Epithelial expression and function of trypsin-3 in irritable bowel syndrome
Open accessAbstract
Objectives: Proteases are key mediators of pain and altered enteric neuronal signalling, although the types and sources of these important intestinal mediators are unknown. We hypothesised that intestinal epithelium is a major source of trypsin-like activity in patients with IBS and this activity signals to primary afferent and enteric nerves and induces visceral hypersensitivity. Design: Trypsin-like activity was determined in tissues from patients with IBS and in supernatants of Caco-2 cells stimulated or not. These supernatants were also applied to cultures of primary afferents. mRNA isoforms of trypsin (PRSS1, 2 and 3) were detected by reverse transcription-PCR, and trypsin-3 protein expression was studied by western blot analysis and immunohistochemistry. Electrophysiological recordings and Ca 2+ imaging in response to trypsin-3 were performed in mouse primary afferent and in human submucosal neurons, respectively. Visceromotor response to colorectal distension was recorded in mice administered intracolonically with trypsin-3. Results: We showed that stimulated intestinal epithelial cells released trypsin-like activity specifically from the basolateral side. This activity was able to activate sensory neurons. In colons of patients with IBS, increased trypsin-like activity was associated with the epithelium. We identified that trypsin-3 was the only form of trypsin upregulated in stimulated intestinal epithelial cells and in tissues from patients with IBS. Trypsin-3 was able to signal to human submucosal enteric neurons and mouse sensory neurons, and to induce visceral hypersensitivity in vivo, all by a protease-activated receptor-2-dependent mechanism. Conclusions: In IBS, the intestinal epithelium produces and releases the active protease trypsin-3, which is able to signal to enteric neurons and to induce visceral hypersensitivity.
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Colonic tissues from patients with inflammatory bowel disease and irritable bowel syndrome have increased serine proteolytic activity.
“colonic tissues from patients with inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) have increased serine proteolytic activity (PA),7,8 suggesting a role in the pathophysiology of the disease.”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [7]
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 [7]
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 [7]
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 [7]
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Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · see citing works
Mutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837 · see citing works
Sperber, A. D., Dumitrascu, D., Fukudo, S., Gerson, C., Ghoshal, U. C., Gwee, K. A., Hungin, A. P. S., Kang, J.-Y., Minhu, C., Schmulson, M., et al. (2017) · Gut · doi:10.1136/gutjnl-2015-311240 · Cited by 554 · 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
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
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
Self-citationCénac, 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-citationCLINICAL 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-citationCénac, 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-citationLarauche, M. H., Gourcerol, G., Wang, L., Pambukchian, K., Brunnhuber, S., Adelson, D. W., Rivier, J., Million, M., & Taché, Y. (2009) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00072.2009 · Cited by 129 · see citing works
Self-citationCirillo, C., Sarnelli, G., Turco, F., Mango, A., Grosso, M., Aprea, G., Masone, S., & Cuomo, R. (2011) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2011.01748.x · Cited by 119 · see citing works
