Xenobiotic receptor regulation of Clostridium difficile associated inflammation and tissue damage

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atmire.migration.oldid6186
dc.contributor.advisorHirota, Simon Andrew
dc.contributor.authorErickson, Sarah Lindsay
dc.contributor.committeememberYipp, Bryan
dc.contributor.committeememberGiembycz, Mark
dc.date.accessioned2017-11-22T16:51:40Z
dc.date.available2017-11-22T16:51:40Z
dc.date.issued2017
dc.date.submitted2017en
dc.description.abstractThe current treatments available for C. difficile infections (CDI) aims to eliminate C. difficile bacteria, however they do not treat the inflammation and tissue damage triggered by the virulence factors, TcdA and TcdB. Indeed, enhanced chemokine/cytokine expression during CDI is associated with poor clinical outcomes. The xenobiotic receptor, pregnane X receptor (PXR) can be activated by antibiotics which are known to target C. difficile. The PXR has also been reported to attenuate intestinal inflammation by inhibiting NFκB signaling. Therefore we hypothesized that targeting the PXR would be an effective strategy to reduce C. difficile toxin-induced inflammation and tissue damage. Activation of the PXR attenuated C. difficile toxin-induced inflammatory mediator release in Caco-2 intestinal epithelial cells (IECs) and in mouse enteroid derived colonic monolayers. In vivo studies demonstrated that PXR activation using the pharmacological agonist pregnenolone-16-α-carbonitrile (PCN) attenuated the expression of pro-inflammatory mediators and significantly reduced neutrophil infiltration to the colonic lamina propria following toxin challenge. Additionally, when compared to wild type mice, PXR-/- mice challenged with toxin displayed a hyper-susceptible phenotype with significant eosinophilic inflammation and increased pro-inflammatory gene expression. Contrary to our hypothesis, this phenotype was not mediated by the loss of the PXR in the epithelium, as determined by the use of a PXRfl/fl x villin cre+ knockout mouse. Taken together, these data will help us expand our knowledge of the PXR’s role in host-pathogen interactions, and its potential to be modulated for the treatment of inflammation and tissue damage in CDI.en_US
dc.identifier.citationErickson, S. L. (2017). Xenobiotic receptor regulation of Clostridium difficile associated inflammation and tissue damage (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/28726en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/28726
dc.identifier.urihttp://hdl.handle.net/11023/4247
dc.language.isoeng
dc.publisher.facultyGraduate Studies
dc.publisher.institutionUniversity of Calgaryen
dc.publisher.placeCalgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subjectMicrobiology
dc.subjectPhysiology
dc.subjectImmunology
dc.subjectPharmacology
dc.titleXenobiotic receptor regulation of Clostridium difficile associated inflammation and tissue damage
dc.typemaster thesis
thesis.degree.disciplineGastrointestinal Sciences
thesis.degree.grantorUniversity of Calgary
thesis.degree.nameMaster of Science (MSc)
ucalgary.item.requestcopytrue
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