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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Some studies failed to demonstrate increased activated mast cells in IBS patients.
“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]
Other studies have reported elevated levels of histamine and tryptase release in patients with IBS compared with controls.
“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]
Trypsin-like activity and tryptase release are increased in colonic biopsies from irritable bowel syndrome patients.
“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]
Studies in mice and humans have provided evidence that host- and bacterial-derived proteases may contribute to irritable bowel syndrome pathogenesis and symptom generation.
“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]
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 [58]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
1 retracted
Uehara, A., Muramoto, K., Takada, H., & Sugawara, S. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.11.5690 · Cited by 157 · see citing works
RetractedBarbara, G., Stanghellini, V., De Giorgio, R., Cremon, C., Cottrell, G. S., Santini, D., Pasquinelli, G., Morselli-Labate, A. M., Grady, E. F., Bunnett, N. W., et al. (2004) · Gastroenterology · doi:10.1053/j.gastro.2003.11.055 · Cited by 1,475 · see citing works
Self-citationSpiller, R. C., Jenkins, D., Thornley, J. P., Hebden, J. M., Wright, T., Skinner, M., & Neal, K. R. (2000) · Gut · doi:10.1136/gut.47.6.804 · Cited by 1,155 · see citing works
Postinfectious Irritable Bowel Syndrome
Spiller, R., & Garsed, K. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.02.074 · Cited by 1,024 · see citing works
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 · see citing works
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 · see citing works
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 · see citing works
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 749 · see citing works
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 · see citing works
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 · see citing works
Self-citationAmadesi, S., Nie, J., Vergnolle, N., Cottrell, G. S., Grady, E. F., Trevisani, M., Manni, C., Geppetti, P., McRoberts, J. A., Ennes, H. S., et al. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.5679-03.2004 · Cited by 412 · see citing works
Self-citationInduction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2.
Cénac, N., Coelho, A., Nguyen, C., Compton, S., Andrade-Gordon, P., MacNaughton, W., Wallace, J., Hollenberg, M., Bunnett, N., Garcia-Villar, R., et al. (2002) · American Journal of Pathology · doi:10.1016/s0002-9440(10)64466-5 · Cited by 386 · see citing works
Self-citationSpiller, R. E. (2003) · Gastroenterology · doi:10.1016/s0016-5085(03)00324-x · Cited by 353 · see citing works
Terminal ileal mucosal mast cells in irritable bowel syndrome
Weston, A. P., Biddle, W. L., Bhatia, P. S., & Miner, P. B. (1993) · Digestive Diseases and Sciences · doi:10.1007/bf01303164 · Cited by 338 · see citing works
Thompson, W., Irvine, E. J., Paré, P., Ferrazzi, S., & Rance, L. (2002) · Digestive Diseases and Sciences · doi:10.1023/a:1013208713670 · Cited by 330 · see citing works
Dai, Y., Moriyama, T., Higashi, T., Togashi, K., Kobayashi, K., Yamanaka, H., Tominaga, M., & Noguchi, K. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0454-04.2004 · Cited by 301 · see citing works
Philip, S., Bulbule, A., & Kundu, G. C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103334200 · Cited by 247 · see citing works
Miller, H. R. P., & Pemberton, A. D. (2002) · Immunology · doi:10.1046/j.1365-2567.2002.01375.x · Cited by 230 · see citing works
Coelho, A.-M., Vergnolle, N., Guiard, B. P., Fioramonti, J., & Bueno, L. P. (2002) · Gastroenterology · doi:10.1053/gast.2002.32387 · Cited by 212 · see citing works
Self-citationIs Irritable Bowel Syndrome a Low-Grade Inflammatory Bowel Disease?
