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UBC Theses and Dissertations

Designer probiotics as a novel therapeutic against inflammatory bowel disease Gill, Sandeep Kaur


Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a major health burden globally. Current pharmaceutical therapies are risky or ineffective, for long-term use and are associated with severe side effects. Therefore, new alternative therapies for IBD are needed. Probiotic therapy, which is the ingestion of non-pathogenic microorganisms to provide health benefits, is considered a potential treatment option. However, clinical trials using probiotics for IBD treatment have yielded very inconsistent and difficult to interpret data. The gut environment of IBD patients undergoes inflammation and oxidative stress, which may interfere with the growth and therefore beneficial effects of probiotics. Current probiotics on the market are ineffective at survival and colonization in the hostile gut of IBD patients. We hypothesize that novel designer probiotics, which are genetically modified to enhance survival and colonization in an IBD gut, will result in better efficacy of probiotic therapy against IBD. The overall objective was to determine if these genetically modified probiotics had improved survival and growth in an inflamed IBD gut and enhanced ability to colonize the mammalian gut. The probiotics were tested in murine colitis models, DSS-induced colitis and Muc2-/- spontaneous colitis, to determine if the modified probiotics were more efficacious during colitis compared to their parent strains. Both the E. coli and L. reuteri designer strains, compared to their parent strains, were shown to be more protective in the DSS-induced colitis through lower clinical scores, reduced histopathological scores, and increased protective responses including butyric acid, RegIIIγ, and Muc2. In the Muc2-/- spontaneous colitis model, the E. coli designer strain, was shown to be protective through lower clinical scores, reduced frequency of rectal prolapses, lower CFU bacterial counts, lower histopathological scores, and decreased expression of pro-inflammatory cytokine IFN-γ gene expression. With strain detection, only the E. coli designer strain had an established detection assay and was shown to have non-persistent detection in C57BL/6 mice but had semi-persistent detection in the Muc2-/- mice. This research could result in genetically improved probiotics, with enhanced persistence and colonization, leading to better efficacy during IBD therapy and a potential alternative therapeutic option for IBD.

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