Intestinal permeability and inflammation mediate the association between nutrient density of complementary foods and biochemical measures of micronutrient status in young children: results from the MAL-ED study

Abstract

Background: Environmental enteric dysfunction (EED) is thought to increase the risk of micronutrient deficiencies, but few studies adjust for dietary intakes and systemic inflammation.

Objective: We tested whether EED is associated with micronutrient deficiency risk independent of diet and systemic inflammation, and whether it mediates the relation between intake and micronutrient status.

Methods: Using data from 1283 children in the MAL-ED (Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health) birth cohort we evaluated the risk of anemia, low retinol, zinc, and ferritin, and high transferrin receptor (TfR) at 15 mo. We characterized gut inflammation and permeability by myeloperoxidase (MPO), neopterin (NEO), and α-1-antitrypsin (AAT) concentrations from asymptomatic fecal samples averaged from 9 to 15 mo, and averaged the lactulose:mannitol ratio z-score (LMZ) at 9 and 15 mo. Nutrient intakes from complementary foods were quantified monthly from 9 to 15 mo and densities were averaged for analyses. α-1-Acid glycoprotein at 15 mo characterized systemic inflammation. Relations between variables were modeled using a Bayesian network.

Results: A greater risk of anemia was associated with LMZ [1.15 (95% CI: 1.01, 1.31)] and MPO [1.16 (1.01, 1.34)]. A greater risk of low ferritin was associated with AAT [1.19 (1.03, 1.37)] and NEO [1.22 (1.04, 1.44)]. A greater risk of low retinol was associated with LMZ [1.24 (1.08, 1.45)]. However, MPO was associated with a lower risk of high transferrin receptor [0.86 (0.74, 0.98)], NEO with a lower risk of low retinol [0.75 (0.62, 0.89)], and AAT with a lower risk of low plasma zinc [0.83 (0.70, 0.99)]. Greater nutrient intake densities (vitamins A and B6, calcium, protein, and zinc) were negatively associated with EED. Inverse associations between nutrient densities and micronutrient deficiency largely disappeared after adjustment for EED, suggesting that EED mediates these associations.

Conclusions: EED is independently associated with an increased risk of low ferritin, low retinol, and anemia. Greater nutrient density from complementary foods may reduce EED, and the control of micronutrient deficiencies may require control of EED.

Keywords: diet; environmental enteropathy; inflammation; intestinal barrier function; micronutrient status.

FIGURE 1

Cohort profile by site. AGP, α-1-acid glycoprotein; BGD, Dhaka, Bangladesh; BRF, Fortaleza, Brazil; INV, Vellore, India; LMZ, lactulose:mannitol ratio z-score; NEB, Bhaktapur, Nepal; PEL, Loreto, Peru; PKN, Naushero Feroze, Pakistan; TfR, transferrin receptor; TZH, Haydom, Tanzania.

FIGURE 2

Schematic of the model used to examine hypothetical relations between variables. Nutrient intake densities from complementary foods are related to fecal biomarkers of inflammation (MPO, myeloperoxidase; NEO, neopterin) to markers of permeability (AAT, α-1-antitrypsin; LMZ, lactulose:mannitol ratio z-score) and to plasma biomarkers of nutrient status, which are also affected by systemic inflammation (AGP, α-1-acid glycoprotein). The plasma biomarkers (including AGP) were measured at 15 mo, whereas all other variables are the averages from 9 to 15 mo (LMZ was measured at 9 and 15 mo only). TfR, transferrin receptor.

FIGURE 3

Results of the multivariate Bayesian network. Arcs (arrows) are shown for parameters that did not include zero in the 95th percentile credibility interval. Positive associations are shown in red and negative in blue. The thickness of the arc is proportional to the magnitude of the association, with solid lines indicating linear associations and dashed lines indicating log odds. AAT, α-1-antitrypsin; AGP, α-1 acid glycoprotein; LMZ, urinary lactulose:mannitol ratio z-score; MPO, myeloperoxidase; NEO, neopterin; TfR, transferrin receptor.