Berčík, P., Verdu, E. F., & Collins, S. M. (2005) · Gastroenterology Clinics of North America · doi:10.1016/j.gtc.2005.02.007 · Cited by 207 · see citing works
Therapeutic Promise of Proteinase-Activated Receptor-2 Antagonism in Joint Inflammation
Kelso, E. B., Lockhart, J. C., Hembrough, T., Dunning, L., Plevin, R. J., Hollenberg, M. D., Sommerhoff, C. P., McLean, J. S., & Ferrell, W. R. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.093807 · Cited by 195 · see citing works
Reed, D. E., Barajas‐Lopez, C., Cottrell, G., Velazquez‐Rocha, S., Dery, O., Grady, E. F., Bunnett, N. W., & Vanner, S. J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.032011 · Cited by 192 · see citing works
Self-citationCorvera, C. U., Déry, O., McConalogue, K., Gamp, P. D., Thoma, M. S., Al‐Ani, B., Caughey, G. H., Hollenberg, M. D., & Bunnett, N. W. (1999) · The Journal of Physiology · doi:10.1111/j.1469-7793.1999.0741s.x · Cited by 184 · see citing works
Self-citationHansen, K. K., Sherman, P. M., Cellars, L., Andrade‐Gordon, P., Pan, Z., Baruch, A., Wallace, J. L., Hollenberg, M. D., & Vergnolle, N. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409535102 · Cited by 176 · see citing works
Self-citationTrypsin IV, a Novel Agonist of Protease-activated Receptors 2 and 4
Cottrell, G. S., Amadesi, S., Grady, E. F., & Bunnett, N. W. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312090200 · Cited by 172 · see citing works
Self-citationAit-Belgnaoui, A., Bradesi, S., Fioramonti, J., Theodorou, V., & Bueno, L. (2005) · Pain · doi:10.1016/j.pain.2004.10.002 · Cited by 171 · see citing works
Symptomatic overlap between irritable bowel syndrome and microscopic colitis
Limsui, D., Pardi, D. S., Camilleri, M., Loftus, E. V., Kammer, P. P., Tremaine, W. J., & Sandborn, W. J. (2006) · Inflammatory Bowel Diseases · doi:10.1002/ibd.20059 · Cited by 167 · see citing works
CLINICAL RELEVANCE OF PROTEINASE ACTIVATED RECEPTORS (PARS) IN THE GUT
Vergnolle, N. (2005) · Gut · doi:10.1136/gut.2004.048876 · Cited by 166 · see citing works
Self-citationMaukonen, J., Satokari, R., Mättö, J., Söderlund, H., Mattila-Sandholm, T., & Saarela, M. (2006) · Journal of Medical Microbiology · doi:10.1099/jmm.0.46134-0 · Cited by 156 · see citing works
Vergnolle, N., MacNaughton, W. K., Al‐Ani, B., Saifeddine, M., Wallace, J. L., & Hollenberg, M. D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7766 · Cited by 154 · see citing works
Self-citationThe putative role of inflammation in the irritable bowel syndrome
Collins, S. M., PICHE, T., & Rampal, P. (2001) · Gut · doi:10.1136/gut.49.6.743 · Cited by 154 · see citing works
Cenac, N., Chin, A. C., Garcia‐Villar, R., Salvador‐Cartier, C., Ferrier, L., Vergnolle, N., Buret, A. G., Fioramonti, J., & Bueno, L. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.061721 · Cited by 140 · see citing works
Self-citationThompson, W. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.03.011 · Cited by 124 · see citing works
Visceral perception: inflammatory and non-inflammatory mediators
Bueno, L. P., & Fioramonti, J. (2002) · Gut · doi:10.1136/gut.51.suppl_1.i19 · Cited by 118 · see citing works
Gao, C., Liu, S., Hu, H., Gao, N., Kim, G. Y., Xia, Y. L., & Wood, J. D. (2002) · Gastroenterology · doi:10.1053/gast.2002.36581 · Cited by 106 · see citing works
Enterokinase (enteropeptidase): comparative aspects
Light, A., & Jańska, H. (1989) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(89)90133-3 · Cited by 105 · see citing works
Proteinase‐activated receptor‐1 agonists attenuate nociception in response to noxious stimuli
Asfaha, S., Brussee, V., Chapman, K., Zochodne, D. W., & Vergnolle, N. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704568 · Cited by 104 · see citing works
Self-citationExpression of Protease-Activated Receptor 2 in Ulcerative Colitis
Kim, J.-A., Choi, S.-C., Yun, K.-J., Kim, D.-K., Han, M.-K., Seo, G.-S., Yeom, J.-J., Kim, T.-H., Nah, Y.-H., & Lee, Y.-M. (2003) · Inflammatory Bowel Diseases · doi:10.1097/00054725-200307000-00002 · Cited by 96 · see citing works
Inflammation as a basis for functional GI disorders
Spiller, R. E. (2004) · Best Practice & Research Clinical Gastroenterology · doi:10.1016/j.bpg.2004.04.002 · Cited by 93 · see citing works
Colitis induced by proteinase-activated receptor-2 agonists is mediated by a neurogenic mechanism
Nguyen, C., Coelho, A.-M., Grady, E., Compton, S. J., Wallace, J. L., Hollenberg, M. D., Cénac, N., Villar, R. G., Bueno, L. P., Steinhoff, M. S., et al. (2003) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y03-080 · Cited by 92 · see citing works
Self-citationNeonatal immune challenge alters nociception in the adult rat
Lomax, L. B., Spencer, S. J., Mouihate, A., Vergnolle, N., & Pittman, Q. J. (2005) · Pain · doi:10.1016/j.pain.2005.09.022 · Cited by 83 · see citing works
Self-citationHiramitsu, T., Yasuda, T., Ito, H., Shimizu, M., Julovi, S. M., Kakinuma, T., Akiyoshi, M., Yoshida, M., & Nakamura, T. (2006) · Rheumatology · doi:10.1093/rheumatology/kel026 · Cited by 75 · see citing works
Kawabata, A., Kuroda, R., Nagata, N., Kawao, N., Masuko, T., Nishikawa, H., & Kawai, K. (2001) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704211 · Cited by 74 · see citing works
Philip, S., Bulbule, A., & Kundu, G. C. (2004) · Glycoconjugate Journal · doi:10.1007/s10719-004-5533-7 · Cited by 71 · see citing works
Green, B. T., Bunnett, N. W., Kulkarni, A. P., Steinhoff, M. S., & Brown, D. R. (2000) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1016/s0022-3565(24)38916-5 · Cited by 70 · see citing works
Self-citationWhat activates visceral afferents?
