Environmental Enteropathy and Fibroblast Growth Factor 21 are associated with early childhood growth in Bangladesh

Chronic undernutrition, marked by stunting (low height for age), is associated with increased child morbidity and mortality worldwide. Current intervention strategies are often ineffective at preventing or reversing stunting; while some children grow in response to nutrition programs, many do not. This dissertation aims to improve understanding of two major challenges in the prevention and treatment of chronic undernutrition in previously accrued cohorts of young Bangladeshi children. CHAPTER 1: Environmental enteropathy (EE), a subclinical intestinal disorder characterized by mucosal inflammation, reduced barrier integrity, and malabsorption, appears to be associated with increased risk of stunting in children in low and middle income countries. Fecal biomarkers indicative of EE [neopterin (NEO), myeloperoxidase (MPO), and alpha-1-antitrypsin (AAT)] have previously been negatively associated with 6-month linear growth. Associations between fecal markers (NEO, MPO and AAT) and short-term linear growth were examined in a birth cohort of 246 children in Bangladesh. Marker concentrations were categorized in stool samples based on their distribution (<1st quartile, IQR, >3rd quartile), and a 10-point composite EE score was calculated. Piecewise linear mixed-effects models were used to examine the association between markers measured quarterly (in months 3-21, 3-9, and 12-21) and 3-month change in length for age z-score (ΔLAZ). Children with high MPO levels at quarterly time points lost significantly more LAZ per 3-month period during the second year of life than those with low MPO (ΔLAZ= -0.100; 95% CI: -0.167, -0.032). AAT and NEO were not associated with subsequent growth, however composite EE score was negatively associated with subsequent 3-month growth. In this birth cohort of children from an urban setting in Bangladesh, elevated MPO levels, but not NEO or AAT levels, were associated with decreases in short-term linear growth during the second year of life, supporting previous data suggesting the relevance of MPO as a marker of EE. CHAPTER 2: Undernutrition as manifest by poor child growth is prevalent in resource limited countries and is associated with child morbidity and mortality. Current nutritional intervention strategies are often insufficient to improve child growth; some children respond while others do not. There is an unmet need to identify children who are likely to respond to supplemental nutrition as well as those in need of additional interventions beyond nutritional rehabilitation. Fibroblast growth factor 21 (FGF21) is an endocrine signal of protein restriction that regulates metabolism and growth during periods of reduced protein intake. This study sought to determine the association between plasma FGF21 levels and growth in children receiving nutritional supplementation. 120 underweight children aged 6–13 months were enrolled from an urban slum in Dhaka, Bangladesh. Children received 300 kcal feeding supplements daily for five months and were followed for seven additional months. FGF21 was measured in stored plasma at enrolment and month five. Linear mixed-effects models were used to examine the association between baseline FGF21 and age-standardized length-for-age Z score (LAZ), weight-for-age Z score (WAZ), and head circumference-for-age Z score (ZHC) during and after nutritional supplementation. At enrolment, the median FGF21 concentration was 241.4 pg/ml (interquartile-range: 111.7, 451.3), and 9 (7.5%) of children had high FGF21. High baseline FGF21 levels were associated with increases in WAZ (0.10 per month, 95%CI: 0.03, 0.16) and ZHC (0.05 per month, 95%CI: 0.01, 0.09) during nutritional supplementation, while low FGF21 levels were associated with decreases in LAZ (-0.09 per month, 95%CI: -0.10, -0.07) and ZHC (-0.04 per month, 95%CI: -0.06, -0.03). Following supplementation, children with low FGF21 continued to experience decreases in LAZ, ZHC, and WAZ. On average, WAZ, LAZ and ZHC did not change during the post-supplementation period among those with high baseline FGF21. FGF21 may be a useful tool to both identify undernourished children likely to benefit from nutritional supplementation and to identify children in whom additional interventions may be necessary to improve growth.