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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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Development of highly potent protease‐activated receptor 2 agonists via synthetic lipid tethering
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BackgroundAminosalicylates and Other Anti-Inflammatory Compounds for Irritable Bowel Syndrome
Barbara, G., Stanghellini, V., Cremon, C., GIORGIO, R. D., Fronzoni, L., Serra, M., & Corinaldesi, R. (2009) · Digestive Diseases · doi:10.1159/000268131 · Cited by 27
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“Permeability (4,5): It refers to altered ability to fight microbial pathogens, which could result in increased contact between microbes and the lamina propria.”
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“We made a simple correlation between the averaged withdrawal latencies of each rat and its Western blot data for PAR2.”
BackgroundInfluentialZhang, H., Zeng, X., & He, S. (2014) · Mediators of Inflammation · doi:10.1155/2014/829068 · Cited by 25
“These pronociceptive effects are absent in PAR-2-deficient mice, indicating that proteases released in IBS can directly stimulate sensory neurons and generate hypersensitivity symptoms through the activation of PAR-2 [152].”
BackgroundMu and delta opioid receptor knockout mice show increased colonic sensitivity
Reiss, D., Ceredig, R. A., Secher, T., Boué, J., Barreau, F., Dietrich, G., & Gavériaux-Ruff, C. (2017) · European Journal of Pain · doi:10.1002/ejp.965 · Cited by 20
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“In a more recent study, we have extended these findings demonstrating that mediators released by the intestinal mucosa of IBS patients (ie, mast cell histamine and proteases), determined a hyperactivation of sensory pathways, providing a functional link between immune activation and pain experience in IBS patients.(21…”
BackgroundSelf-citationActivity of Protease-Activated Receptors in Primary Cultured Human Myenteric Neurons
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“Some studies found mast cell hyperplasia and an increase in the release of their products (histamine, tryptase) in the mucosal biopsies from the rectum of PI-IBS and NI-IBS patients (O’Sullivan et al., 2000; Park et al., 2003; Barbara et al., 2004, 2007; Cenac et al., 2007; Cremon et al., 2009).”
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BackgroundLuminal contents from the gut of colicky infants induce visceral hypersensitivity in mice
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“PAR4 as a central and common mediator has been shown to inhibit colonic hypersensitivity associated with inflammatory bowel syndrome.(95) Importantly, it exerts an endogenous role in modulating visceral pain, as PAR4-deficient mice experienced significantly more pain in response to mustard oil compared with wild-type…”
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“Indeed, there is a correlation between the number of mast cells in proximity to nerves and the severity of symptoms, particularly relating to pain and discomfort (Barbara et al. 2004, 2007; Cenac et al. 2007; Akbar et al. 2008).”
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“In the context of functional gastrointestinal disorders such as irritable bowel syndrome or inflammatory bowel disease, there is strong evidence that cleavage of protease-activated receptors 2 (PAR2) by tryptase leads to visceral hypersensitivity.(13,35) A significant increase in PAR2 expression in the intestine after…”
BackgroundModulation of visceral nociceptive pathways
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RETRACTED ARTICLE: Gut microbiota and related diseases: clinical features
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“Furthermore, application of extracts derived from colonic mucosal biopsies of IBS patients, but not healthy controls, to the gut of naive murine laboratory animals evoked increased activation of pain-related visceral pathways(4) and an ‘‘IBS-like’’ visceral hyperalgesia.(5)”
Self-citationEndogenous Regulation of Inflammatory Pain by T-cell-derived Opioids
Basso, L., Boué, J., Bourreille, A., & Dietrich, G. (2014) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000073 · Cited by 17
Han, W., Lu, X., Jia, X., Zhou, T., & Guo, C. (2011) · Digestive Diseases and Sciences · doi:10.1007/s10620-011-1897-2 · Cited by 17
Review: Do patients with functional gastrointestinal disorders have an altered gut flora?
Quigley, E. M. M. (2009) · Therapeutic Advances in Gastroenterology · doi:10.1177/1756283x09335636 · Cited by 17
“…studies have provided further evidence of T-lymphocyte [Holmen et al. 2007; Ohman et al. 2005] and mast cell activation [Barbara et al. 2007, 2004; Cenac et al. 2007, Guilarte et al. 2007] in the mucosa in IBS; others have demonstrated an extension of inflammation into the myo-neural compartments…”
ResultAndresen, V., Pehl, C., Allescher, H. ‐., Bischoff, S. C., Enck, P., Frieling, T., Haag, S., Holtmann, G., Karaus, M., Keller, J., et al. (2011) · Cited by 17
Irritable bowel syndrome: When food is a pain in the gut
Hussein, H., Remoortel, S. V., & Boeckxstaens, G. E. (2024) · Immunological Reviews · doi:10.1111/imr.13374 · Cited by 16
GPR35 agonists inhibit TRPA1-mediated colonic nociception through suppression of substance P release
Gupta, R. A., Higham, J. P., Pearce, A., Urriola‐Muñoz, P., Barker, K. H., Paine, L. W., Ghooraroo, J., Raine, T., Hockley, J. R. F., Rahman, T., et al. (2024) · Pain · doi:10.1097/j.pain.0000000000003399 · Cited by 16
“33 The mediators responsible for visceral hypersensitivity are not fully understood, although mast cell–derived mediators, 3,4 such as histamine, 1 serotonin (5-HT), 41 nerve growth factor and tryptase, 18 as well as lipids such as 5-oxo-ETE, 9 are implicated in IBS.”
