MSTP in PhD Training
Program: Molecular Genetics and Genomics
Current advisor: Jeffrey I. Gordon, MD
Undergraduate university: University of Chicago, 2017
Enrollment year: 2017
Characterization of the role of the small intestinal microbiota in the pathogenesis of environmental enteric dysfunction
Worldwide, one in five children under five years of age demonstrates impaired linear growth, or stunting. Stunting, defined as length-for-age z-score (LAZ) < -2, is associated with poor developmental outcomes, including impaired neurodevelopment and immune responses. Furthermore, stunting and its long- term sequelae persist across generations, contributing to an intergenerational cycle of undernutrition. Existing nutritional interventions fail to substantially improve stunting, highlighting the need to (i) better understand other factors contributing to stunting and (ii) focus clinical efforts towards treating maternal undernutrition in order to break the cycle of intergenerational undernutrition. In recent years, a subclinical disorder called environmental enteric dysfunction (EED) has been suggested to contribute to 45% of childhood stunting globally. EED is an inflammatory enteropathy localized to the small intestine; it is characterized histologically by loss of villi and absorptive surface area, epithelial barrier dysfunction, and an immunoinflammatory infiltrate in the lamina propria. While the pathogenesis of EED is poorly understood, researchers have postulated a role for enteric microorganisms. However, the small intestinal microbiota remains largely understudied, in part due to challenges in gaining access to samples. Moreover, few experimental models of EED exist, none of which account for the intergenerational nature of undernutrition. Our lab has established several novel gnotobiotic mouse models, generated by colonizing germ-free mice with a defined community of microbes cultured from duodenal aspirates of Bangladeshi children with EED. These models reflect both the chronic and intergenerational nature of undernutrition and also demonstrate many pathologic features characteristic in individuals with EED. I am characterizing the developmental and immunological profiles of these mouse models as well as integrating genomic and transcriptomic datasets (host and microbial) to elucidate the pathogenesis of EED. These experiments will provide a pre-clinical test of whether the small intestinal microbiota plays a causal role in EED and stunting, and if so, help delineate some of the underlying mechanisms and identify therapeutic targets. Better understanding the pathogenesis of EED offers the potential to develop novel therapeutic approaches for children at risk for, or who already manifest stunting.