Grundy, D. (2004) · Gut · doi:10.1136/gut.2003.033415 · Cited by 67 · see citing works
Activation of ion secretion via proteinase-activated receptor-2 in human colon
Mall, M. A., Gonska, T. Y., Thomas, J., Hirtz, S., Schreiber, R., & Kunzelmann, K. (2002) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00137.2001 · Cited by 67 · see citing works
Irritable bowel syndrome and inflammatory bowel disease: interrelated diseases?
Quigley, E. M. M. (2005) · Chinese Journal of Digestive Diseases · doi:10.1111/j.1443-9573.2005.00202.x · Cited by 64 · see citing works
Barau, E., & Dupont, C. M. (1990) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/00005176-199007000-00015 · Cited by 64 · see citing works
Macfarlane, S. R., Sloss, C. M., Cameron, P., Kanke, T., McKenzie, R. C., & Plevin, R. J. (2005) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0706204 · Cited by 62 · see citing works
Cuffe, J. E., Bertog, M., Velázquez‐Rocha, S., Déry, O., Bunnett, N. W., & Korbmacher, C. (2002) · The Journal of Physiology · doi:10.1113/jphysiol.2001.013159 · Cited by 61 · see citing works
Self-citationMechanisms in IBS: something old, something new, something borrowed…
Camilleri, M. (2005) · Neurogastroenterology and Motility · doi:10.1111/j.1365-2982.2004.00632.x · Cited by 61 · see citing works
Larsson, M., ARVIDSSON, S., Ekman, C., & Bayati, A. I. (2003) · Neurogastroenterology & Motility · doi:10.1046/j.1365-2982.2003.00418.x · Cited by 59 · see citing works
c-Src Mediates Thrombin-Induced NF-κB Activation and IL-8/CXCL8 Expression in Lung Epithelial Cells
Lin, C., Cheng, H.-W., Hsu, M., Chen, M.-C., Lin, C., & Chen, B.-C. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.5.3427 · Cited by 53 · see citing works
Mishra, D. P., Pal, R., & Shaha, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508648200 · Cited by 53 · see citing works
Dual effect mediated by protease‐activated receptors on the mechanical activity of rat colon
Mulè, F., Baffi, M. C., & Cerra, M. C. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704746 · Cited by 51 · see citing works
Stimulation of proteinase-activated receptor 2 excites jejunal afferent nerves in anaesthetised rats
Kirkup, A. J., Jiang, W., Bunnett, N. W., & Grundy, D. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2003.049387 · Cited by 50 · see citing works
Uehara, A., Muramoto, K., Imamura, T., Nakayama, K., Potempa, J., Travis, J. W., Sugawara, S., & Takada, H. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.9.6076 · Cited by 48 · see citing works
Agonists of proteinase-activated receptor 2 excite guinea pig ileal myenteric neurons
Linden, D. R., Manning, B. P., Bunnett, N. W., & Mawe, G. M. (2001) · European Journal of Pharmacology · doi:10.1016/s0014-2999(01)01447-9 · Cited by 47 · see citing works
Self-citationPAR-2 agonists induce contraction of murine small intestine through neurokinin receptors
Zhao, A., & Shea‐Donohue, T. (2003) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00064.2003 · Cited by 33 · see citing works
Johanson, J. F. (2004) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2004.00550.x · Cited by 31 · see citing works
The pathophysiology of irritable bowel syndrome.
Schwetz, I., Bradesi, S., & Mayer, E. A. (2004) · PubMed · Cited by 24 · see citing works
Treatments targeting putative mechanisms in irritable bowel syndrome
Cremonini, F., & Talley, N. J. (2005) · Nature Clinical Practice Gastroenterology & Hepatology · doi:10.1038/ncpgasthep0096 · Cited by 23 · see citing works
Thompson, W. G. (1999) · Gut · doi:10.1136/gut.45.2008.ii80 · Cited by 16 · see citing works
Mouse mast cells express the tryptic protease neuropsin/Prss19
Wong, G. W., Yang, Y., Yasuda, S., Li, L., & Stevens, R. L. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)00339-5 · Cited by 5 · see citing works
Simmering Innards: Does Irritable Bowl Syndrome Have an Immunological Basis?
Andrews, C. N., & Shaffer, E. A. (2004) · Canadian Journal of Gastroenterology · doi:10.1155/2004/707528 · Cited by 2 · see citing works
Self-citation
Flagged first, then by citations
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 1,057 · see citing works
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 · see citing works
“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 · see citing works
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 · see citing works
“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 · see citing works
“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-citationThe brain-gut axis in abdominal pain syndromes.
Mayer, E. A., & Tillisch, K. (2011) · Annual Review of Medicine · doi:10.1146/annurev-med-012309-103958 · Cited by 511 · see citing works
“An extensive amount of preclinical and some clinical data support a role for the central (and to a certain degree the peripheral) CRF-CRF1 receptor signaling system in mediating some forms of acute and chronic stress-induced visceral hyperalgesia of the colon (32, 49).”