Aguilera‐Lizarraga, J., López-López, C., Jaramillo-Polanco, J., Florens, M. V., Yu, Y., Tsang, Q. K., Chakraborty, A., Gand, S. D., Pia, F., Quan, R., et al. (2025) · Gastroenterology · doi:10.1053/j.gastro.2025.01.246 · Cited by 21
A Bacteroides fragilis protease activates host PAR2 to induce intestinal pain and inflammation
Lakemeyer, M., Latorre, R., Blažková, K., Wood, H. M., Jensen, D. D., Shakil, N., Thomas, S. C., Saxena, D. B., Mulpuri, Y., Poolman, D., et al. (2025) · Cell Host & Microbe · doi:10.1016/j.chom.2025.09.010 · Cited by 26
Self-citationThe proteolytic activity in inflammatory bowel disease: insight from gut microbiota
Hou, J., Ding, L., Yang, T., Yang, Y.-F., Jin, Y., Zhang, X., Ma, A.-H., & Qin, Y. (2024) · Microbial Pathogenesis · doi:10.1016/j.micpath.2024.106560 · Cited by 20
Quan, R., Decraecker, L., Appeltans, I., Cuende‐Estévez, M., Remoortel, S. V., Aguilera‐Lizarraga, J., Wang, Z., Hicks, G. A., Wykosky, J., McLean, P. G., et al. (2024) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000003042 · Cited by 16
“Supernatants of colonic biopsies or feces from patients with IBS with high proteolytic activity have been reported to sensitize sensory neurons by activating PAR-2 (36,37,46,48).”
Tahir, A. H., Li, J., & Tang, Y. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.696843 · Cited by 16
“Fecal supernatant of IBS patients was injected into the colon of healthy mice that resulted in higher mucosal inflammation and increased intestinal permeability, hence contributing to VH through a PAR-2 activation mechanism (Cenac et al., 2007; Annaházi et al., 2009; Shah et al., 2020).”
BackgroundHoffman, J. M., Sideri, A., Ruiz, J. J., Stavrakis, D. G., Shih, D. Q., Turner, J. R., Pothoulakis, C., & Karagiannides, I. (2018) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2018.02.001 · Cited by 16
The relationship between gut microbiota and proteolytic activity in irritable bowel syndrome
Hou, J., Wang, X., Li, Y., Su, S., Wang, Y., & Wang, B. (2021) · Microbial Pathogenesis · doi:10.1016/j.micpath.2021.104995 · Cited by 18
Liu, L., Cai, X., Yan, J., Luo, Y., Shao, M., Lu, Y., Sun, Z., & Cao, P. (2012) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2012/983801 · Cited by 16
“It has been reported that the intracolonic infusion of supernatants from the colonic biopsies of IBS patients led to somatic and visceral hyperalgesia [5] as well as impaired colonic permeability and sensitivity of mice [6].”
BackgroundInhibition of Serine Proteases as a Novel Therapeutic Strategy for Abdominal Pain in IBS
Decraecker, L., Boeckxstaens, G. E., & Denadai‐Souza, A. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.880422 · Cited by 15
“FUT-175 could prevent development of VHS in WT mice when co-administered intracolonic with IBS supernatants (Cenac et al., 2007).”
BackgroundResultIdentifying the Ion Channels Responsible for Signaling Gastro-Intestinal Based Pain
Brierley, S. M., Hughes, P. A., Harrington, A. M., Rychkov, G. Y., & Blackshaw, L. A. (2010) · Pharmaceuticals · doi:10.3390/ph3092768 · Cited by 17
“Furthermore, serine proteases levels [129,130], 5-HT signalling [131] and histamine [24–26] are all known to be increased in IBS patients and TRPV4 interacts with these mediators.”
BackgroundVisceral afferents: What role in post-inflammatory pain?
Vergnolle, N. (2009) · Autonomic Neuroscience · doi:10.1016/j.autneu.2009.07.015 · Cited by 15
“Further, in those neurons, TRPV4 response was potentiated by activation of the protease-activated receptor-2 (PAR2), but also activation of histamine or serotonin (Cenac et al., 2008a).”
