Controlled Access. Restriction lift date: 2029-05-31
Secondary bile acids as modulators of colonic secretion and immunity: mechanistic insights and implications for irritable bowel syndrome
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Date
2025
Authors
Xiao, Qiao
Journal Title
Journal ISSN
Volume Title
Publisher
University College Cork
Published Version
Abstract
Bile 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.
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Controlled Access
Keywords
Bile acids (BAs) , LCA (lithocholic acid) , Colonic secretion , Interleukin-6 (IL-6) , Irritable bowel syndrome (IBS) , Wistar Kyoto rat
Citation
Xiao, 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.