BackgroundBrain gut microbiome interactions and functional bowel disorders
Mayer, E. A., Savidge, T., & Shulman, R. J. (2014) · Gastroenterology · doi:10.1053/j.gastro.2014.02.037 · Cited by 496 · see citing works
Klooker, T. K., Braak, B., Koopman, K. E., Welting, O., Wouters, M. M., der Heide, S. V., Schemann, M., Bischoff, S. C., van den Wijngaard, R. M., & Boeckxstaens, G. E. (2010) · Gut · doi:10.1136/gut.2010.213108 · Cited by 413 · see citing works
“Fourth, exposure to the supernatant obtained from colonic biopsies of patients with IBS but not from healthy controls increases the excitability of rat mesenteric sensory nerves and induces visceral hypersensitivity in mice.(8) 9 Finally, in animal models, administration of the mast cell stabiliser doxantrazole preven…”
Camilleri, M., Lasch, K. L., & Zhou, W. (2012) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00155.2012 · Cited by 397 · see citing works
“Increased infiltration of mast cells in the gut mucosa of IBS patients has been reported in many studies (1, 6, 7, 17, 29–31, 49, 79, 87, 90, 123, 126) but not in others (24, 61) (Table 3).”
BackgroundResultInfluentialStress and the Microbiota–Gut–Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome
Moloney, R. D., Johnson, A. C., O’Mahony, S. M., Dinan, T. G., Meerveld, B. G., & Cryan, J. F. (2015) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.12490 · Cited by 396 · see citing works
Wouters, M. M., Balemans, D., Van Wanrooy, S., Dooley, J., Cibert-Goton, V., Alpizar, Y. A., Valdez-Morales, E. E., Nasser, Y., Van Veldhoven, P. P., Vanbrabant, W., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2015.12.034 · Cited by 372 · see citing works
Structure, function and pathophysiology of protease activated receptors
Adams, M. N., Ramachandran, R., Yau, M.-K., Suen, J. Y., Fairlie, D. P., Hollenberg, M. D., & Hooper, J. D. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.003 · Cited by 370 · see citing works
Buhner, S., Li, Q., Vignali, S., Barbara, G., De Giorgio, R., Stanghellini, V., Cremon, C., Zeller, F., Langer, R., Daniel, H., et al. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.07.005 · Cited by 351 · see citing works
Self-citationCremon, C., Gargano, L., Morselli-Labate, A. M., Santini, D., Cogliandro, R. F., De Giorgio, R., Stanghellini, V., Corinaldesi, R., & Barbara, G. (2009) · The American Journal of Gastroenterology · doi:10.1038/ajg.2008.94 · Cited by 342 · see citing works
Self-citationThe Intestinal Microenvironment and Functional Gastrointestinal Disorders
Barbara, G., Feinle-Bisset, C., Ghoshal, U. C., Santos, J., Vanner, S. J., Vergnolle, N., Zoetendal, E. G., & Quigley, E. M. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.02.028 · Cited by 335 · see citing works
Self-citationGecse, K., Róka, R., Ferrier, L., Leveque, M., Eutamene, H., Cartier, C., Ait-Belgnaoui, A., Rosztóczy, A., Izbéki, F., Fioramonti, J., et al. (2008) · Gut · doi:10.1136/gut.2007.140210 · Cited by 314 · see citing works
Targeting proteinase-activated receptors: therapeutic potential and challenges
Ramachandran, R., Noorbakhsh, F., DeFea, K., & Hollenberg, M. D. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3615 · Cited by 313 · see citing works
“In addition, increased levels of PAR2-activating serine proteinases have been detected in patients with inflammatory bowel diseas”
BackgroundThe role of mast cells in functional GI disorders
Wouters, M. M., Vicario, M., & Santos, J. (2016) · Gut · doi:10.1136/gutjnl-2015-309151 · Cited by 308 · see citing works
Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more
Ramachandran, R., & Hollenberg, M. D. (2007) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0707507 · Cited by 306 · see citing works
“In a study on colonic tissue from individuals with inflammatory bowel syndrome, it was shown further that levels of trypsin, tryptase and other unidentified serine proteinase that favoured cleavage at an arginine site are significantly upregulated (Cenac et al., 2007).”
BackgroundChen, Y., Yang, C., & Wang, Z. J. (2011) · Neuroscience · doi:10.1016/j.neuroscience.2011.06.085 · Cited by 302 · see citing works
“PAR2, as well as its ligand mast cell tryptase, have been shown to be important for inflammation (Noorbakhsh et al., 2006; Barbara et al., 2007; Cenac et al., 2007).”
BackgroundProtease-activated receptor 2 signaling in inflammation
Rothmeier, A. S., & Ruf, W. (2011) · Seminars in Immunopathology · doi:10.1007/s00281-011-0289-1 · Cited by 289 · see citing works
“PAR2 is expressed throughout the intestine and trypsins as well, as tryptase are found in high levels in intestinal fluids of patients with inflammatory bowel disease, indicating a potential role of PAR2 in the pathogenesis of intestinal inflammation [123].”
