Date of Award
Spring 5-15-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Affecting more than 795 million children under the age of 5, childhood undernutrition is one of the greatest impediments to the flourishing of humankind. Current dietary interventions fail to ameliorate many of the long-term sequelae of undernutrition, including immune system dysfunction, impaired vaccine responses, persistent central nervous system (CNS) dysfunction, and early mortality. These shortcomings suggest that our understanding of the biological state of undernutrition is incomplete, and that traditional food therapies fail to target key drivers of undernutrition-dependent pathologies. Recently, work from our lab has provided preclinical evidence demonstrating that impaired development of the distal gut microbiota plays a causal role in growth-faltering. The gut microbiome – the collection of organisms and their genes residing within our intestines – undergoes a defined process of assembly that mirrors the timing of human growth and development. This process is perturbed in acutely malnourished children and is not repaired by existing therapeutic foods. The inability of existing supplementary foods to completely restore host and microbial development raises several key questions. How do features of the gut microbiome interact with expressed mediators of host biological state? Could knowledge of host-microbiome co-development enable rationally designed food interventions that repair the gut microbiota, and in-turn, improve childhood growth? Finally, what role does the gut microbiota in the proximal small-intestine – a region of the gut with immense nutritional absorptive capacity - have in childhood undernutrition? My central hypothesis is that refining our understanding of the biological state of malnutrition to include molecular and microbial features will be critical to developing effective dietary interventions that prevent or treat the long-term sequelae of undernourished children. In this thesis, I demonstrate using a combination of novel statistical methods, experimental paradigms and clinical studies that (i) states of undernutrition can be better defined using proteomic analyses of plasma harvested prior to, during and after nutritional supplementation combined with culture-independent analysis of serially sampled gut microbiomes, (ii) repair of microbiota immaturity by microbiota-directed therapeutic foods offers an opportunity to ‘connect’ components of the microbiome to the responses of host systems, and (iii) the small-intestinal microbiota plays a causal role in the pathogenesis of a prevalent enteropathy found in chronically undernourished children.
Language
English (en)
Chair and Committee
Jeffrey I. Gordon
Committee Members
Megan Baldridge, Barak Cohen, Marco Colonna, Daniel Goldberg, David Holtzman, Samantha Morris
Recommended Citation
Chen, Robert Yuzen, "An Evolving View of Host-Microbiome Co-Development in Healthy and Undernourished Children" (2023). Arts & Sciences Electronic Theses and Dissertations. 2840.
https://openscholarship.wustl.edu/art_sci_etds/2840