UC Davis

The intestinal barrier separates the gut lumen from the internal tissues of the body. It is comprised of a layer of mucus, a monolayer of intestinal epithelial cells adjoined and maintained by junctional protein complexes, and a lamina propria which contains specialized immune cells. This barrier is responsible for the absorption of nutrients, preventing the entry of harmful pathogens and substances, and is a critical component of the innate immune system. This dissertation presents a comprehensive review of the role of the intestinal barrier and innate immune response to the apicomplexan parasite, Cryptosporidium parvum, and the use of intestinal organoids as a model of study (Chapter 1) and the effects of both inflammation and Diabetes mellitus on the function of the intestinal epithelium (Chapter 2). It shows that inflammatory cytokines directly increase the permeability of the bovine intestinal epithelium while altering tight junction morphology and reducing cellular turnover, using bovine intestinal organoids as a model (Chapter 3). Finally, this work uses feline intestinal organoids to show that hyperglycemia-like conditions directly increase the permeability of feline intestinal epithelium while altering tight junctional morphology, as mediated through the activation of protein kinase C-α (PKCα); the drug fenofibrate prevents hyperglycemia-induced barrier dysfunction and restores PKCα activity to baseline levels (Chapter 4).