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Role for protease activity in visceral pain in irritable bowel syndrome
Open accessAbstract
Mediators involved in the generation of symptoms in patients with irritable bowel syndrome (IBS) are poorly understood. Here we show that colonic biopsy samples from IBS patients release increased levels of proteolytic activity (arginine cleavage) compared to asymptomatic controls. This was dependent on the activation of NF-kappaB. In addition, increased proteolytic activity was measured in vivo, in colonic washes from IBS compared with control patients. Trypsin and tryptase expression and release were increased in colonic biopsies from IBS patients compared with control subjects. Biopsies from IBS patients (but not controls) released mediators that sensitized murine sensory neurons in culture. Sensitization was prevented by a serine protease inhibitor and was absent in neurons lacking functional protease-activated receptor-2 (PAR2). Supernatants from colonic biopsies of IBS patients, but not controls, also caused somatic and visceral hyperalgesia and allodynia in mice, when administered into the colon. These pronociceptive effects were inhibited by serine protease inhibitors and a PAR2 antagonist and were absent in PAR2-deficient mice. Our study establishes that proteases are released in IBS and that they can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR2.
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“However, some studies failed to demonstrate increased activated mast cells in IBS patients (35, 36, 57, 58, 168) and there are no consistent differences in the tissue concentrations of activated mast cells in patients with different IBS subtypes (36, 189).”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [35]
In the citing paper
“Other studies have reported elevated levels of histamine and tryptase release in patients with IBS compared with controls (11, 13, 35, 73).”
From Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome (2013) · cites this paper as [35]
In the citing paper
“For example, Trypsin-like activity and tryptase release are increased in colonic biopsies from IBS patients.7,58”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [58]
In the citing paper
“Similar to IBD, studies in mice and humans have provided evidence that host- and bacterial-derived proteases may contribute to pathogenesis and symptom generation.7,13,57,58”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [58]
In the citing paper
“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 [58]
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“Supernatants of colonic biopsies from patients with IBS display increased levels of proteolytic activity, which depends on the activation of nuclear factor (NF)-κB [22].”
BackgroundMicrobiota in Functional Gastrointestinal Disorders in Infancy: Implications for Management
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“Increased proteolytic activity that could be explained both by the increased production of proteases and a decreased expression of endogenous antiproteases highlights the dysregulation of the protease/antiprotease balance during the course of IBD [7–11].”
BackgroundSelf-citationOmer, F., Song, X., Qiao, E., Sun, X., Zhang, H., Wang, M., & Jing, Y. (2025) · Fermentation · doi:10.3390/fermentation11120678 · Cited by 12
Rao, S. E., & Grover, M. (2023) · Current Opinion in Gastroenterology · doi:10.1097/mog.0000000000000972 · Cited by 10
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“of PAR2 (Cenac et al., 2007; Hughes et al., 2013; Valdez-Morales et al., 2013).”
Self-citationRepublished: Bacterial proteases in IBD and IBS
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“Changes in diversity and composition as well as functionality of the intestinal microbiota were associated with IBD17 18 and IBS.19 Pathogenic infections are suggested as the starting point for IBD20 and IBS,21 but further work is needed to understand the role of commensal bacteria and their possible contribution to t…”
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“Besides, further research reported that psychological stress is also one of the factors to activate intestinal MC,(35) MC degranulated tryptase influence neuronal signaling by activating pro-inflammatory and PAR-2 pathways.(39) Therefore, we speculate that not only the low level of neuropeptide but also the activation…”
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“On the other hand, increased levels of proteases have been described in jejunal aspirates (64), colonic biopsy supernatants (29), and stool samples from IBS patients (56).”
BackgroundPAR4: A new role in the modulation of visceral nociception
Bradesi, S. (2009) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2009.01373.x · Cited by 10
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“Although many years of intensive research have shown that electroacupuncture (EA) can alleviate PI-IBS-associated VH [11, 12], our understanding of the molecular signaling mechanisms affected by EA remains incomplete.”
BackgroundRelationship between infectious gastroenteritis and irritable bowel syndrome
Kanazawa, M., & Fukudo, S. (2013) · Clinical Journal of Gastroenterology · doi:10.1007/s12328-013-0444-4 · Cited by 9
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Molfetta, R., Carnevale, A., Marangio, C., Putro, E., & Paolini, R. (2025) · Biomedicines · doi:10.3390/biomedicines13020320 · Cited by 8
“Once activated, those MCs release histamine and tryptase that may act on intestinal neurons through histamine receptors and proteinase-activated receptor (PAR-2) [115,116], thus explaining not only the pain but also gut sensorimotor dysfunction and related diarrhea in patients with IBS [117,118].”
Proteases in intestinal health and disease
Deraison, C., & Vergnolle, N. (2025) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-025-01129-w · Cited by 9
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InfluentialSelf-citationQuantitative Analysis of Intramucosal Mast Cells in Irritable Bowel Syndrome
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“Age [median (range)] (y) 39 (26-72) 40 (11-66) 36 (16-65) 42 (27-72) 51 (29-71) 70 (45-87) Ascending colon 2 4 14 4 5 1 Transverse colon 4 8 6 5 5 0 Descending colon 1 4 4 6 6 2 Sigmoid colon 2 10 4 3 3 1”
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Preclinical models of irritable bowel syndrome
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Self-citationThe role of mast cells in Autism Spectrum Disorder
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“Histamine, serotonin and proteases released by MCs can sensitize ion channels in enteric neurons or afferent nerves, leading to neuronal activation and nociception (Cenac et al., 2007, 2010).”
