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dc.contributor.authorSessenwein, Jessicaen
dc.date.accessioned2017-09-30T17:45:19Z
dc.date.available2017-09-30T17:45:19Z
dc.identifier.urihttp://hdl.handle.net/1974/22806
dc.description.abstractPeripheral pain signaling reflects a balance of pro and anti-nociceptive influences; the contribution by the gastrointestinal (GI) microbiota to this balance has received little attention. GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) are associated with exaggerated visceral nociceptive actions that may involve altered microbial signaling, particularly given the evidence for bacterial dysbiosis in these conditions. Despite ongoing research, the cellular mechanisms underpinning bacterial modulation of visceral pain remain incompletely understood. Accordingly, we tested whether a community of commensal GI bacteria derived from a healthy human donor (microbial ecosystem therapeutics; MET-1) could alter the excitability of small dorsal root ganglion (DRG) neurons from mice. Additionally, we tested whether perturbation of the healthy GI microbiota in vivo by antibiotic administration could also alter neuronal excitability in mice. Furthermore, we examined whether nociceptive signaling in a humanized IBS mouse model could be modulated by a diet low in fermentable carbohydrates, an intervention known to alter GI microbiota and improve overall symptoms of IBS patients. Exposure of DRG neurons to supernatant from MET-1 reduced their excitability by significantly increasing rheobase by 32% compared to controls (p=0.0003). The effect of MET-1 was mediated in part by serine proteases through activation of protease-activated receptor (PAR)-4. Perturbation of gut microbiota in vivo by administration of non-absorbable antibiotics increased thermal somatic pain responses by 16% (p=0.008) and increased the excitability of DRG neurons by decreasing rheobase by 22% (p=0.0039) compared to controls. The increase in excitability of DRG neurons was reversible, independent of immune activation and not restricted to DRG neurons that innervate the gut. Supernatant from the colonic mucosa of mice colonized with the microbiota of IBS patients and fed a diet high in fermentable carbohydrates increased the excitability of DRG neurons by decreasing rheobase up to 24% compared to mice fed a diet low in fermentable carbohydrates (p=0.0002). The increase in excitability of DRG neurons appeared to be due to histamine and proteases. Together, these results indicate that pain signaling can be modulated by microbiota-neuronal interactions. Therefore, therapies that induce or correct microbial dysbiosis may affect visceral pain.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectMicrobiotaen
dc.subjectSensory Neuronsen
dc.subjectNociceptionen
dc.subjectVisceral Painen
dc.subjectGastrointestinalen
dc.titleMicrobial Modulation of Nociceptionen
dc.typethesisen
dc.description.degreePhDen
dc.contributor.supervisorLomax, Alanen
dc.contributor.departmentNeuroscience Studiesen
dc.degree.grantorQueen's University at Kingstonen


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