The digestive neuronal–glial–epithelial unit: a new actor in gut health and disease
Neunlist, M., Landeghem, L. V., Mahé, M. M., Derkinderen, P., Varannes, S. B. D., & Rolli‐Derkinderen, M. (2012) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2012.221 · Cited by 277 · see citing works
Advances in mast cell biology: new understanding of heterogeneity and function
Moon, T. C., Laurent, C. D. S., Morris, K., Marcet, C. T., Yoshimura, T., Sekar, Y., & Befus, A. D. (2009) · Mucosal Immunology · doi:10.1038/mi.2009.136 · Cited by 274 · see citing works
Food-Grade Bacteria Expressing Elafin Protect Against Inflammation and Restore Colon Homeostasis
Motta, J.-P., Bermúdez-Humarán, L. G., Deraison, C., Martin, L., Rolland, C., Rousset, P., Boue, J., Dietrich, G., Chapman, K., Kharrat, P., et al. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004212 · Cited by 257 · see citing works
“Indeed, elevated proteolytic activity has been detected in intestinal tissues from CD and UC patients (5, 6).”
BackgroundSelf-citationSingle-cell RNAseq reveals seven classes of colonic sensory neuron
Hockley, J. R. F., Taylor, T. S., Callejo, G., Wilbrey, A. L., Gutteridge, A., Bach, K., Winchester, W. J., Bulmer, D. C., McMurray, G., & Smith, E. S. J. (2018) · Gut · doi:10.1136/gutjnl-2017-315631 · Cited by 251 · see citing works
Layer, P., Andresen, V., Pehl, C., Allescher, H. ‐., Bischoff, S., Claßen, M., Enck, P., Frieling, T., Haag, S., Holtmann, G., et al. (2011) · Zeitschrift für Gastroenterologie · doi:10.1055/s-0029-1245976 · Cited by 231 · see citing works
Protease inhibition as new therapeutic strategy for GI diseases
Vergnolle, N. (2016) · Gut · doi:10.1136/gutjnl-2015-309147 · Cited by 226 · see citing works
Self-citationMartínez, C., Vicario, M., Ramos, L., Lobo, B., Mosquera, J. L., Alonso, C., Sánchez, A., Guilarte, M., Antolín, M., de Torres, I., et al. (2012) · American Journal of Gastroenterology · doi:10.1038/ajg.2011.472 · Cited by 214 · see citing works
Tissue Factor, Blood Coagulation, and Beyond: An Overview
Chu, A. J. (2011) · International Journal of Inflammation · doi:10.4061/2011/367284 · Cited by 222 · see citing works
“FUT-175 consistent with PAR deficiency eases inflammatory bowel disease/symptom [395].”
BackgroundCremon, C., Carini, G., Wang, B., Vasina, V., Cogliandro, R. F., De Giorgio, R., Stanghellini, V., Grundy, D., Tonini, M., De Ponti, F., et al. (2011) · American Journal of Gastroenterology · doi:10.1038/ajg.2011.86 · Cited by 223 · see citing works
Self-citationMatricon, J., Méleine, M., Gelot, A., Piche, T., Dapoigny, M. C., Muller, E., & Ardid, D. (2012) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.12080 · Cited by 216 · see citing works
Stress and visceral pain: From animal models to clinical therapies
Larauche, M. H., Mulak, A., & Taché, Y. (2011) · Experimental Neurology · doi:10.1016/j.expneurol.2011.04.020 · Cited by 212 · see citing works
The immune system in irritable bowel syndrome
Barbara, G., Cremon, C., Carini, G., Bellacosa, L., Zecchi, L., Giorgio, R. D., Corinaldesi, R., & Stanghellini, V. (2011) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm.2011.17.4.349 · Cited by 211 · see citing works
“Proteases are markedly increased in the mucosa of patients with IBS(5,47,58) and may act as signaling pain molecules via the activation of protease activated receptors (PAR) located on intestinal nerves conveying pain stimuli to the brain.(5,47,59) Trypsin and tryptase nociceptive effects evoked in mice were reduced b…”
InfluentialSelf-citationFord, A. C., & Talley, N. J. (2011) · Journal of Gastroenterology · doi:10.1007/s00535-011-0379-9 · Cited by 200 · see citing works
“Unaltered O’Sullivan et al. [35], Chadwick et al. [27], Cenac et al. [ 26 ]”
BackgroundMethodInfluentialClinical significance of lymph node metastasis in gastric cancer
Deng, J. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i14.3967 · Cited by 198 · see citing works
Sensory neuro-immune interactions differ between Irritable Bowel Syndrome subtypes
Hughes, P. A., Harrington, A. M., Castro, J., Liebregts, T., Adam, B., Grasby, D. J., Isaacs, N. J., Maldeniya, L., Martin, C. M., Persson, J., et al. (2012) · Gut · doi:10.1136/gutjnl-2011-301856 · Cited by 195 · see citing works
Novel Fecal Biomarkers That Precede Clinical Diagnosis of Ulcerative Colitis
Galipeau, H. J., Caminero, A., Turpin, W., Bermudez-Brito, M., Santiago, A., Libertucci, J., Constante, M., Raygoza Garay, J. A., Rueda, G., Armstrong, S., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2020.12.004 · Cited by 190 · see citing works
Self-citationCathepsin S Causes Inflammatory Pain via Biased Agonism of PAR2 and TRPV4
Zhao, P., Lieu, T., Barlow, Ν., Metcalf, M. D., Veldhuis, N. A., Jensen, D. D., Kočan, M., Sostegni, S., Haerteis, S., Baraznenok, V., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.599712 · Cited by 189 · see citing works
“Given the established contributions of PAR2 and TRPV4 to arthritis (63) and colitis (30, 64, 65), antagonists of Cat-S, PAR2, and TRPV4 may be valuable treatments for these and other inflammatory diseases.”