Self-citationPrevalence of coeliac disease in idiopathic dilated cardiomyopathy
Curione, M., Barbato, M., Biase, L. D., Viola, F., Russo, L., & Cardi, E. (1999) · The Lancet · doi:10.1016/s0140-6736(99)01501-9 · Cited by 117 · 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-citationChin, A. C., Lee, W. Y., Nusrat, A., Vergnolle, N., & Parkos, C. A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.8.5702 · Cited by 106 · see citing works
Self-citationProtease-activated receptor-2 activation: a major actor in intestinal inflammation
Hyun, E., Andrade‐Gordon, P., Steinhoff, M. S., & Vergnolle, N. (2008) · Gut · doi:10.1136/gut.2008.150722 · Cited by 106 · see citing works
Self-citationKnecht, W., Cottrell, G. S., Amadesi, S., Mohlin, J., Skåregärde, A., Gedda, K., Peterson, A., Chapman, K., Hollenberg, M. D., Vergnolle, N., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m703840200 · Cited by 104 · see citing works
Self-citationIbeakanma, C. O., Ochoa‐Cortés, F., Miranda‐Morales, M., McDonald, T. G., Spreadbury, I., Cénac, N., Cattaruzza, F., Hurlbut, D. J., Vanner, S., Bunnett, N. W., et al. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.08.006 · Cited by 92 · see citing works
Self-citationTooth, D., Garsed, K., Singh, G., Marciani, L., Lam, C., Fordham, I., Fields, A., Banwait, R., Lingaya, M., Layfield, R., et al. (2013) · Gut · doi:10.1136/gutjnl-2012-304042 · Cited by 87 · see citing works
Kerckhoffs, A. P. M., Linde, J. J. M. T., Akkermans, L. M. A., & Samsom, M. (2008) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2008.01100.x · Cited by 82 · see citing works
Οικονομοπούλου, Κ., Hansen, K. K., Saifeddine, M., Vergnolle, N., Téa, I., Diamandis, E. P., & Hollenberg, M. D. (2006) · Biological Chemistry · doi:10.1515/bc.2006.086 · Cited by 79 · see citing works
Self-citationLarauche, M. H., Mulak, A., Kim, Y. S., Labus, J. S., Million, M., & Taché, Y. (2012) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2012.01980.x · Cited by 60 · see citing works
Self-citationMoussaoui, N., Larauche, M. H., Biraud, M., Molet, J., Million, M., Mayer, E. A., & Taché, Y. (2016) · PLoS ONE · doi:10.1371/journal.pone.0155037 · Cited by 53 · see citing works
Self-citationIsolation of high-purity myenteric plexus from adult human and mouse gastrointestinal tract
Grundmann, D., Klotz, M., Rabe, H., Glanemann, M., & Schäfer, K. (2015) · Scientific Reports · doi:10.1038/srep09226 · Cited by 51 · see citing works
Activity of Protease-Activated Receptors in the Human Submucous Plexus
Mueller, K., Michel, K., Krueger, D., Demir, İ. E., Ceyhan, G. O., Zeller, F., Kreis, M. E., & Schemann, M. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.08.034 · Cited by 44 · see citing works
Sequence and Conformational Specificity in Substrate Recognition
Pendlebury, D. F., Wang, R., Henin, R. D., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.609560 · Cited by 38 · see citing works
Inhibitory effects of galanin on evoked [Ca2+]i responses in cultured myenteric neurons
Sarnelli, G., Berghe, P. V., Raeymaekers, P., et al. (2004) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00255.2003 · Cited by 35 · see citing works
Self-citationMesotrypsin Has Evolved Four Unique Residues to Cleave Trypsin Inhibitors as Substrates
Alloy, A. P., Kayode, O., Wang, R., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.662429 · Cited by 29 · see citing works
Hyun, E., Ramachandran, R., Cénac, N., Houle, S., Rousset, P., Saxena, A., Liblau, R., Hollenberg, M. D., & Vergnolle, N. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902171 · Cited by 23 · see citing works
Self-citationCeliac disease in idiopathic dilated cardiomyopathy.
