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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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Cénac, N., Bautzová, T., Faouder, P. L., Veldhuis, N. A., Poole, D. P., Rolland, C., Bertrand, J., Liedtke, W., Dubourdeau, M., Bertrand‐Michel, J., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.04.011 · Cited by 152
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“53 Interestingly, administration of IBS supernatant into the colon of mice resulted in increased pain responses evoked by colorectal distension.”
BackgroundSerum and Colonic Mucosal Immune Markers in Irritable Bowel Syndrome
Chang, L., Adeyemo, M. A., Karagiannidis, I., Videlock, E. J., Bowe, C., Shih, W., Presson, A. P., Yuan, P., Cortina, G. R., Gong, H., et al. (2011) · The American Journal of Gastroenterology · doi:10.1038/ajg.2011.423 · Cited by 150
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“, 2006); visceral pain (Cenac et al., 2007), aortic aneurysms (Zhang et al.”
BackgroundFunctional gastrointestinal disorders and gut-brain axis: What does the future hold?
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“Proteases released from the intestinal mucosa of patients with irritable bowel syndrome, including trypsins and tryptase, cause visceral hyperalgesia in mice by activating PAR2, suggesting a role for proteases and PAR2 in pain in humans (13).”
BackgroundSelf-citationMartínez, C., Rodiño‐Janeiro, B. K., Lobo, B., Stanifer, M. L., Klaus, B., Granzow, M., González-Castro, A. M., Salvo‐Romero, E., Alonso, C., Pigrau, M., et al. (2017) · Gut · doi:10.1136/gutjnl-2016-311477 · Cited by 143
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Barbara, G., Cremon, C., GIORGIO, R. D., Dothel, G., Zecchi, L., Bellacosa, L., Carini, G., Stanghellini, V., & Corinaldesi, R. (2011) · Current Gastroenterology Reports · doi:10.1007/s11894-011-0195-7 · Cited by 153
“These proteases were involved in the activation of sensory neurons, as well as generation of colonic hypersensitivity when infused in the colon of recipient mice, through a mechanism involving the activation of protease activated receptor-2 [61].”
BackgroundSelf-citationFoley, S., Garsed, K. C., Singh, G., Duroudier, N. P., Swan, C., Hall, I. P., Zaitoun, A. M., Bennett, A. J., Marsden, C. A., Holmes, G. K. T., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.01.052 · Cited by 140
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New treatments and therapeutic targets for IBS and other functional bowel disorders
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Self-citationMast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside
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“Several studies also demonstrated that serine protease inhibitors and PAR2 antagonist could control the mucosal inflammation and block the pro-nociceptive effects in mice colon.(101) Accordingly, antagonizing PAR2 may be a highly compelling means for IBS treatment.”
BackgroundBlastocystis subtypes in irritable bowel syndrome and inflammatory bowel disease in Ankara, Turkey
Al, F. D., Kuştımur, S., Yoshikawa, H., Tunçer, C., Şimşek, Z., Tanyüksel, M., Araz, E., & Boorom, K. (2009) · Memórias do Instituto Oswaldo Cruz · doi:10.1590/s0074-02762009000500011 · Cited by 137
“A study of colonic biopsies taken from IBS and IBD patients found that gastrointestinal symptoms in these diseases are a result of serine protease production (Cenac et al. 2007).”
BackgroundModulation of the TRPV4 ion channel as a therapeutic target for disease
Grace, M. S., Bonvini, S. J., Belvisi, M. G., & McIntyre, P. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.019 · Cited by 136
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Self-citationModifying the Protease, Antiprotease Pattern by Elafin Overexpression Protects Mice From Colitis
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Self-citationA Global Perspective on Irritable Bowel Syndrome
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“Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders that cause inflammation of the digestive tract.”
BackgroundInfluentialSelf-citationProtease-activated receptors as drug targets in inflammation and pain
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Self-citationTransient receptor potential ankyrin-1 has a major role in mediating visceral pain in mice
Cattaruzza, F., Spreadbury, I., Miranda‐Morales, M., Grady, E. F., Vanner, S. J., & Bunnett, N. W. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00221.2009 · Cited by 123
“Proteases are prominent mediators of inflammation and pain in many tissues, including the intestine (8, 15).”
BackgroundInfluentialSelf-citationInfection, inflammation, and the irritable bowel syndrome
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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…”
BackgroundResultInfluentialLinley, J. E., Rose, K. E., Patil, M. J., Robertson, B., Akopian, A. N., & Gamper, N. L. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2297-08.2008 · Cited by 121
“In in vivo studies, injection of PAR-2 agonists induced both spontaneous nociception and hyperalgesia (Vergnolle et al., 2001; Paszcuk et al., 2008), whereas a PAR-2 antagonist produced antinociceptive effects in an inflammatory pain model (Cenac et al., 2007).”
Backgroundvan den Wijngaard, R. M., Klooker, T. K., Welting, O., Stanisor, O. I., Wouters, M. M., van der Coelen, D., Bulmer, D. C., Peeters, P. J., Aerssens, J., Hoogt, R. D., et al. (2009) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2009.01339.x · Cited by 117
Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome
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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).”
BackgroundResultNeuroanatomy of lower gastrointestinal pain disorders.
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“As the production of such a trypsin-like compound by colonic biopsies is present in all IBS/IBD patients, but is of unknown origin [29,30,31], the biopsy data from this study may help elucidate the source of that compound.”
BackgroundMethodResultInfluentialCellular and Molecular Basis of Intestinal Barrier Dysfunction in the Irritable Bowel Syndrome
Martínez, C., González-Castro, A. M., Vicario, M., & Santos, J. (2012) · Gut and Liver · doi:10.5009/gnl.2012.6.3.305 · Cited by 117
“Among these mediators, major basic protein has been described to induce epithelial barrier dysfunction associated with the down-regulation of occluding.75 It has recently been identify increased number of eosinophils along with mucosal hyperplasia and lymphocyte aggregation in the lamina propria of the colon in IBS pa…”
BackgroundInfluentialProtease-activated receptors in health and disease
Peach, C. J., Edgington-Mitchell, L. E., Bunnett, N. W., & Schmidt, B. L. (2023) · Physiological Reviews · doi:10.1152/physrev.00044.2021 · Cited by 116
Self-citationRecent developments in the pathophysiology of irritable bowel syndrome
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Self-citation
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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