BackgroundSelf-citationGebhart, G. F., & Bielefeldt, K. (2016) · Comprehensive physiology · doi:10.1002/cphy.c150049 · Cited by 224 · see citing works
Protease-activated receptor-2 in endosomes signals persistent pain of irritable bowel syndrome
Jimenez-Vargas, N. N., Pattison, L. A., Zhao, P., Lieu, T., Latorre, R., Jensen, D. D., Castro, J., Aurelio, L., Le, G. T., Flynn, B., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1721891115 · Cited by 185 · see citing works
Self-citationOh my aching gut: irritable bowel syndrome, Blastocystis, and asymptomatic infection
Boorom, K., Smith, H. V., Nimri, L. F., Viscogliosi, É., Spanakos, G. K., Parkar, U., Li, L., Zhou, X., Ok, Ü. Z., Leelayoova, S., et al. (2008) · Parasites & Vectors · doi:10.1186/1756-3305-1-40 · Cited by 186 · see citing works
“Recent research into the etiology of abdominal pain, constipation and diarrhea in patients with symptoms attributed to IBS has suggested that the these symptoms are produced by high levels of serine protease produced in the gastrointestinal tract which are capable of exciting neurons directly through the protease-acti…”
BackgroundCrosstalk at the mucosal border: importance of the gut microenvironment in IBS
Öhman, L., Törnblom, H., & Simrén, M. (2014) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2014.200 · Cited by 181 · see citing works
Ayvaz, H., Cabaroğlu, T., Akyıldız, A., Pala, Ç. U., Temizkan, R., Ağçam, E., Ayvaz, Z., Durazzo, A., Lucarini, M., Direito, R., et al. (2022) · Antioxidants · doi:10.3390/antiox12010048 · Cited by 182 · see citing works
The enteric nervous system: normal functions and enteric neuropathies
Furness, J. (2008) · Neurogastroenterology and Motility · doi:10.1111/j.1365-2982.2008.01094.x · Cited by 188 · see citing works
Transient Receptor Potential Vanilloid-4 Has a Major Role in Visceral Hypersensitivity Symptoms
Cénac, N., Altier, C., Chapman, K., Liedtke, W., Zamponi, G. W., & Vergnolle, N. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.05.024 · Cited by 181 · see citing works
Self-citationIrritable bowel syndrome: towards biomarker identification
Clarke, G. A., Quigley, E. M. M., Cryan, J. F., & Dinan, T. G. (2009) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2009.08.001 · Cited by 180 · see citing works
Mucosal cytokine imbalance in irritable bowel syndrome
Macsharry, J., O'Mahony, L., Fanning, A., Bairead, E., Sherlock, G., Tiesman, J., Fulmer, A., Kiely, B., Dinan, T. G., Shanahan, F., et al. (2008) · Scandinavian Journal of Gastroenterology · doi:10.1080/00365520802276127 · Cited by 174 · see citing works
“subsequently documented increased tryptase levels in the stool in IBS patients and went on to show that these proteases had pronociceptive effects in experimental animal models [15].”
BackgroundCénac, N., Altier, C., Motta, J., d'Aldebert, E., Galeano, S., Zamponi, G. W., & Vergnolle, N. (2010) · Gut · doi:10.1136/gut.2009.192567 · Cited by 172 · see citing works
Self-citationVeldhuis, N. A., Poole, D. P., Grace, M. S., McIntyre, P., & Bunnett, N. W. (2014) · Pharmacological Reviews · doi:10.1124/pr.114.009555 · Cited by 172 · see citing works
“These proteases are present in biopsy supernatants and can activate PARs (particularly PAR2), leading to the sensitization of mouse sensory neurons and colonic afferents (Cenac et al., 2007).”
BackgroundSelf-citationVisceral hypersensitivity in non-erosive reflux disease
Knowles, C. H., & Aziz, Q. (2007) · Gut · doi:10.1136/gut.2007.127886 · Cited by 171 · see citing works
Basic and clinical aspects of gastrointestinal pain
Knowles, C. H., & Aziz, Q. (2009) · Pain · doi:10.1016/j.pain.2008.12.011 · Cited by 170 · see citing works
“In keeping with a role in GI nociception, expression of all relevant GPCRs, e.g. Bradykinin 2 (B2) receptors [43], PG receptors [159], histamine receptors [212], 5HT receptors [96], TrK A [73], Ret [84] and PAR2 [55] receptors, has been demonstrated in several classes of GI afferents with a further subset of GPCRs hav…”
BackgroundInfluentialEngineering lactococci and lactobacilli for human health
Bermúdez‐Humarán, L. G., Aubry, C., Motta, J., Deraison, C., Steidler, L., Vergnolle, N., Chatel, J., & Langella, P. (2013) · Current Opinion in Microbiology · doi:10.1016/j.mib.2013.06.002 · Cited by 164 · see citing works
“Indeed, intestinal tissues from CD and UC patients show elevated proteolytic activity [8 ,9].”
