Abstract

Undernutrition affects over 200 million children worldwide with the greatest burden of disease in Africa and South Asia. Long-term sequelae of undernutrition include but are not limited to linear growth faltering (stunting), impaired cognitive development plus immune and metabolic dysfunction. Current nutritional interventions have had limited success in alleviating stunting or ameliorating other comorbidities, suggesting that factors beyond food insecurity contribute to disease pathogenesis. Our lab is testing the hypothesis that there is a causal relationship between disrupted postnatal gut microbiome development and childhood undernutrition, and the corollary that healthy growth depends upon properly choreographed co-development of the microbiome and host physiologic systems. Our lab’s randomized controlled clinical trial (RCT) of a microbiome-directed complementary food-based formulation (MDCF-2), performed in collaboration with colleagues at the International Centre for Diarrhoeal Disease Research in Bangladesh (iccdr,b), demonstrated its superiority over a current ready-to-use supplementary food (RUSF) in improving ponderal and linear growth in 12-18-month-old Bangladeshi children with moderate acute malnutrition (MAM), and highlighted bacterial strains positively associated with growth responses as well as plasma protein mediators of various facets of improved host development. These results inspired this thesis which involved a multi-step “structure-function” guided effort designed to identify food staples containing polysaccharide structures that target these growth-associated organisms and that are candidates for incorporation into next generation MDCFs and/or as sources of prebiotics. The first step involved leveraging metagenomic and metatranscriptomic data from the RCT that indicated that pectic glycans were an important bioactive component of the MDCF and selecting sweet potato as a source of these glycans based on its monosaccharide composition and high level of consumption in sub-Saharan Africa and South Asia where the burden of undernutrition is high. The second step involved comparing the effects, in a gnotobiotic mouse model of dam-to-pup human microbiome transmission/assembly, of each of the four complementary food ingredients in MDCF-2 (soy, chickpea, peanut and banana) versus sweet potato on (i) expression of carbohydrate active enzymes (CAZymes) plus various metabolic pathways represented in the genomes of a consortium of cultured age- and growth-associated Bangladeshi bacteria strains, with a focus on the primary consumer of these glycans – Segatella copri. The third step consisted of in vitro culture experiments involving S. copri and an identified syntrophic partner in defined medium with and without supplementation of structural components of pectic glycans, and microbial RNA-Seq analyses to further characterize glycan structures that target S. copri and their nutrient-sharing relationships. The final step, a single-blind, randomized trial in Bangladeshi children with MAM and follow-up multi-omic analyses of microbiome responses, established the translatability of the preclinical results. Together, the work of this thesis illustrates an approach for connecting the molecular constituents of food to microbiome function and the nutritional resuscitation of undernourished children.

Committee Chair

Jeffrey Gordon

Committee Members

Barbara Warner; Clay Semenkovich; Daniel Goldberg; Michael Province

Degree

Doctor of Philosophy (PhD)

Author's Department

Biology & Biomedical Sciences (Computational & Systems Biology)

Author's School

Graduate School of Arts and Sciences

Document Type

Dissertation

Date of Award

8-17-2026

Language

English (en)

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Available for download on Saturday, August 14, 2027

Included in

Nutrition Commons

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