All ETDs from UAB

Advisory Committee Chair

Craig L Maynard

Advisory Committee Members

Charles O Elson III

Laurie E Harrington

Jennifer S Pollack

Jessica A Scoffield

Document Type

Dissertation

Date of Award

2023

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Inflammatory bowel disease (IBD) results from the interplay of genetic susceptibility, environmental influences, the microbiota, and aberrant immune responses. Despite the fact that over 200 genetic susceptibility loci have been identified, the genetic contribution to disease onset is believed to be less than 50%. Environmental factors have arisen as key drivers of disease. Early life stress (ELS) is an understudied environmental trigger linked to IBD susceptibility. Utilizing 2 separate models of ELS, we show that ELS results in diminished colonic corticosterone and prolonged intestinal inflammation upon colitogenic insult. ELS-exposed animals consistently demonstrated high levels of colonic Tnf, concurrently with decreased expression of genes associated with corticosterone responsiveness and local synthesis. We further establish a connection between the elevated Tnf and locally impaired corticosterone, by demonstrating that ex vivo TNF stimulation of colonic crypt cells from ELS mice led to enhanced inhibition of corticosterone production. Thus, this study identified impaired local corticosterone synthesis as a potential mechanism whereby ELS predisposes to exacerbated colitis. Environmental factors also heavily influence the microbiota, with some researchers even considering the microbiota as an internal environmental factor. Endothelial dysfunction and vascular complications commonly manifest in chronic inflammatory conditions, including IBD. The microbiota has been identified as a critical factor in vascular physiology – thus, we investigated the impact of the microbiota on colonic expression of the endothelin (ET) system. We reveal that the microbiota regulates colonic gene expression of both ET receptors and peptides. Given the importance of the microbiota in IBD pathology, we further assessed the role of the ET system in colitis. We show that prophy-lactic antagonism of ET receptor type A prevents the development of colitis and maintains colonic epithelial and endothelial barrier integrity. Further, gene expression data from colonic barrier cells indicates that barrier integrity is maintained by preventing coli-tis-induced alterations in junctional proteins. Collectively, my thesis work reveals an environmental trigger and molecular mediator of colitis and demonstrates potential mechanistic pathways of therapeutic potential related to each.

Share

COinS