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Ghesquiere, Chanel May

University of British Columbia

Inflammatory bowel disease is a chronic inflammatory condition of the gastrointestinal tract characterized by chronic, relapsing and remitting, or progressive disease. The two primary subtypes of IBD include Crohn’s disease and ulcerative colitis. SHIP deficient mice develop spontaneous, discontinuous, and fully penetrant CD-like ileitis. Our collaborator, Dr. Deanna Gibson’s, laboratory has developed two bioengineered strains of bacterial probiotics, BioPersist and BioColonize, which have demonstrated superior efficacy to reduce inflammation compared to their parent strains, E. coli Nissle, and L. reuteri, in two murine models of colitis. We predicted that these two bioengineered strains would be more effective at reducing ileitis in our SHIP-/- model than their parent strains. However, we did not observe any significant amelioration in gross pathology, histological disease, or ileal inflammatory cytokine concentrations in SHIP-deficient mice that received parent strains or bioengineered probiotics. Additionally, the inability to detect BioPersist and BioColonize in the ileum, the site of inflammation in SHIP-/- mice, indicates that these bacteria are unable to colonize the ileum in this mouse model. Therefore, our findings do not support the use of these probiotics to treat ileitis. These results have broader implications for human disease, since understanding that these probiotics are only effective at specific disease sites is important for clinical relevancy in IBD. In addition to bacterial probiotics, yeast-based therapies have demonstrated efficacy in both mouse and human studies of intestinal inflammation. Our collaborators at Renaissance BioSciences have developed a bioengineered strain of S. cerevisiae that expresses shRNA against the inflammatory cytokine IL-1β. This macrophage-derived cytokine is known to drive inflammation in SHIP deficient mice. We evaluated the ability of this yeast probiotic to reduce ileitis in the SHIP-/- mouse model. We demonstrated that S. cerevisiae reduces histological disease and ileal IL-1β concentrations in a dose-dependent manner, regardless of the presence or absence of the shRNA construct. This indicates that S. cerevisiae itself, and not the IL-1β shRNA, modestly reduces disease in the SHIP-deficient mouse model of ileitis. Thus, our findings suggest S. cerevisiae may be a novel therapeutic option for reducing ileitis; however, further studies are required to elucidate its mechanism of action.

Text

2024-10-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86160

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/