BackgroundSelf-citationDothel, G., Barbaro, M. R., Boudin, H., Vasina, V. I., Cremon, C., Gargano, L., Bellacosa, L., GIORGIO, R. D., Berre‐Scoul, C. L., Aubert, P., et al. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.01.042 · Cited by 162 · see citing works
“Proteases obtained from IBS patients induced proteinase receptor-2-dependent activation of pain pathways in mice.(13) In addition, colonic low-grade immune activation correlated with TRPV-1 immunoreactivity and with the severity of abdominal pain.”
BackgroundSelf-citationPathophysiology, Evaluation, and Management of Chronic Watery Diarrhea
Camilleri, M., Sellin, J. H., & Barrett, K. E. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.10.014 · Cited by 163 · see citing works
Colonic immune cells in irritable bowel syndrome: A systematic review and meta‐analysis
Bashashati, M., Moossavi, S., Cremon, C., Barbaro, M. R., Moraveji, S., Talmon, G., Rezaei, N., Hughes, P. A., Bian, Z. X., Choi, C. H., et al. (2018) · Neurogastroenterology & Motility · doi:10.1111/nmo.13192 · Cited by 175 · see citing works
Self-citationMast Cell Proteases as Protective and Inflammatory Mediators
Caughey, G. H. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-9533-9_12 · Cited by 163 · see citing works
The enteric nervous system in gastrointestinal disease etiology
Holland, A. M., Bon‐Frauches, A. C., Keszthelyi, D., Melotte, V., & Boesmans, W. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03812-y · Cited by 164 · see citing works
Poole, D. P., Amadesi, S., Veldhuis, N. A., Abogadie, F. C., Lieu, T., Darby, W. G., Liedtke, W., Lew, M. J., McIntyre, P., & Bunnett, N. W. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.438184 · Cited by 159 · see citing works
“These mechanisms contribute to painful inflammation of the intestine (5, 6), pancreas (7, 8), and joints (9).”
BackgroundSelf-citationPalma, G. D., Shimbori, C., Reed, D. E., Yu, Y., Rabbia, V., Lu, J., Jiménez-Vargas, N. N., Sessenwein, J. L., López-López, C., Pigrau, M., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abj1895 · Cited by 159 · see citing works
d'Aldebert, E., Cénac, N., Rousset, P., Martin, L., Rolland, C., Chapman, K., Sèlves, J., Alric, L., Vinel, J., & Vergnolle, N. (2010) · Gastroenterology · doi:10.1053/j.gastro.2010.09.045 · Cited by 154 · see citing works
Self-citationMast Cell-Mediated Mechanisms of Nociception
Aich, A., Afrin, L. B., & Gupta, K. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161226151 · Cited by 156 · see citing works
“PAR2 may sensitize neurons via Ca2+ mobilization [143,152] and TRPV1 channel activation [154].”
BackgroundPiche, T. (2014) · Neurogastroenterology & Motility · doi:10.1111/nmo.12315 · Cited by 154 · see citing works
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 · see citing works
Self-citationVanuytsel, T., Berčík, P., & Boeckxstaens, G. E. (2023) · Gut · doi:10.1136/gutjnl-2020-320633 · Cited by 157 · see citing works
“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 148 · see citing works
Mast cell proteases as pharmacological targets
Caughey, G. H. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.04.045 · Cited by 151 · see citing works
“, 2006); visceral pain (Cenac et al., 2007), aortic aneurysms (Zhang et al.”
BackgroundFunctional gastrointestinal disorders and gut-brain axis: What does the future hold?
Mukhtar, K., Nawaz, H., & Abid, S. (2019) · World Journal of Gastroenterology · doi:10.3748/wjg.v25.i5.552 · Cited by 152 · see citing works
Immune Activation in Irritable Bowel Syndrome: Can Neuroimmune Interactions Explain Symptoms?
