Undernutrition, microbiota maturation, and adaptive immunity in Bangladeshi children

PROJECT SUMMARY/ABSTRACT Benjamin Lee, MD – Principal Investigator (PI) Childhood undernutrition affects approximately 200 million children around the world and is associated with increased risk of child mortality from infectious diseases. It is generally accepted that undernutrition, as manifested by growth impairment, causes functional immune deficiency that increases susceptibility to severe infections. However, other than in the most extreme form of severe acute malnutrition (SAM), an immunologic basis for this increased risk in undernourished children has yet to be convincingly demonstrated. This may be due in part to previous methodologic limitations, such as reliance on cross-sectional evaluations that cofounded identification of children at highest risk and use of rudimentary methods of immune assessment. This project will address this knowledge gap via longitudinal evaluation of underexplored aspects of pediatric immune development in undernourished and healthy children from a birth cohort study conducted in Dhaka, Bangladesh (PROVIDE). In Aim 1, the multidisciplinary research team will first use stool metagenomic sequencing to investigate the critical contribution of gut microbiota maturation to growth phenotype during the first 2 years of life, and persistence of these effects into later childhood. Children with SAM from this community have previously demonstrated impaired microbiota maturation. This study will assess whether similar perturbations, along with measures of diversity, taxonomic community structure, and metabolic pathways may affect children with other forms of growth impairment, including growth failure, stunting, and underweight. In Aim 2, the project will evaluate measures of T cell diversity and systemic inflammation in these children, along with exploratory analyses using single-cell proteogenomics to identify immune cell profiles unique to each growth phenotype. Finally, the impact of the gut microbiota on these immune outcomes will be investigated. This project will use careful case selection in a well-characterized longitudinal cohort to address critical knowledge gaps relating to undernutrition, microbiota development, and development and maintenance of immune diversity. The knowledge gained herein will provide a major contribution to basic understanding of fundamentally important aspects of the “first 1000 days of life,” the window period from conception to age 2 most critical for establishment of healthy growth and development in children. Ultimately, this work may help inform needed interventions to improve children and development, particularly in resource-limited settings where undernutrition and child mortality due to infections is most prevalent.