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. 2018 Feb 14;8(1):2966.
doi: 10.1038/s41598-018-21319-8.

Promising Biomarkers of Environmental Enteric Dysfunction: A Prospective Cohort study in Pakistani Children

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Promising Biomarkers of Environmental Enteric Dysfunction: A Prospective Cohort study in Pakistani Children

Najeeha Talat Iqbal et al. Sci Rep. .

Abstract

Environmental Enteric Dysfunction (EED), a syndrome characterized by chronic gut inflammation, contributes towards stunting and poor response to enteric vaccines in children in developing countries. In this study, we evaluated major putative biomarkers of EED using growth faltering as its clinical proxy. Newborns (n = 380) were enrolled and followed till 18 months with monthly anthropometry. Biomarkers associated with gut and systemic inflammation were assessed at 6 and 9 months. Linear mixed effects model was used to determine the associations of these biomarkers with growth faltering between birth and 18 months. Fecal myeloperoxidase (neutrophil activation marker) at 6 months [β = -0.207, p = 0.005], and serum GLP 2 (enterocyte proliferation marker) at 6 and 9 months [6M: β = -0.271, p = 0.035; 9M: β = -0.267, p = 0.045] were associated with decreasing LAZ score. Ferritin at 6 and 9 months was associated with decreasing LAZ score [6M: β = -0.882, p < 0.0001; 9M: β = -0.714, p < 0.0001] and so was CRP [β = -0.451, p = 0.039] and AGP [β = -0.443, p = 0.012] at 9 months. Both gut specific and systemic biomarkers correlated negatively with IGF-1, but only weakly correlated, if at all with each other. We therefore conclude that EED may be contributing directly towards growth faltering, and this pathway is not entirely through the pathway of systemic inflammation.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Enrollments of children in the cohort. All newborn were recruited in the cohort through active surveillance within 24 hrs. of birth. Biological samples were collected from children at 6 and 9 month. Monthly anthropometry measurement from birth to 18 months, weekly record of acute respiratory infections (ARI) and diarrhea were recorded through home visits. Between 6 and 9 months nutritional intervention was done on 65 children selected on the basis of WHZ < −2.0. Furthermore 4 week educational session was carried out by showing video to mother of children (http://www.dailymotion.com/video/x1mztre_infant-dietary-counseling-pakistan_lifestyle). Children who showed no improvement in growth after interventions were further evaluated for detailed histopathalogical analysis by two independent physicians. Complete data were obtained on 325 samples where both 6 and 9 months paired samples were available. Of these, *272 had a complete set of all biomarkers analyzed.
Figure 2
Figure 2
Longitudinal assessment of LAZ scores of children from birth to 18th month. Figure 2 illustrates the longitudinal Z scores of 380 children from birth to 18th month in 3 categories of LAZ (LAZ < −2.0, LAZ between −1.99 to 0 and LAZ > 0.01).
Figure 3
Figure 3
Framework of EED showing gut/systemic inflammation influencing growth in children. This figure describes the hypothetical pathway of EED through the gut (A) and systemic inflammation (B). Factors driving the inflammatory pathway include respiratory illnesses, enteropathogen infection (measured by TaqMan Array), translocation of bacteria from the gut (IgG/IgA against LPS and Flagellin) due to repeated diarrheal episodes. The two distinct pathways regulating growth hormone, are being measured by gut-specific and systemic biomarkers shown in boxes (A) & (B). The negative association of biomarkers with IGF results in growth failure in children as shown by the black arrow. The dotted arrows show a weak relationship between the gut and systemic inflammatory biomarkers. *Information collected through weekly morbidity data. ≠Estimated through TaqMan array card for bacterial, viral and protozoal targets at 6 and 9 month fecal samples. ±IgG/IgA antibodies against LPS and Flagellin was measured in serum samples at 6 and 9 months.
Figure 4
Figure 4
Principal component analysis of EED biomarkers at 6 and 9 months. All biomarkers are shown here in three dimensional plots of 6 and 9 months. Component plot of 6 month biomarker is shown in Fig. 4A. The component loadings of biomarkers of PC1 (systemic inflammation) are shown in red and PC2 (intestinal inflammation) is shown in black. Component plot of 9 month biomarker is shown in Fig. 4B. The component loading of PC1 (Systemic Inflammation) is shown in red. PC2 is shown in black and PC3 is shown in blue as a marker of intestinal inflammation.

References

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