InfluentialSelf-citationGuarino, M. P. L., Barbara, G., Cicenia, A., Altomare, A., Barbaro, M. R., Cocca, S., Scirocco, A., Cremon, C., Emerenziani, S., Stanghellini, V., et al. (2016) · Neurogastroenterology & Motility · doi:10.1111/nmo.12928 · Cited by 15
Self-citationEffectiveness of mesalazine to treat irritable bowel syndrome
Zhang, F., Li, S., Ding, L., Xiang, S.-H., Zhu, H.-T., Yu, J., & Xu, G. (2019) · Medicine · doi:10.1097/md.0000000000016297 · Cited by 17
“Previous studies have revealed that the intestinal mucosa of patients with IBS contains more immune cells,([1,13]) cytokines,([14,15]) immunemediators, which represents immune activation and mucosal impairment.”
BackgroundZhan, M.-X., Tang, L., Lu, Y., Wu, H., Guo, Z.-B., Shi, Z.-M., Yang, C.-L., Zou, Y.-Q., Yang, F., & Chen, G. (2021) · Journal of Pain Research · doi:10.2147/jpr.s303595 · Cited by 15
Bashashati, M., Fichna, J., Piscitelli, F., Capasso, R., Izzo, A. A., Sibaev, A., Timmermans, J., Cénac, N., Vergnolle, N., Marzo, V. D., et al. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.13148 · Cited by 15
Self-citationMargiotta, F., Lucarini, E., Toti, A., Curti, L., Masi, A., Mello, T., Gall, G. L., Mattei, G., Magi, A., Vauzour, D., et al. (2025) · Gut Microbes · doi:10.1080/19490976.2025.2547029 · Cited by 14
Campaniello, M. A., Harrington, A. M., Martin, C. M., Blackshaw, L. A., Brierley, S. M., & Hughes, P. A. (2015) · Neurogastroenterology & Motility · doi:10.1111/nmo.12696 · Cited by 14
Hypothesis: Mechanism of irritable bowel syndrome in inflammatory bowel disease
Uno, Y. (2019) · Medical Hypotheses · doi:10.1016/j.mehy.2019.109324 · Cited by 14
“When supernatants of mucosal biopsies from patients with IBS were injected into the mesenteric vessels of rats, intestinal sensory neurons were activated [131].”
BackgroundMenthacarin induces calcium ion influx in sensory neurons, macrophages and colonic organoids of mice
Zhang, Z., Engel, M. A., Koch, E., Reeh, P. W., & Khalil, M. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118682 · Cited by 14
What Is the Value of Counting Mast Cells in Gastrointestinal Mucosal Biopsies?
Panarelli, N. C., Hornick, J. L., & Yantiss, R. K. (2023) · Modern Pathology · doi:10.1016/j.modpat.2022.100005 · Cited by 17
The effect of PDIA3 gene knockout on the mucosal immune function in IBS rats.
Zhuang, Z., Wang, X., Zhang, L., Tao, L., & Lü, B. (2015) · Europe PMC (PubMed Central) · Cited by 14
Role of mast cell-miR-490-5p in irritable bowel syndrome
Ren, H., Zhang, F., Luo, H., Zhang, G., & Liang, L. (2017) · World Journal of Gastroenterology · doi:10.3748/wjg.v23.i1.93 · Cited by 14
Relationship of peripheral blood neutrophil to lymphocyteratio and irritable bowel syndrome
GÜÇLÜ, M., & Ağan, A. F. (2017) · TURKISH JOURNAL OF MEDICAL SCIENCES · doi:10.3906/sag-1509-44 · Cited by 14
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What is the evidence for the use of probiotics in functional disorders?
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bruyn, M. D., Ceuleers, H., Hanning, N., Berg, M., Man, J. G. D., Hulpiau, P., Hermans, C., Stenman, U., Koistinen, H. K., Lambeir, A., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms221910711 · Cited by 13
“The Km for thrombin with Boc-QAR-AMC was considerably higher compared to the trypsins, indicating that the affinity of thrombin for Boc-QAR-AMC is lower compared to trypsin-1, trypsin-2 and trypsin-3.”
BackgroundMethodInfluentialRole of the E3 ubiquitin-ligase Hakai in intestinal inflammation and cancer bowel disease
Roca‐Lema, D., Quiroga, M., Khare, V., Díaz-Díaz, A., Barreiro-Alonso, A., Rodríguez-Alonso, A., Concha, Á., Romay, G., Cerdán, M. E., Gasché, C., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-22295-w · Cited by 13
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A Novel, Nonpeptidic, Orally Active Bivalent Inhibitor of Human β-Tryptase
Giardina, S. F., Werner, D. S., Pingle, M., Bergstrom, D. E., Arnold, L. D., & Barany, F. (2018) · Pharmacology · doi:10.1159/000492078 · Cited by 11
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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