Secondary bile acids as modulators of colonic secretion and immunity: mechanistic insights and implications for irritable bowel syndrome

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dc.check.date2029-05-31
dc.check.infoControlled Access
dc.contributor.advisorO'Malley, Dervla
dc.contributor.advisorJoyce, Susan
dc.contributor.authorXiao, Qiao
dc.contributor.funderChina Scholarship Council
dc.contributor.funderUniversity College Cork
dc.date.accessioned2026-01-26T16:07:04Z
dc.date.available2026-01-26T16:07:04Z
dc.date.issued2025
dc.date.submitted2025
dc.descriptionControlled Access
dc.description.abstractBile acids (BAs) are best known for aiding lipid digestion but are increasingly recognized as signaling molecules that regulate gut function. Through receptors such as FXR, VDR, and TGR5—widely expressed in intestinal epithelial cells and enteric neurons—BAs influence secretion, motility, gut-brain communication, and immune responses. Disruptions in these pathways have been linked to disorders of gut-brain interaction, particularly irritable bowel syndrome (IBS), where altered profiles of luminal BA profiles are commonly observed. However, key questions remain relating to their role as signalling molecules. For example, how do BAs communicate with enteric neurons, how do their receptors respond to inflammatory signals, and do interactions between BAs, immune factors, and neural pathways contribute to IBS symptoms? We propose that disrupted BA signaling may drive bowel dysfunction through their modulatory actions on interconnected neuroendocrine and immune pathways intrinsic and extrinsic to the gut. This project used mass spectrometry, Ussing chamber electrophysiology, ELISA, calcium imaging and transcriptomic analyses to investigate BA profiles in the lumen and gut tissues of healthy Sprague-Dawley (SD) rats and stress-sensitive Wistar Kyoto (WKY) rats. Impaired microbial deconjugation markedly reduced luminal BA levels, including lithocholic acid (LCA) in WKY rat tissue. This reduction was associated with a remodeled immune environment marked by concurrent upregulation of pro- and anti-inflammatory mediators, indicating a newly established immune homeostasis. Furthermore, we specifically focused on the modulatory actions of LCA, a secondary BA, on colonic function. LCA potently inhibited colonic secretory currents evoked by veratridine, carbachol, and capsaicin, an effect that was independent of classical endocrine mediators such as GLP-1 and 5-HT, but appeared to be linked to local secretion of interleukin-6 (IL-6). Indeed, LCA had the capacity to activate the JAK-STAT signaling pathway, suggesting a link between BA signaling and mucosal immune activation. These findings identify a novel immunomodulatory role for LCA in regulating colonic secretion and suggest that disrupted BA metabolism and immune adaptation may contribute to bowel dysfunction in IBS.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationXiao, Q. 2025. Secondary bile acids as modulators of colonic secretion and immunity: mechanistic insights and implications for irritable bowel syndrome. PhD Thesis, University College Cork.
dc.identifier.endpage356
dc.identifier.urihttps://hdl.handle.net/10468/18470
dc.language.isoenen
dc.publisherUniversity College Corken
dc.relation.projectUniversity College Cork (Department of Physiology)
dc.rights© 2025, Qiao Xiao.
dc.rights.urihttps://creativecommons.org/licenses/by-nc-sa/4.0/
dc.subjectBile acids (BAs)en
dc.subjectLCA (lithocholic acid)en
dc.subjectColonic secretionen
dc.subjectInterleukin-6 (IL-6)en
dc.subjectIrritable bowel syndrome (IBS)en
dc.subjectWistar Kyoto raten
dc.titleSecondary bile acids as modulators of colonic secretion and immunity: mechanistic insights and implications for irritable bowel syndrome
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD - Doctor of Philosophyen
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