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UBC Theses and Dissertations

The intestinal epithelium during times of dynamic change : development and enteric infection Bhinder, Ganive


Enteric infections and neonatal intestinal development both represent times of significant change in the intestine. Mode of delivery as well as food source, i.e. breast milk or formula, may impact later susceptibility to the development of allergies, asthma and other inflammatory diseases. Similarly, the development of pathological conditions such as irritable bowel syndrome and inflammatory bowel disease have been reported as long-term sequelae of infection by various enteric pathogens. The single cell layer of epithelial cells lining the intestine are in closest proximity to the luminal changes that occur, be it interaction with a bacterial pathogen or the introduction of breast milk. This positions intestinal epithelial cells (IEC)s to serve as key players in shaping responses during these times. To address the importance of IEC responses during enteric infections, we first examined the intricacies of IEC innate immune-mediated responses (MyD88-dependent) using in vivo models. Following infection with the common food poisoning pathogen Salmonella Typhimurium, IEC-specific MyD88 signalling was required to limit pathogen penetration of intestinal crypts and mediate goblet cell/antimicrobial responses. IECs lacking MyD88 also displayed decreased bactericidal capacity against Salmonella and Citrobacter rodentium, a close relative of enteropathogenic Escherichia coli. Thus, IEC MyD88 signalling promotes early, protective responses during enteric infection. Next, IEC changes during intestinal development, as well as the impact of food source during this process (i.e. mother’s milk versus formula) were explored using a neonate pup-in-a-cup model. Specifically, the role of milk fats found in mammalian milk (and currently not widely used in formulas), referred to as milk fat globule membrane (MFGM), were assessed for their ability to normalize intestinal development to that seen with mother’s milk. Interestingly, MFGM addition to formula resulted in similar villus and crypt development, as well as goblet cell, Paneth cell and enterocyte numbers and/or expression to that of mother’s milk fed pups. Further, addition of MFGM protected the formula fed neonate from intestinal damage by bacterial toxins. These studies highlight IECs as key players in shaping beneficial responses during enteric infection and intestinal development and have important implications for newborn health as well as for populations vulnerable to enteric infections.

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