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Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS
Open accessAbstract
Objective: The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS. Design: 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states. Results: Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota. Conclusion: A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.
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“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 [13]
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“Elevated PA was also observed in stool supernatants from IBD and IBS patients compared to samples from healthy subjects, suggesting that enhanced PA in IBD and IBS may be due to elevations in PA from both host and microbial origin.12,13”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [13]
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“suggesting that enhanced PA in IBD and IBS may be due to elevations in PA from both host and microbial origin.12,13”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [13]
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Interaction of Intestinal Microbiota with Medications
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Proteolytische Aktivität bei Reizdarm
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Gut microbiota plays a role in irritable bowel syndrome by regulating 5-HT metabolism
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IRRITABLE BOWEL SYNDROME: THE ROLE OF GUT MICROBIOTA IN ETIOLOGY AND TREATMENT. A LITERATURE REVIEW
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Self-citationPlace de la diversité bactérienne et de sa dynamique dans la surveillance épidémiologique
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Metadata
- Authors
- 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., Graham, R., Chen, J., Kashyap, P., Farrugia, G., & Grover, M.
- Affiliations
- Mayo Clinic (US)
- Corresponding author
- Grover, Madhusudan
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2019-03-28
- Volume
- 69
- Issue
- 1
- Pages
- 62-73
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC6765451
- OpenAlex
- W2933912422
- Cited by
- 101
- References
- 60
- Citations by year
- 2026: 7 · 2025: 17 · 2024: 14 · 2023: 13 · 2022: 21 · 2021: 20 · 2020: 8 · 2019: 1
- FWCI
- 11.39
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Gut (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Keywords
- irritable bowel syndrome, serine protease, intestinal barrier dysfunction, colonic permeability, tight junction proteins, occludin, myosin light chain phosphorylation, protease-activated receptor 2, irritable bowel syndrome with constipation, gut microbiota, microbial diversity, symptom severity
- MeSH terms
- Gastrointestinal Microbiome, Adult, Animals, Biopsy, Colon, Feces, Female, Humans, Intestinal Absorption, Intestinal Mucosa, Male, Middle Aged, Permeability, Prospective Studies, Severity of Illness Index, Case-Control Studies, Caco-2 Cells, Irritable Bowel Syndrome, Mice, Serine Proteases, Proteolysis, Tight Junction Proteins, Dysbiosis
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