Date of Award

4-6-2026

Embargo Period

4-6-2028

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Regenerative Medicine and Cell Biology

College

College of Graduate Studies

First Advisor

Amy Engevik

Abstract

The intestinal epithelium is a critical interface between the host and the external environment. This dissertation investigates how external and internal forces converge on secretory cell biology and mucus barrier homeostasis across the gastrointestinal tract.

We first investigated how the mucin-degrading microbe, Akkermansia muciniphila, alters the small intestinal epithelium in a gnotobiotic model. Mono-colonization of germ-free mice with A. muciniphila increased epithelial proliferation, expanded tuft cell populations, and altered mucin glycosylation without altering goblet cell numbers. We identified bacterial-derived succinate as a candidate mediator of tuft cell expansion. Further analysis revealed activation of a type 2 immune response, known to drive tuft cell expansion. These findings establish that A. muciniphila alone can expand secretory tuft cell populations.

Next, we evaluated how endogenous epithelial dysfunction disrupts the colonic epithelium and mucus barrier. Tamoxifen inducible intestinal deletion of Myosin Vb (MYO5B), a motor protein that regulates vesicular trafficking, resulted in a thinner inner colonic mucus layer, depleted tuft cells, reduced mucus-filled goblet cells, and altered mucin glycosylation. Mice lacking intestinal epithelial MYO5B also had significant changes in their luminal and mucosa-associated microbiomes marked by expansion of pro-inflammatory microbes. We further identified robust activation of the Unfolded Protein Response (UPR) in the colon of mice lacking MYO5B both in vivo and in vitro. These findings demonstrate that inactivation of MYO5B directly alters the colonic microbiome and inhibits secretory cell differentiation and function, likely through UPR activation.

Together, these studies highlight the responsiveness of intestinal secretory cell populations to both extrinsic and intrinsic factors.

Rights

Copyright is held by the author. All rights reserved.

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Available for download on Thursday, April 06, 2028

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