Hughes, P. A., Zola, H., Penttila, I., Blackshaw, L. A., Andrews, J. M., & Krumbiegel, D. (2013) · The American Journal of Gastroenterology · doi:10.1038/ajg.2013.120 · Cited by 147 · see citing works
Sipe, W. E. B., Brierley, S. M., Martin, C. M., Phillis, B. D., Cruz, F. B., Grady, E. F., Liedtke, W., Cohen, D., Vanner, S. J., Blackshaw, L. A., et al. (2008) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00002.2008 · Cited by 146 · see citing works
“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 · see citing works
Brain-derived neurotrophic factor contributes to abdominal pain in irritable bowel syndrome
Yu, Y., Zuo, X., Zhao, Q.-J., Chen, F.-X., Yang, J., Dong, Y., Wang, P., & Li, Y. (2011) · Gut · doi:10.1136/gutjnl-2011-300265 · Cited by 144 · see citing works
Mechanisms Underlying Visceral Hypersensitivity in Irritable Bowel Syndrome
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 144 · see citing works
“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 141 · see citing works
Vivinus-Nébot, M., Dainese, R., Anty, R., Saint‐Paul, M., Nano, J. L., Gonthier, N., Marjoux, S., Frin-Mathy, G., Bernard, G., Hébuterne, X., et al. (2011) · The American Journal of Gastroenterology · doi:10.1038/ajg.2011.315 · Cited by 141 · see citing works
Gut Microbiota as Potential Orchestrators of Irritable Bowel Syndrome
Bennet, S., Öhman, L., & Simrén, M. (2015) · Gut and Liver · doi:10.5009/gnl14344 · Cited by 143 · see citing works
New treatments and therapeutic targets for IBS and other functional bowel disorders
Simrén, M., & Tack, J. (2018) · Nature reviews: Gastroenterology & hepatology · doi:10.1038/s41575-018-0034-5 · Cited by 127 · see citing works
Caminero, A., McCarville, J. L., Galipeau, H. J., Deraison, C., Bernier, S. P., Constante, M., Rolland, C., Meisel, M., Murray, J. A., Yu, X. B., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09037-9 · Cited by 139 · see citing works
Self-citationMast Cells and Irritable Bowel Syndrome: From the Bench to the Bedside
Zhang, L., Song, J., & Hou, X. (2016) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm15137 · Cited by 138 · see citing works
“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 · see citing works
“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 133 · see citing works
CORINALDESI, R., STANGHELLINI, V., CREMON, C., GARGANO, L., COGLIANDRO, R. F., DE GIORGIO, R., BARTESAGHI, G., CANOVI, B., & BARBARA, G. (2009) · Alimentary Pharmacology & Therapeutics · doi:10.1111/j.1365-2036.2009.04041.x · Cited by 131 · see citing works
Self-citationModifying the Protease, Antiprotease Pattern by Elafin Overexpression Protects Mice From Colitis
Motta, J., Magne, L., Descamps, D., Rolland, C., Squarzoni–Dale, C., Rousset, P., Martin, L., Cenac, N., Balloy, V., Huerre, M., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2010.12.050 · Cited by 130 · see citing works
Self-citationA Global Perspective on Irritable Bowel Syndrome
Quigley, E. M. M., Abdel-Hamid, H., Barbara, G., Bhatia, S. J., Boeckxstaens, G. E., GIORGIO, R. D., Delvaux, M. M., Drossman, D. A., Foxx–Orenstein, A. E., Guarner, F., et al. (2012) · Journal of Clinical Gastroenterology · doi:10.1097/mcg.0b013e318247157c · Cited by 131 · see citing works
Self-citationDu, Q., Liao, Q., Chen, C., Yang, X., Xie, R., & Xu, J. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.01064 · Cited by 127 · see citing works
Bermúdez‐Humarán, L. G., Motta, J., Aubry, C., Kharrat, P., Martin, L., Sallenave, J., Deraison, C., Vergnolle, N., & Langella, P. (2015) · Microbial Cell Factories · doi:10.1186/s12934-015-0198-4 · Cited by 128 · see citing works
“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
Vergnolle, N. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.05.004 · Cited by 124 · see citing works
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 · see citing works
“Proteases are prominent mediators of inflammation and pain in many tissues, including the intestine (8, 15).”
BackgroundInfluentialSelf-citationInfection, inflammation, and the irritable bowel syndrome
Spiller, R., & Garsed, K. (2009) · Digestive and Liver Disease · doi:10.1016/j.dld.2009.07.007 · Cited by 122 · see citing works
Bacterial proteases in IBD and IBS
Steck, N., Mueller, K., Schemann, M., & Haller, D. (2011) · Gut · doi:10.1136/gutjnl-2011-300775 · Cited by 119 · see citing works
“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 · see citing works
“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 · see citing works
Intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome
Ringel, Y., & Maharshak, N. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00207.2012 · Cited by 115 · see citing works
“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
Vermeulen, W. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i4.1005 · Cited by 116 · see citing works
Vicario, M., González-Castro, A. M., Martínez, C., Lobo, B., Pigrau, M., Guilarte, M., de Torres, I. M., Mosquera, J. L., Fortea, M., Sevillano-Aguilera, C., et al. (2014) · Gut · doi:10.1136/gutjnl-2013-306236 · Cited by 116 · see citing works
Al, F. D., Şimşek, Z., Boorom, K., Ekici, E., Şahin, M., Tunçer, C., Kuştımur, S., & Altınbaş, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015484 · Cited by 116 · see citing works
“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 115 · see citing works
“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 · see citing works
Self-citationRecent developments in the pathophysiology of irritable bowel syndrome
El-Salhy, M. (2015) · World Journal of Gastroenterology · doi:10.3748/wjg.v21.i25.7621 · Cited by 111 · see citing works
Beatty, J. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i14.3976 · Cited by 107 · see citing works
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. (2013) · American Journal of Gastroenterology · doi:10.1038/ajg.2013.241 · Cited by 107 · see citing works
Self-citation
- 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 › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
