The DOI matches its Crossref record; 66 of the 66 references it cites were found in a registry or an index.
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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Citations
Cites
1 retracted
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Two types of human mast cells that have distinct neutral protease compositions.
Irani, A.-M. A., Schechter, N. M., Craig, S. S., DeBlois, G., & Schwartz, L. B. (1986) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.83.12.4464 · Cited by 1,007
Altered rectal perception is a biological marker of patients with irritable bowel syndrome
Mertz, H., Naliboff, B. D., Munakata, J., Niazi, N., & Mayer, E. A. (1995) · Gastroenterology · doi:10.1016/0016-5085(95)90267-8 · Cited by 976
Agonists of proteinase-activated receptor 2 induce inflammation by a neurogenic mechanism
Steinhoff, M. S., Vergnolle, N., Young, S. H., Tognetto, M., Amadesi, S., Ennes, H. S., Trevisani, M., Hollenberg, M. D., Wallace, J. L., Caughey, G. H., et al. (2000) · Nature Medicine · doi:10.1038/72247 · Cited by 936
Self-citationPossible new role for NF-κB in the resolution of inflammation
Lawrence, T., Gilroy, D. W., Colville‐Nash, P., & Willoughby, D. A. (2001) · Nature Medicine · doi:10.1038/nm1201-1291 · Cited by 753
Malinen, E., Rinttila, T., Kajander, K., Matto, J., Kassinen, A., Krogius, L., Saarela, M., Korpela, R., & Palva, A. (2005) · The American Journal of Gastroenterology · doi:10.1111/j.1572-0241.2005.40312.x · Cited by 699
Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway
Vergnolle, N., Bunnett, N. W., Sharkey, K. A., Brussee, V., Compton, S. J., Grady, E. F., Cirino, G., Gerard, N. P., Basbaum, A. I., Andrade‐Gordon, P., et al. (2001) · Nature Medicine · doi:10.1038/89945 · Cited by 465
Self-citation
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Cited by
Sorted by citations
Enck, P., Aziz, Q., Barbara, G., Farmer, A. D., Fukudo, S., Mayer, E. A., Niesler, B., Quigley, E. M. M., Rajilić-Stojanović, M. D., Schemann, M., et al. (2016) · Nature Reviews Disease Primers · doi:10.1038/nrdp.2016.14 · Cited by 1,102
Self-citationBrain-gut-microbe communication in health and disease
Grenham, S., Clarke, G., Cryan, J. F., & Dinan, T. G. (2011) · Frontiers in Physiology · doi:10.3389/fphys.2011.00094 · Cited by 952
“Cenac et al. (2007) demonstrated increased proteolytic activity in colonic washes from IBS compared with control patients while the analysis of TLR expression in colonic biopsies has demonstrated increased expression of TLR4 and TLR5 and decreased levels of TLR7 and TLR8 in IBS patients (Brint et…”
Intestinal microbiota in functional bowel disorders: a Rome foundation report
Simrén, M., Barbara, G., Flint, H. J., Spiegel, B. M. R., Spiller, R. C., Vanner, S., Verdu, E. F., Whorwell, P. J., & Zoetendal, E. G. (2013) · Gut · doi:10.1136/gutjnl-2012-302167 · Cited by 939
Self-citationPathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions
Öhman, L., & Simrén, M. (2010) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2010.4 · Cited by 617
“Increased numbers of mucosal mast cells have not, however, been shown consistently in all studies”
BackgroundPiche, T., Barbara, G., Aubert, P., Bruley des Varannes, S., Dainese, R., Nano, J. L., Cremon, C., Stanghellini, V, De Giorgio, R., Galmiche, J. P., et al. (2009) · Gut · doi:10.1136/gut.2007.140806 · Cited by 540
“Previous studies (10, 11) have shown that candidates such as protease and histamine are involved in the effects of SUP of IBS upon the neuronal excitability.”
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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