Serum anti-flagellin and anti-lipopolysaccharide immunoglobulins as predictors of linear growth faltering in Pakistani infants at risk for environmental enteric dysfunction

Background: Environmental Enteric Dysfunction (EED) in children from low-income countries has been linked to linear growth declines. There is a critical need to identify sensitive and early EED biomarkers.Objective: Determine whether levels of antibodies against bacterial components flagellin (flic) and lipopolysaccharide (LPS) predict poor growth.Design/Methods: In a prospective birth cohort of 380 children in rural Pakistan blood and stool samples were obtained at ages 6 and 9 months. Linear mixed effects models were used to examine longitudinal associations between quartiles of anti-flic and anti-LPS antibodies and changes in LAZ, WAZ and WLZ scores. Spearman\u27s correlations were measured between anti-flic and anti-LPS immunoglobulins with measures of systemic/enteric inflammation and intestinal regeneration.Results: Anti-LPS IgA correlated significantly with CRP, AGP and Reg1 serum at 6mo and with MPO at 9mo. In multivariate analysis at 6mo of age, higher anti-LPS IgA levels predicted greater declines in LAZ scores over subsequent 18mo (comparing highest to lowest quartile, β (SE) change in LAZ score/year = -0.313 (0.125), p-value = 0.013). Anti-flic Ig A in the two highest quartiles measured at 9mo of age had declines in LAZ of -0.269 (0.126), p = 0.033; and -0.306 (0.129), p = 0.018 respectively, during the subsequent 18mo of life, compared to those in the lowest quartile of anti-flic IgA.Conclusions and Relevance: Elevated anti-flic IgA and anti-LPS IgA antibodies at 6 and 9mo, predict declines in linear growth. Systemic and enteric inflammation correlated with anti-LPS IgA provides mechanistic considerations for potential future interventions

Low placental weight is associated with an increased risk of adverse perinatal outcomes.

<p>Forest plots of adjusted relative risk for perinatal outcomes with placental weight in (a) the bottom tenth percentile and (b) the top tenth percentile. Forest plots depict adjusted relative risk and 95% confidence interval. Multivariate models adjusted for treatment arm (placebo, multivitamin), maternal age (years), sex of child (male, female), gestational age at trial enrolment (weeks), and gestational age at delivery (week).</p

Baseline descriptive characteristics of the study cohort (n = 6,579)

<p>Baseline descriptive characteristics of the study cohort (n = 6,579)</p

Relative risk of adverse perinatal outcomes dependent on placental weight in the bottom and top 10^th percentiles

<p>Relative risk of adverse perinatal outcomes dependent on placental weight in the bottom and top 10^th percentiles</p

Multivariate relative risk for placental weight according to biomarker levels by quartile

<p>Multivariate relative risk for placental weight according to biomarker levels by quartile</p

Biomarker concentrations (quartiles) at 6 weeks of age and associations with growth outcomes at 12 months of age¹.

Biomarker concentrations (quartiles) at 6 weeks of age and associations with growth outcomes at 12 months of age1.</p

Infant and Maternal Characteristics at six and nine months^*.

<p>Infant and Maternal Characteristics at six and nine months^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0193768#t001fn002" target="_blank">*</a>}.</p

The association of anti-flagellin and anti-lipopolysaccharide immunoglobulin concentrations at 6 and 9 months with annual Z score changes for length using linear mixed effects models.

<p>The association of anti-flagellin and anti-lipopolysaccharide immunoglobulin concentrations at 6 and 9 months with annual Z score changes for length using linear mixed effects models.</p

Flow diagram for study.

Abbreviations: CREDI, Caregiver Reported Early Development Instruments; EED, environmental enteric dysfunction; FliC, flagellin; Ig, immunoglobulin; LAZ, length-for-age z-score; LPS, lipopolysaccharide; MEEDAT, Multi-Micronutrient and Environmental Enteric Dysfunction Assessment Tool.</p

Associations between biomarkers concentrations (log₂-transformed) at 6 weeks and 6 months of age and growth outcomes at 12 months of age.

Associations between biomarkers concentrations (log2-transformed) at 6 weeks and 6 months of age and growth outcomes at 12 months of age.</p