UBC Theses and Dissertations
The impact of malnutrition on host-microbe interactions in the intestine Brown, Eric
Early-life malnutrition results in childhood growth stunting, increased intestinal permeability, along with significant changes in the intestinal microbiota and metabolite composition. Here, we aim to characterize and further understand how malnutrition results in these intestinal consequences, and use this knowledge to develop a model to study environmental enteropathy (EE), a chronic inflammatory disease of the small intestine. Three-week-old C57BL/6 mice administered a protein and fat malnourished diet where compared with mice fed an isocaloric standard diet and found to be moderately growth stunted, with barrier dysfunction as observed decreased abundance of tight-junction proteins and increase in intestinal permeability to dextran. Mice given the malnourished diet were also found to have an altered small intestinal microbiota and metabolome, notably including profound changes in the Bacteroidetes and Proteobacteria species able to colonize the upper small intestine, correlated with large differences in the bile acid composition. The colon of malnourished mice had an altered mucosal microbiota composition, a thinner mucus layer and a greater number of microbes able to cross the mucus barrier was visualized by microscopy. We used these data to inform our development of a model for EE in mice. Features of EE include growth stunting, intestinal permeability, villous blunting and chronic intestinal inflammation. After screening a number of microbial cocktails, we demonstrate that early life consumption of a malnourished diet, in combination with exposure to a cocktail of Bacteroidales and E. coli species, remodels the small intestine to resemble the major features of EE observed in humans. Furthermore, this Bacteroidales and E. coli exposure induces an influx of pro-inflammatory intraepithelial lymphocytes in the small intestine, along with increased prevalence of bacterial species adhering to the epithelium, each of which could be initiating the onset of EE features. Further, we infected the malnourished mice with the enteric pathogens H. polygyrus, and S. Typhimurium, and observed striking differences in number of microbes able to colonize the small intestine. These findings provide new evidence of the intestinal impacts of malnutrition, and describe a novel murine model that can be used to elucidate the pathophysiology of this understudied disease.
Item Citations and Data
Attribution-NonCommercial-NoDerivatives 4.0 International