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ORCID

http://orcid.org/0000-0002-1160-7452

Date of Award

Summer 8-15-2020

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Childhood undernutrition accounts for more than 45% of deaths in children under the age of ve. Children who receive current therapeutic treatment and survive often have long-term complications. These survivors usually exhibit stunted growth, impaired cognitive development and are at risk for immune dysfunction, obesity and associated metabolic abnormalities. Recent studies have revealed a causal relationship between development of the gut microbiota and healthy growth. However, standard therapeutic foods were not designed with a consideration of the developmental biology of the gut microbial community and have limited ef cacy in repairing the perturbed microbiota of undernourished children.

We hypothesized that repairing the microbiota of undernourished children with microbiota-directed complementary foods (MDCFs) would improve their growth. Locally available, culturally acceptable food ingredients were tested in a gnotobiotic mouse model for their ability to increase the relative abundance of weaning-phase age-/growth-discriminatory bacterial taxa that are underrepresented in the microbiota of children with moderate and severe acute malnutrition (MAM, SAM). Two isocaloric MDCF prototypes were developed using the lead candidates from the gnotobiotic mouse experiments. MDCF(PCSB) contains all four lead ingredients: peanut, chickpea, soybean and banana, whereas MDCF(CS) only contains two lead ingredients: chickpea and soybean. A gnotobiotic piglet model was used to evaluate the ef cacy of these two MDCF prototypes. Piglets were colonized with a consortium of cultured, sequenced, weaning-phase age-/growth-discriminatory taxa and weaned onto either MDCF(PCSB) or MDCF(CS). Gnotobiotic piglets fed MDCF(PCSB) exhibited greater growth and increased cortical bone volume than piglets consuming MDCF(CS). MDCF(PCSB) also signi cantly increased the relative abundance of targeted weaning-phase age-/growth-discriminatory taxa. Lead MDCFs were then advanced to a month-long, pre-Proof-of-Concept controlled feeding trial in 12-18-month old Bangladeshi children with MAM. Compared to the standard-of-care and other MDCFs, MDCF-2, which also contains all four lead ingredients, repaired the microbiota and increased plasma levels of biomarkers/mediators of growth towards a healthy state � a finding that illustrated the translatability of findings from gnotobiotic mice and piglets models to humans.

The mechanisms by which immature microbiota affect the metabolic features of undernourished individuals remains unclear. To address this gap, an intergenerational pig model of diet restriction was developed to model the perturbed microbiota in undernourished individuals. Incorporating concepts from quantum information theory, I developed a new algorithm, Entropy-based Method for Microbial Ecology Research (EMMER), to identify characteristics that distinguish the gut microbiomes from diet-restricted (DR) pigs to that of their full-fed (FF) counterparts. Compared to FF microbiomes, DR microbiomes have a lower representation of genes associated with the degradation of dominant ingredients represented in the later phase postnatal diets consumed by these animals. To characterize the functional signi cance of these differences in vivo, microbiota from DR and FF pigs were introduced into germ-free mice who were fed a diet resembling that of the pig microbiota donors. Gnotobiotic mice colonized with DR microbiota exhibited reduced levels of cecal butyrate, a bacterial fermentation product of indigestible polysaccharides that serves as a key energy source for the host, and resulted in decreased hepatic fatty acid oxidation in mice. Stunted children who survive undernutrition also exhibit reduced fatty acid oxidation activity which may predispose them to future obesity when consuming high-fat diets. Further investigation is needed to elucidate the mechanism by which MDCF-2-repair of the microbiota mediates various facets of the postnatal development of children, including their metabolic phenotypes.

Language

English (en)

Chair and Committee

Jeffrey Gordon

Committee Members

Daniel Goldberg, Scott Hultgren, Lora Iannotti, Michael Province,

Available for download on Wednesday, August 13, 2025

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