Crohn’s disease (CD) is an inflammatory disease of the gastrointestinal tract attributed to an aberrant immune response to environmental and microbial triggers. Individuals with CD exhibit an enrichment of pro-inflammatory strains of Adherent-Invasive E. coli (AIEC) and often report a relapse of symptoms following a period of acute psychological stress. Despite a known immunosuppressive role, the mechanism by which stress contributes toward the development and progression of intestinal inflammation remains unknown. Here, we use a well characterized model of restraint stress to investigate the influence of psychological stress on host protection against a CD-associated strain of AIEC. We found that stress results in profound intestinal dysbiosis, allowing for a complete dominance of Enterobacteriaceae. Interestingly, while stress alone drives a state of low-grade inflammation and loss of barrier integrity in the gut, in the presence of a pathobiont strain of AIEC, stress drives a substantially heightened inflammatory response which exacerbated the resultant loss of barrier integrity. Moreover, we have found stress induces an augmented nutritional immune response, providing AIEC a competitive niche against commensal bacteria lacking alternative methods of iron uptake. Further, we see that stress-induced glucocorticoids mediate broad apoptosis of the CD45+CD90+ lymphocytic population in the gut. The loss of this population prevents an appropriate IL-22 mediated response to dysbiosis. Accordingly, blocking glucocorticoid signalling or exogenous administration of IL-22 prevents the stress-induced expansion of AIEC. This work underscores the complex nature of psychological stress such that the combination of iron limitation and glucocorticoid mediated immune attrition are simultaneously required for the stress-induced expansion of AIEC. These findings present novel insight into the mechanistic consequences of glucocorticoid signalling on impaired immune function and the provision of an inflammatory environment, resulting in a distinct impact on CD susceptibility. As such, deeper insight regarding the complex underpinnings of CD will assist in efforts to design representative models and will strengthen the discovery of targeted therapeutics. / Thesis / Master of Science (MSc) / Crohn’s disease (CD) is an inflammatory disease of the gastrointestinal tract resulting from an exaggerated immune response. CD patients often report a relapse of symptoms following a period of psychological stress and are at an increased likelihood of having pro-inflammatory strains of E. coli within their gut. Here, we use a model of restraint stress to investigate how psychological stress modulates the abundance of bacterial species associated with CD. We found stress results in the limitation of essential nutrients, allowing for an outgrowth of E. coli. Further, stress hormones lead to the loss of a protective immune response in which E. coli expansion can be prevented by blocking these hormones or restoring immune signalling. Together, we conclude that stress leads to immune cell death and creates an iron limited environment that favours E. coli expansion. Such work begins to uncover the functional consequence of stress and its’ role in disease progression.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/26923 |
| Date | January 2021 |
| Creators | Parco, Alexandra |
| Contributors | Coombes, Brian, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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