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Gut. 2017 Oct;66(10):1767-1778. doi: 10.1136/gutjnl-2016-312094. Epub 2017 Jan 17.

Epithelial expression and function of trypsin-3 in irritable bowel syndrome.

Author information

1
IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France.
2
Laboratory for Enteric Neuroscience (LENS), TARGID, University of Leuven, Leuven, Belgium.
3
Gastrointestinal Diseases Research Unit, , General Hospital, Queen's University School of Medicine, Kingston, Ontario, Canada.
4
Oppenheimer Family Center for Neurobiology of Stress and Resilience and CURE: Digestive Diseases Research Center, Vatche and Tamar Manoukian Division of Digestive Diseases, UCLA David Geffen School of Medicine, Los Angeles, California, USA.
5
Inserm, UMR913, Nantes, France.
6
Nantes University, Nantes, France.
7
Institut des Maladies de l'Appareil Digestif, IMAD, CHU Nantes, Hopital Hôtel-Dieu, Nantes, France.
8
Department of Internal Medicine and Digestive Diseases, Pole Digestif, CHU Toulouse, Toulouse, France.
9
Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.

Abstract

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 Ca2+ 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.

KEYWORDS:

ABDOMINAL PAIN; IRRITABLE BOWEL SYNDROME; NERVE - GUT INTERACTIONS; TRYPSIN

PMID:
28096305
PMCID:
PMC5595105
DOI:
10.1136/gutjnl-2016-312094
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: None declared.

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