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Fancy, Noah

University of British Columbia

Inflammatory Bowel Disease (IBD) is a chronic disorder of the gut characterized by immune system-mediated destruction of the epithelia. The cause is unknown, but these aberrant immune responses are associated with the microbiota. Colonic mucus is essential for colon homeostasis, and functions to both serve as a barrier separating microbes from the host, and to provide a niche that commensal microbes can colonize. A disrupted mucus barrier is a tenet of gut inflammation and a feature in IBD. Recent studies have redefined our understanding of colonic mucus, noting the majority of secreted colonic mucus associates with fecal material and is derived from the proximal colon. The secretion of proximal-derived mucus is dependent on the presence of the microbiota, however the mechanism by which this occurs remains unknown. This project aimed to determine how proximal colon goblet cells sense the microbiota and in response produce mucus. My hypothesis, based on inference from published data, is that this occurs through innate Toll-like Receptor (TLR) signaling. This project evaluated TLR-driven mucus secretion and microbial encapsulation through both ex vivo and in vivo assessments. Specific TLR ligands were found to induce mucus production in the proximal colon ex vivo, but in vivo results with TLR-deficient germ-free (GF) mice were inconclusive. Both GF WT and TLR-deficient mice displayed a blunted mucosal response to two different introduced microbial communities for reasons that are unclear. To gain further mechanistic insight, we developed a model of germ-free goblet cell reporter mice (RedMUC2) which are amenable to fluorescent sort-purification and transcriptomic sequencing. High-quality RNA from sorted GCs and non-GC ECs was obtained for future use in RNA sequencing studies. Together, these results indicate that while several TLR ligands have the potential to stimulate a mucosal response in the proximal colon, a clear role for TLR-mediated mucus secretion in the proximal colon in vivo remains inconclusive.

Text

2025-06-28

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/88580

Biology

University of British Columbia

UBCO

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