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

Iqbal, Najeeha Talat; Sadiq, Kamran; Syed, Sana; Akhund, Tauseefullah; Umrani, Fayyaz; Ahmed, Sheraz; Yakoob, Mohammad Yawar; Rahman, Najeeb; Qureshi, Shahida; Xin, Wenjun; Jennie, Z.; Hughes, Molly A.; Ali, Syed Asad

doi:10.1038/s41598-018-21319-8

Cited by 50 publications

(58 citation statements)

References 30 publications

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“…After a flurry of biopsy studies four decades ago [24][25][26][27][28], there has been a paucity of histologic studies of the small bowel until recently. However, markers in blood, stool, and urine (e.g., urine dual sugar permeability testing) have lent credence to the concept that poor growth and EED are tightly linked in children in LMICs [14,[29][30][31][32]. Nonetheless, the origin and pathophysiology of EED remains elusive.…”

Section: Introductionmentioning

confidence: 99%

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth

et al. 2020

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BackgroundA major limitation to understanding the etiopathogenesis of environmental enteric dysfunction (EED) is the lack of a comprehensive, reproducible histologic framework for characterizing the small bowel lesions. We hypothesized that the development of such a system will identify unique histology features for EED, and that some features might correlate with clinical severity. Data Availability Statement: All relevant analyses are within the manuscript and its Supporting was assessed. The histology index was further used to identify within-and between-child variations as well as features common across and unique to each cohort, and those that correlated with host phenotype. ResultsEight of the 11 histologic scoring parameters showed useful degrees of variation. The overall concordance across all parameters was 96% weighted agreement, kappa 0.70, and Gwet's AC 0.93. Zambian and Pakistani tissues shared some histologic features with GSE, but most features were distinct, particularly abundance of intraepithelial lymphocytes in the Pakistani cohort, and marked villous destruction and loss of secretory cell lineages in the Zambian cohort. ConclusionsWe propose the first EED histology index for interpreting duodenal biopsies. This index should be useful in future clinical and translational studies of this widespread, poorly understood, and highly consequential disorder, which might be caused by multiple contributing processes, in different regions of the world. Author summaryThe study of EED has been limited by the lack of a rigorously tested, reproducible histology index that can provide insight to the pathogenesis of this entity. In this study we report the first duodenal histology index that was developed using an unbiased approach, with excellent inter-observer reproducibility, for the study of EED. The EED histology index readily identified histologic features that are common or unique to cohorts of distinct geographic locations. Incorporating the histology index into future clinical studies will provide useful insight into the pathogenesis and for intervention strategy development.

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Section: Introductionmentioning

confidence: 99%

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth

et al. 2020

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“…Myeloperoxidase (MPO), a marker of neutrophil activity in intestinal mucosa, and lipocalin-2 (LCN-2), a glycoprotein upregulated in tissue damage under infection conditions, have been considered as biomarkers of environmental enteric dysfunction, including EPEC, in children [35][36][37][38]. To ensure that our EPEC infection model mimics the alterations of these biomarkers as observed in children, we measured MPO and LCN-2 in the ileal and colonic tissues, as well as in cecal contents and stools.…”

Section: Epec Infection Promotes Acute Intestinal Tissue Damage and Imentioning

confidence: 99%

EnteropathogenicEscherichia coli(EPEC) Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations and Increased Intestinal Permeability in a Murine Model

Ledwaba

Costa

Bolick

et al. 2020

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Enteropathogenic E. coli (EPEC) are recognized as one of the leading bacterial causes of infantile diarrhea worldwide. Weaned C57BL/6 mice pretreated with antibiotics were challenged orally with wild-type EPEC or escN mutant (lacking type 3 secretion system) to determine colonization, inflammatory responses and clinical outcomes during infection. Antibiotic disruption of intestinal microbiota enabled efficient colonization by wild-type EPEC resulting in growth impairment and diarrhea. Increase in inflammatory biomarkers, chemokines, cellular recruitment and pro-inflammatory cytokines were observed in intestinal tissues.Metabolomic changes were also observed in EPEC infected mice with changes in TCA cycle intermediates, increased creatine excretion and shifts in gut microbial metabolite levels. In addition, by 7 days after infection, although weights were recovering, EPEC-infected mice had increased intestinal permeability and decreased colonic claudin-1 levels. The escN mutant colonized the mice, but had no weight changes or increased inflammatory biomarkers, showing the importance of the T3SS in EPEC virulence in this model. In conclusion, a murine infection model treated with antibiotics has been developed to mimic many clinical outcomes seen in children with EPEC infection and to examine potential roles of selected virulence traits. This model can help in further understanding mechanisms involved in the pathogenesis of EPEC infections and potential outcomes and thus assist in the development of potential preventive or therapeutic interventions.

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“…As part of a 4-year prospective study, researchers at Aga Khan University in Pakistan collected data for 380 children from the rural village of Matiari, Sindh, Pakistan (12). The data comprised a combination of demographic, biometric, and laboratory measures.…”

Section: Data Collectionmentioning

confidence: 99%

Machine Learning Model Demonstrates Stunting at Birth and Systemic Inflammatory Biomarkers as Predictors of Subsequent Infant Growth – A Four-year Prospective Study.

Harrison

Syed

Ehsan

et al. 2020

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Background: Stunting affects up to one-third of children in low-to-middle income countries (LMICs) and has been correlated with cognitive decline and vaccine immunogenicity. Infants with stunting often have growth refractory to nutritional interventions. Early identification of at-risk infants is critical for early intervention and prevention of subsequent morbidity. The aim of this study was to investigate patterns of growth in infants up through 48 months of age, as well as potential predictors of growth.Methods: Height-for-age z-scores (HAZ) of children from Matiari (rural site in Pakistan) at birth, 18 months, and 48 months were obtained. Results of serum-based biomarkers collected at 6 and 9 months were recorded. A descriptive analysis of the population was followed by biomarker prediction assessment via machine learning methods; random forest classification bins of z-scores and random forest regression for continuous z-scores. Results: Of 107 children who were followed up to 48 months, about half were stunted (HAZ < -2) at birth which increased to 54% by 48 months of age. HAZ at 18 months had a positive linear correlation with HAZ at 48 months, while HAZ at birth was less strongly correlated with HAZ at either 18 or 48 months. Stunting status for the majority of children at 48 months was found to be the same as at 18 months. Most children with large gains started off stunted or severely stunted, while all of those with notably large losses were not stunted at birth. Random forest models identified HAZ at birth as the most important feature in predicting HAZ at 18 months. Of the biomarkers, AGP (Alpha- 1-acid Glycoprotein), CRP (C-Reactive Protein), and IL1 (interleukin-1) were assigned the highest importance rankings across both the classification and regressor models.Conclusion: We demonstrated that HAZ at birth is a strong predictor of subsequent growth in infants up through 48 months of age. Biomarkers of systemic inflammation, AGP, CRP, IL1, were also strong predictors of growth outcomes. These findings provide support for continued focus on interventions at birth and early infancy in children at risk for stunting who live in resource-constrained regions of the world.

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

Cited by 50 publications

References 30 publications

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth

A novel histological index for evaluation of environmental enteric dysfunction identifies geographic-specific features of enteropathy among children with suboptimal growth

EnteropathogenicEscherichia coli(EPEC) Infection Induces Diarrhea, Intestinal Damage, Metabolic Alterations and Increased Intestinal Permeability in a Murine Model

Machine Learning Model Demonstrates Stunting at Birth and Systemic Inflammatory Biomarkers as Predictors of Subsequent Infant Growth – A Four-year Prospective Study.

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