Examining the activation of xenobiotic receptors using microbial metabolites and chemical ligands

Shenoda, Eva Ibrahim Gorgy

Examining the activation of xenobiotic receptors using microbial metabolites and chemical ligands

dc.contributor.advisor	Hirota, Simon
dc.contributor.author	Shenoda, Eva Ibrahim Gorgy
dc.contributor.committeemember	Nasser, Yasmin
dc.contributor.committeemember	McCafferty, Donna-Marie
dc.date.accessioned	2024-09-19T20:06:47Z
dc.date.available	2024-09-19T20:06:47Z
dc.date.issued	2024-09-18
dc.description.abstract	The aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) are key xenobiotic receptors involved in regulating chemical metabolism and detoxification. Traditionally, these receptors were known for mediating toxic responses by sensing and responding to chemicals. Recent research shows their role in maintaining gut homeostasis and regulating inflammation. However, the mechanisms by which they induce these responses are not clear. This thesis examines whether the activation of AhR and PXR in epithelial cells by microbial metabolites versus chemical ligands drives unique transcriptional responses and could explain differences in beneficial versus deleterious biological outcomes in the host. PXR and AhR were activated with indole-3-propionic acid (IPA) and indole-3-pyruvic acid (IPyA) as microbial metabolites, and pregnenolone 16α-carbonitrile (PCN) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) as chemical ligands, respectively. We compared responses to these ligands, revealing significant gene expression differences. Further analysis showed both IPyA and TCDD activated genes involved in hypoxia-inducible factor (HIF) signaling and metabolism. IPyA upregulated genes for ATP synthesis and purine biosynthesis, while TCDD promoted genes related to cell cycle, cancer, and apoptosis. Given that AhR translocates to the nucleus upon activation, we hypothesized that the differences in transcriptomic responses and gene induction might be attributed to differences in nuclear translocation of AhR, with TCDD potentially inducing greater nuclear translocation compared to IPyA. To test this hypothesis, we established a cellular fractionation protocol for organoids. However, our results revealed no significant difference in AhR nuclear translocation between the two treatments, suggesting that other factors may affect gene expression in the AhR pathway. These findings highlight AhR and PXR's complex roles in gut health and inflammation, suggesting receptor activation can have both adverse and beneficial effects. This research enhances our understanding of AhR and PXR mechanisms and their potential for therapeutic strategies targeting gut disorders and inflammation.
dc.identifier.citation	Shenoda, E. I. G. (2024). Examining the activation of xenobiotic receptors using microbial metabolites and chemical ligands (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.
dc.identifier.uri	https://hdl.handle.net/1880/119807
dc.language.iso	en
dc.publisher.faculty	Graduate Studies
dc.publisher.institution	University of Calgary
dc.rights	University 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.subject	Xenobiotic receptors
dc.subject	organoids
dc.subject	3D culture
dc.subject	2D culture
dc.subject	Aryl Hydrocarbon Receptor (AhR)
dc.subject	Pregnane X Receptor (PXR)
dc.subject	Xenobiotic Metabolism
dc.subject	Gut microbiota
dc.subject	Transcriptomic Responses
dc.subject	2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD)
dc.subject	Indole-3-pyruvic Acid (IPyA)
dc.subject	Pregnenolone-16α-carbonitrile (PCN)
dc.subject	Indole-3-propionic Acid (IPA)
dc.subject.classification	Biology--Molecular
dc.subject.classification	Pharmacology
dc.subject.classification	Genetics
dc.subject.classification	Immunology
dc.title	Examining the activation of xenobiotic receptors using microbial metabolites and chemical ligands
dc.type	master thesis
thesis.degree.discipline	Medicine – Gastrointestinal Sciences
thesis.degree.grantor	University of Calgary
thesis.degree.name	Master of Science (MSc)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.