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

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

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

Associations between biomarker concentrations (log₂-transformed) at 6 weeks and 6 months of age and CREDI z-scores at 12 months of age.

Associations between biomarker concentrations (log2-transformed) at 6 weeks and 6 months of age and CREDI z-scores at 12 months of age.</p

Correlation coefficient matrix of biomarker concentrations at 6 weeks and 6 months of age¹.

Correlation coefficient matrix of biomarker concentrations at 6 weeks and 6 months of age1.</p

Checklist of items that should be included in reports of cohort studies.

Checklist of items that should be included in reports of cohort studies.</p

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

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

Descriptive characteristics for 467 infants and their mothers in Dar es Salaam, Tanzania.

Descriptive characteristics for 467 infants and their mothers in Dar es Salaam, Tanzania.</p

Associations between biomarker concentrations (quartiles) at 6 weeks and 6 months of age and overall CREDI z-score at 12 months of age¹.

Associations between biomarker concentrations (quartiles) at 6 weeks and 6 months of age and overall CREDI z-score at 12 months of age1.</p