Identification of Novel Biomarkers for Environmental Enteropathy in Children Using an Evidence Based Approach

EE is increasingly recognized as a key factor underlying malnutrition, weakened immune response and impaired cognitive development in children in developing countries. Absence of a distinct biomarker of EE in the blood, urine or stool makes it difficult to study the impact of interventions against it. Biomarkers for EE have been challenging to find, partly because of our inadequate understanding of its pathophysiology. Investigators aim to identify novel biomarkers for EE, based on our hypothesis that EE is a result of two processes: 1) repeated exposure to enteric pathogens and environmental toxins leading to gut inflammation and 2) weaning on diets high in carbohydrates but low in proteins and fat, leading to atrophy of the intestinal mucosa. This leads to gut dysfunction, including leaky gut, small bowel stasis, bacterial overgrowth, decreased immune response to infections, and frequent diarrhea. The candidate biomarkers investigators have selected for our study (CRP, GLP- 2, Claudin 3, Reg-1, plasma amino acids profile, serum cytokine profile, Neopterin and Myeloperoxidase) are markers of inflammation, hormonal dysfunction and tight junction malfunction of the small intestines. The 'gold standard test' for EE will be direct histopathologic analysis of the duodenal mucosa, which will be available in a subset of study children undergoing upper GI endoscopy. For other study subjects, clinical surrogates for EE will be used to calculate the sensitivity and specificity of biomarkers being tested. These clinical surrogates of EE include HAZ and WAZ score < 2 SD at 12 months and 15 months of age, and the worsening in HAZ and WAZ scores between 6, 9, 12 and 15 months of age. Investigators plan to study and compare duodenal biopsies from children with and without EE using cutting edge technologies including electron microscopy, immunofluorescence, and mRNA sequencing. This will allow direct correlation of the biomarkers in the blood, urine and stools with the histopathologic features of the gut mucosa. The mRNA sequencing of the gut tissue will allow us to identify new evidence-based biomarkers for EE, which could be further tested in the future.

This is a strong, multidisciplinary collaboration between investigators in Pakistan and the United States with expertise in complementary areas including chemokines, inflammation, gut architecture, infectious diseases, field studies, and technology development.