Dynamics and Trends in Fecal Biomarkers of Gut Function in Children from 1–24 Months in the MAL-ED Study

Abstract

Abstract. Growth and development shortfalls that are disproportionately prevalent in children living in poor environmental conditions are postulated to result, at least in part, from abnormal gut function. Using data from The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal cohort study, we examine biomarkers of gut inflammation and permeability in relation to environmental exposures and feeding practices. Trends in the concentrations of three biomarkers, myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT), are described from fecal samples collected during the first 2 years of each child's life. A total of 22,846 stool samples were processed during the longitudinal sampling of 2,076 children 0-24 months of age. Linear mixed models were constructed to examine the relationship between biomarker concentrations and recent food intake, symptoms of illness, concurrent enteropathogen infection, and socioeconomic status. Average concentrations of MPO, NEO, and AAT were considerably higher than published references for healthy adults. The concentration of each biomarker tended to decrease over the first 2 years of life and was highly variable between samples from each individual child. Both MPO and AAT were significantly elevated by recent breast milk intake. All three biomarkers were associated with pathogen presence, although the strength and direction varied by pathogen. The interpretation of biomarker concentrations is subject to the context of their collection. Herein, we identify that common factors (age, breast milk, and enteric infection) influence the concentration of these biomarkers. Within the context of low-and middle-income communities, we observe concentrations that indicate gut abnormalities, but more appropriate reference standards are needed.

Enteric Infections in Young Children are Associated with Environmental Enteropathy and Impaired Growth

“…The presence of ETEC in stool was associated with elevated faecal calprotectin concentrations. This is consistent with the recent literature demonstrating an association between enteric pathogens and elevated EE faecal markers [40]. In the MAL-ED study, a higher number of enteric pathogens in stool was associated with elevated concentrations of faecal myeloperoxidase and alpha-1antitrypsin in young children.…”

“…In the MAL-ED study, a higher number of enteric pathogens in stool was associated with elevated concentrations of faecal myeloperoxidase and alpha-1antitrypsin in young children. In addition, Campylobacter infections were associated with elevated faecal myeloperoxidase concentrations, and Giardia intestinalis infections were associated with elevated faecal neopterin concentrations [27,40,41]. In a later paper from this study, ETEC and Shigella were found to be positively associated with elevated myeloperoxidase concentrations [27].…”

Rice bran supplementation modulates growth, microbiome and metabolome in weaning infants: a clinical trial in Nicaragua and Mali

“…Rice bran was shown to reduce AAT in neonatal pigs challenged with human Rotavirus infection 22 and is of translational importance herein as rice bran intake improved AAT levels in Nicaraguan infants ( Table 2 ). The lack of significant differences in levels of EED biomarkers for Mali may be due to the higher number of overall diarrheal episodes, the level of variability within individuals, and breastfeeding over time and across groups, yet these findings did concur with concentrations reported in the MAL-ED cohort 34 . EED biomarkers merit continuous review for relevance with growth outcomes due to extensive global variability in concentrations reported across studies 6,49–51 .…”

“…Stool EED biomarkers, gut microbiome 32 and metabolome analysis 15, 33 became important surrogate markers for analysis as intestinal tissue from infants is not easily accessible to evaluate. Stool myeloperoxidase (MPO) 34 , calprotectin (CAL) 35 , and neopterin (NEO) 36 are indicators of inflammation; and alpha-1-antitrypsin (AAT) 34 is an indicator of barrier lumen disruption. Chronic, elevated concentrations of all four biomarkers have been associated with poor linear growth in infants up to 24 months old 10,34–36 , and as the gut microbiome is maturing over the first 3 years of life 37, 38 .…”

“…Stool myeloperoxidase (MPO) 34 , calprotectin (CAL) 35 , and neopterin (NEO) 36 are indicators of inflammation; and alpha-1-antitrypsin (AAT) 34 is an indicator of barrier lumen disruption. Chronic, elevated concentrations of all four biomarkers have been associated with poor linear growth in infants up to 24 months old 10,34–36 , and as the gut microbiome is maturing over the first 3 years of life 37, 38 . Gut microbiome composition and metabolism is influenced by delivery mode, environment, and nutrition 39, 40 .…”