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“…but is highly expressed in colonic epithelial cells (Green et al., 2000; Kong et al., 1997), its activation causing visceral hypersensitivity (Cenac et al., 2007; Vergnolle, 2004), and neurogenic inflammation (Nguyen et al., 2003), thus emphasizing that mucosa may be a site of action for…”
Self-citationMechanisms of chronic abdominal pain in inflammatory bowel disease and implications for treatment
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“(17)] were the first groups to use this technique to demonstrate that acute application of IBS colonic biopsy supernatants excited mesenteric afferent nerves and increased intracellular calcium in DRG neurons from animals, compared with supernatants from healthy controls.”
Sung, T. S., Lu, H., Sung, J., Yeom, J. H., Perrino, B. A., & Koh, S. D. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00255.2018 · Cited by 5
“These endogenous proteases are massively increased in various diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and ischemia (7, 8, 31, 43, 56).”
BackgroundMeasurement of novel intestinal secretory and barrier pathways and effects of proteases
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“A study of colonic biopsies of IBD patients showed that GIT symptoms is related to serine protease production(32) which is pro-”
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BackgroundMast Cell Disorders of the Gastrointestinal Tract
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“According to some research, the primary cause of gastrointestinal symptoms in individuals with IBS can believed to be the production of serine proteases [62].”
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Animal Models and Experimental Research in Medicine
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Recent advances in chronic visceral pain
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GPCR signaling from endosome: mechanistic insights and therapeutic potentials
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Targeting of Transient Receptor Potential Channels in Digestive Disease
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Self-citationFunctional Gastrointestinal Disorders in Patients with Inflammatory Bowel Disease
Kim, K. O. (2022) · Korean Journal of Gastroenterology · doi:10.4166/kjg.2022.001 · Cited by 3
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Immune activation in irritable bowel syndrome: from basic to clinic
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“26 Consistent with a role for enhanced protease activity in IBS, nafamostat, a serine protease inhibitor, reduced abdominal pain in a rodent model of post-inflammatory IBS.”
Probing the activity of cysteine cathepsins in inflammatory bowel diseases
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“The use of PAR2-specific antagonists or gene knockout technology to treat IBS rats can block the sensitization effect of colon biopsy fluid from IBS patients on dorsal root ganglia (DRG) neurons, confirming that PAR2 signals play a key role in regulating the excitability of IBS neurons [52,53].”
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Reizdarmsyndrom – Epidemiologie und Pathophysiologie
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Functional Gastrointestinal Disorders in Children
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Proteases and Inflammatory Pain
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“Further, this proteolytic activity was able to signal sensory neurons and reproduce hypersensitivity symptoms when injected into the mouse colonic lumen [ 7 ].”
InfluentialLuo, Y., Wang, F., Qin, J., Feng, M., Lv, Y., Wang, Q., Liu, K., & Liu, C. (2010) · Regulatory Peptides · doi:10.1016/j.regpep.2010.03.002 · Cited by 2
“Although it is well known that PAR-2 is involved in the hypersensitivity of IBS patients [31], litter is know about its effect on the dysmotility following gastrointestinal inflammation.”
Current Status of Translational Research on Irritable Bowel Syndrome
Kwon, Y. H., & Kim, H. J. (2016) · Korean Journal of Gastroenterology · doi:10.4166/kjg.2016.68.3.138 · Cited by 2
Reizdarmsyndrom – Epidemiologie und Pathophysiologie
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“Electromyographic Assessments of the Visceromotor Response to Colorectal Distension in Mice Colorectal distension was performed as already described (13, 14) to measure the effect of EDN1 on visceral sensitivity in 8 week-old C57Bl/6 male mice.”
Method
Metadata
- Authors
- Cenac, N., Andrews, C. N., Holzhausen, M., Chapman, K., Cottrell, G., Andrade-Gordon, P., Steinhoff, M., Barbara, G., Beck, P., Bunnett, N. W., Sharkey, K. A., Ferraz, J. G. P., Shaffer, E., & Vergnolle, N.
- Affiliations
- University of Calgary (CA)
- University of California, San Francisco (US)
- University of Münster (DE)
- University of Bologna (IT)
- Corresponding author
- Vergnolle, Nathalie
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-03-01
- Volume
- 117
- Issue
- 3
- Pages
- 636-647
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1794118
- OpenAlex
- W2140528350
- Cited by
- 591
- References
- 66
- Citations by year
- 2026: 12 · 2025: 19 · 2024: 22 · 2023: 19 · 2022: 21 · 2021: 24 · 2020: 26 · 2019: 27 · 2018: 25 · 2017: 32 · 2016: 37 · 2015: 28 · 2014: 36 · 2013: 38 · 2012: 41
- FWCI
- 39.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CentAUR (University of Reading) (submittedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- Crohn's and Colitis Foundation
- Crohn's and Colitis Foundation of Canada
- Canadian Association of Gastroenterology
- Fondation pour la Recherche Médicale
- Alberta Heritage Foundation for Medical Research
- National Institutes of Health (DK43207, DK57480)
- Canadian Institutes of Health Research (DK43207)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 43207, R01DK043207, DK-57480, R56DK043207)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- irritable bowel syndrome, visceral pain, proteolytic activity, NF-κB, trypsin, tryptase, protease-activated receptor 2, sensory neuron sensitization, visceral hypersensitivity, allodynia, serine protease inhibitors, colonic biopsy
- MeSH terms
- Adult, alpha 1-Antitrypsin, Colon, Female, Humans, Hyperalgesia, Male, Middle Aged, Neurons, Afferent, Endopeptidases, Trypsin, Abdominal Pain, Serine Proteinase Inhibitors, NF-kappa B, Irritable Bowel Syndrome, Receptor, PAR-2, Tryptases
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