Leone, EED was assessed in all children enrolled using: 1) lactulose: mannitol (L: M) test (n = 422), 2) fifteen host fecal mRNA transcripts (n = 441), and 3) host fecal proteins [alpha-1-anti trypsin (AAT), myeloperoxidase (MPO), neopterin (NEO)] (n = 200). Data were also collected on anthropometry and z scores computed for length-for-age (LAZ), and weight-for-length (WLZ). Length and weight gain were assessed over 2 weeks and recovery from MAM was defined as mid-upper arm circumference ≥12.5 cm. Factor analysis was used to identify EED scores using the mRNA transcripts and mixed effects regression was conducted to test for associations. Results The fifteen host fecal mRNA transcripts clustered into three scores using factor analysis (Eigen value >1). These were termed the Gut Inflammation (GI) score (Eigen value = 5.55), Gut Structure (GS) score (Eigen value = 2.48), and Gut Defense (GD) score (Eigen value = 2.22). We found agreement between the GI score and MPO (P < 0.001), the GS score and AAT (P = 0.001), and between AAT and L: M excretion ratio (P = 0.036). The GD score was negatively associated with %L (P < 0.001). A lower LAZ was associated with higher inflammation (GI score, P = 0.014). A lower length gain was associated with higher permeability (AAT, P = 0.001). A lower WLZ was associated with higher inflammation (GI score, P = 0.021) and higher permeability (GS score, P = 0.002). A lower weight gain was associated with lower gut defense (GD score, P = 0.044) and higher inflammation (MPO, P = 0.002). High gut defense (GD score, P = 0.011) and low permeability (AAT, P = 0.007) predicted recovery from MAM. Conclusions Fifteen mRNA transcripts clustered into three scores with clusters reflecting inflammation, permeability and gut defense. These were variably correlated with the L: M test and host fecal proteins but seemed to measure the same characteristics of EED. Markers of inflammation, permeability, and gut defense were associated with growth outcomes, and predicted recovery from MAM. Funding Sources U.S. Agency for International Development (USAID).