Sensitization of Peripheral Sensory Nerves by Mediators From Colonic Biopsies of Diarrhea-Predominant Irritable Bowel Syndrome Patients: A Role for PAR2
Abstract
OBJECTIVES: This study examined whether mediators from biopsies of human irritable bowel syndrome (IBS) colons alter intrinsic excitability of colonic nociceptive dorsal root ganglion (DRG) neurons by a protease activated receptor 2 (PAR2)-mediated mechanism. METHODS: Colonic mucosal biopsies from IBS patients with constipation (IBS-C) or diarrhea (IBS-D) and from healthy controls were incubated in medium, and supernatants were collected. Small-diameter mouse colonic DRG neurons were incubated in supernatants overnight and perforated patch current-clamp recordings obtained. Measurements of rheobase and action potential discharge at twice rheobase were compared between IBS and controls to assess differences in intrinsic excitability. RESULTS: Supernatants from IBS-D patients elicited a marked increase in neuronal excitability compared with controls. These changes were consistent among individual patients but the relative contribution of rheobase and action potential discharge varied. In contrast, no differences in neuronal excitability were seen with IBS-C patient supernatants. The increased excitability seen with IBS-D supernatant was not observed in PAR2 knockout mice. A cysteine protease inhibitor, which had no effect on the pronociceptive actions of a serine protease, inhibited the proexcitatory actions of IBS-D supernatant. CONCLUSIONS: Soluble mediators from colonic biopsies from IBS-D but not IBS-C patients sensitized colonic nociceptive DRG neurons, suggesting differences between these two groups. PAR2 signaling plays a role in this action and this protease signaling pathway could provide novel biomarkers and therapeutic targets for treatment.
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Biopsy supernatants from IBS patients excite spinal afferent neurons via PAR-2 activation.
“Biopsy supernatants from IBS patients have also been shown to excite spinal afferent neurons via PAR-2 activation.7,58,155”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [155]
In the gut, the GM and its metabolites modulate gastrointestinal functions via effects on intestinal permeability, mucosal immune function, intestinal motility and sensitivity, and the ENS.
“In the gut, the GM and its metabolites have been shown to modulate gastrointestinal functions via their effects on intestinal permeability (32–35), mucosal immune function (36–38), intestinal motility and sensitivity (39, 40), and the enteric nervous system (ENS) (21, 24, 25, 41).”
From Signalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis (2023) · cites this paper as [40]
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- Authors
- Valdez-Morales, E. E., Overington, J., Guerrero-Alba, R., Ochoa-Cortes, F., Ibeakanma, C. O., Spreadbury, I., Bunnett, N. W., Beyak, M., & Vanner, S. J.
- Affiliations
- Kingston General Hospital (CA)
- Monash University (AU)
- Corresponding author
- Vanner, Stephen J
- Venue
- American Journal of Gastroenterology
- Published
- 2013-10
- Volume
- 108
- Issue
- 10
- Pages
- 1634-1643
- ISSN
- 0002-9270 (ISSN-L)
- OpenAlex
- W2088483375
- Cited by
- 107
- References
- 40
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 4 · 2023: 13 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 8 · 2018: 12 · 2017: 5 · 2016: 17 · 2015: 7 · 2014: 10 · 2013: 2
- FWCI
- 11.35
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The American Journal of Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- diarrhea-predominant irritable bowel syndrome, protease-activated receptor 2, dorsal root ganglion neurons, intrinsic excitability, cysteine protease inhibition, serine protease, irritable bowel syndrome with constipation, biomarkers, therapeutic target
- MeSH terms
- Action Potentials, Adult, Aged, Animals, Biopsy, Colon, Constipation, Diarrhea, Female, Ganglia, Spinal, Humans, Male, Middle Aged, Nociceptors, Case-Control Studies, Mice, Knockout, Patch-Clamp Techniques, Irritable Bowel Syndrome, Receptor, PAR-2, Mice, Young Adult
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