Chimenti, C., Pieroni, M., & Frustaci, A. (2001) · PubMed · Cited by 19 · see citing works
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Aguilera-Lizarraga, J., Florens, M. V., Viola, M. F., Jain, P., Decraecker, L., Appeltans, I., Cuende-Estevez, M., Fabre, N., Van Beek, K., Perna, E., et al. (2021) · Nature · doi:10.1038/s41586-020-03118-2 · Cited by 311 · see citing works
Self-citationProtease-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-citationEdwinson, A. L., Yang, L., Peters, S., Hanning, N., Jeraldo, P., Jagtap, P., Simpson, J. B., Yang, T.-Y., Kumar, P., Mehta, S., et al. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01103-1 · Cited by 105 · see citing works
Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS
Edogawa, S., Edwinson, A. L., Peters, S. A., Chikkamenahalli, L. L., Sundt, W., Graves, S., Gurunathan, S. V., Breen-Lyles, M., Johnson, S., Dyer, R., et al. (2020) · Gut · doi:10.1136/gutjnl-2018-317416 · Cited by 101 · see citing works
Fecal Serine Protease Profiling in Inflammatory Bowel Diseases
Jablaoui, A., Kriaa, A., Mkaouar, H., Akermi, N., Soussou, S., Wysocka, M., Wołoszyn, D., Amouri, A., Gargouri, A., Maguin, E., et al. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00021 · Cited by 101 · see citing works
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Denadai-Souza, A., Bonnart, C., Tapias, N. S., Marcellin, M., Gilmore, B., Alric, L., Bonnet, D., Burlet-Schiltz, O., Hollenberg, M. D., Vergnolle, N., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-26282-y · Cited by 91 · see citing works
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Ceuleers, H., Hanning, N., Heirbaut, J., Van Remoortel, S., Joossens, J., Van Der Veken, P., Francque, S. M., De bruyn, M., Lambeir, A., De Man, J. G., et al. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14396 · Cited by 49 · see citing works
Plasse, T. F., Barton, G., Davidson, E., Abramson, D., Kalfus, I., Fathi, R., Raday, G., & Harris, M. S. (2020) · American Journal of Gastroenterology · doi:10.14309/ajg.0000000000000727 · Cited by 40 · see citing works
Motta, J.-P., Rolland, C., Edir, A., Florence, A.-C., Sagnat, D., Bonnart, C., Rousset, P., Guiraud, L., Quaranta-Nicaise, M., Mas, E., et al. (2021) · Mucosal Immunology · doi:10.1038/s41385-021-00375-w · Cited by 40 · see citing works
Self-citationWiley, J. W., Higgins, G. A., & Hong, S. (2022) · PeerJ · doi:10.7717/peerj.13287 · Cited by 21 · see citing works
- Authors
- Rolland-Fourcade, C., Denadai-Souza, A., Cirillo, C., Lopez, C., Jaramillo, J. O., Desormeaux, C., Cenac, N., Motta, J.-P., Larauche, M., Taché, Y., Berghe, P. V., Neunlist, M., Coron, E., Kirzin, S., Portier, G., Bonnet, D., Alric, L., Vanner, S., Deraison, C., & Vergnolle, N.
- Affiliations
- Université Toulouse III - Paul Sabatier (FR)
- IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
- KU Leuven (BE)
- Queen's University (CA)
- University of California, Los Angeles (US)
- Inserm (FR)
- Centre Hospitalier Universitaire de Toulouse (FR)
- Corresponding author
- Vergnolle, Nathalie
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2017-01-17
- Volume
- 66
- Issue
- 10
- Pages
- 1767-1778
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC5595105
- OpenAlex
- W2574980908
- Cited by
- 126
- References
- 29
- Citations by year
- 2026: 7 · 2025: 11 · 2024: 13 · 2023: 15 · 2022: 13 · 2021: 18 · 2020: 13 · 2019: 10 · 2018: 19 · 2017: 7
- FWCI
- 14.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc)
- Lirias (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Equipex (ANR-11-EQPX-0003)
- Agence Nationale de la Recherche (R12177BB, ANR-11-EQPX-0003)
- Institut National de la Santé et de la Recherche Médicale (U1043, ANR-11-EQPX-0003)
- Fonds Wetenschappelijk Onderzoek
- National Institutes of Health (NIH-R01, NIH P50, DK41301, DK064539)
- National Institute of Diabetes and Digestive and Kidney Diseases (P50DK064539, P30DK041301, R01DK057238, K01DK088937)
- 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, intestinal epithelium, proteolytic enzymes, visceral hypersensitivity, primary afferent neurons, enteric neurons, protease-activated receptor 2, submucosal neurons, colorectal distension, basolateral secretion, Caco-2 cells
- MeSH terms
- Animals, Colon, Dipeptides, Epithelial Cells, Female, Ganglia, Spinal, Humans, Hypersensitivity, Intestinal Mucosa, Isoxazoles, Lipopolysaccharides, Male, Neurons, Afferent, Permeability, RNA, Messenger, Trypsin, Trypsinogen, Up-Regulation, Case-Control Studies, Culture Media, Conditioned, Enteric Nervous System, Microscopy, Confocal, Caco-2 Cells, Irritable Bowel Syndrome, Receptor, PAR-2, Mice, Rats
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