Luminal Cysteine-Proteases Degrade Colonic Tight Junction Structure and Are Responsible for Abdominal Pain in Constipation-Predominant IBS
Abstract
OBJECTIVES: Luminal serine-proteases lead to increased colonic paracellular permeability and visceral hypersensitivity in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Other proteases, namely cysteine-proteases (CPs), increase airway permeability by digesting epithelial tight junction proteins. In this study, we focused on constipation-predominant IBS (IBS-C) and we aimed to (i) evaluate CP levels in two cohorts of IBS patients, (ii) test if IBS-C fecal supernatant (FSN) affects permeability, and visceral sensitivity after repeated administrations in mice, and (iii) evaluate occludin expression in IBS-C colonic biopsies. METHODS: Fecal CP activity was determined using selective substrate and inhibitor (E64). The effect of papain, as positive control, and IBS-C FSN administrations were evaluated on colonic paracellular permeability and mucosal occludin levels in mice and T84 monolayers. Occludin protein levels were evaluated in IBS-C colonic biopsies. Sensitivity to colorectal distension (CRD) was measured after repeated administrations of IBS-C FSN. RESULTS: We found in a subset of IBS-C patients an enhanced fecal CP activity, in comparison with healthy controls and IBS-D patients. CP activity levels positively correlated with disease severity and abdominal pain scoring. This association was confirmed by receiver operating characteristic curve analysis. In mice, repeated application of IBS-C FSN into colon triggered increased permeability, linked to the enzymatic degradation of occludin, and was associated with enhanced visceral sensitivity to CRD. Finally, occludin levels were found decreased in colonic biopsies from IBS-C patients, and IBS-C FSNs were able to degrade recombinant human occludin in vitro. All these effects were abolished by preincubation of IBS-C FSN with a CP inhibitor, E64. CONCLUSIONS: These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.
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Based on the study of fecal proteases from IBS-C patients, enhancement of abdominal pain did not appear to be due to direct excitatory actions of proteases on neuronal PARs.
“Based on the study of fecal proteases from IBS-C patients, enhancement of abdominal pain did not appear to be due to direct excitatory actions of proteases on neuronal PARs.160”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [160]
Intracolonic administration of fecal supernatants from IBS-D and IBS-C patients increased the visceromotor response to distension, with evidence of both allodynia and hyperalgesia.
“Intracolonic administration of fecal supernatants from IBS-D and IBS-C patients increased the visceromotor response to distension, with evidence of both allodynia and hyperalgesia.159,160”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [160]
Intracolonic administration of cysteine proteases within IBS-C fecal supernatants to mice increased colonic permeability and led to degradation of occludin, which in turn led to increased visceral pain.
“Instead, intracolonic administration of cysteine proteases within IBS-C fecal supernatants to mice increased colonic permeability and led to degradation of occluding, which in turn led to increased visceral pain.”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [160]
Mucosal biopsies from IBS-C patients displayed evidence of epithelial occludin degradation compared to biopsies from healthy controls.
“Mucosal biopsies from IBS-C patients also displayed evidence of epithelial occludin degradation compared to biopsies from healthy controls.160”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [160]
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- Authors
- Annaházi, A., Ferrier, L., Bézirard, V., Lévêque, M., Eutamène, H., Ait-Belgnaoui, A., Coëffier, M., Ducrotté, P., Róka, R., Inczefi, O., Gecse, K., Rosztóczy, A., Molnár, T., Ringel-Kulka, T., Ringel, Y., Piche, T., Theodorou, V., Wittmann, T., & Bueno, L.
- Affiliations
- University of Szeged (HU)
- Ecole d'Ingénieurs de PURPAN (FR)
- University of North Carolina at Chapel Hill (US)
- Inserm (FR)
- Corresponding author
- Bueno, Lionel
- ORCID
- Venue
- American Journal of Gastroenterology
- Published
- 2013-08
- Volume
- 108
- Issue
- 8
- Pages
- 1322-1331
- ISSN
- 0002-9270 (ISSN-L)
- OpenAlex
- W2011776892
- Cited by
- 96
- References
- 44
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 7 · 2018: 4 · 2017: 7 · 2016: 10 · 2015: 5 · 2014: 13 · 2013: 1
- FWCI
- 9.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The American Journal of Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HAL (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- cysteine protease, irritable bowel syndrome with constipation, tight junctions, visceral hypersensitivity, abdominal pain, fecal supernatants, colorectal distension, papain, disease severity
- MeSH terms
- Adult, Analysis of Variance, Animals, Biopsy, Cells, Cultured, Constipation, Electromyography, Feces, Female, Humans, Intestinal Absorption, Male, Mice, Inbred C57BL, Middle Aged, Pain Measurement, Surveys and Questionnaires, ROC Curve, Blotting, Western, Abdominal Pain, Case-Control Studies, Polymerase Chain Reaction, Tight Junctions, Irritable Bowel Syndrome, Mice, Cysteine Proteases, Occludin
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