Luminal Cysteine-Proteases Degrade Colonic Tight Junction Structure and Are Responsible for Abdominal Pain in Constipation-Predominant IBS

Annaházi, Anita; Ferrier, Laurent; Bézirard, Valérie; Lévêque, Mathilde; Eutamène, Hélène; Ait-Belgnaoui, Afifa; Coëffier, Moı̈se; Ducrotté, Philippe; Róka, R; Inczefi, Orsolya; Gecse, Krisztina; Rosztóczy, A; Molnár, Tamás; Ringel–Kulka, Tamar; Ringel, Yehuda; Piche, Thierry; Théodorou, Vassilia; Wittmann, Tibor; Buéno, Lionel

doi:10.1038/ajg.2013.152

Cited by 80 publications

(83 citation statements)

References 39 publications

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“…In line with these findings, serine proteases in faecal supernatants from individuals with IBS-D evoked colonic hypersensitivity to distension 44 . By contrast, faecal cysteine protease activity was augmented in some patients with IBS-C compared with controls and increased protease activity correlated with abdominal pain and impaired epithelial permeability 45 . Further work showed the implication of serine proteases that act on protease-activated nociceptors located on intestinal nerves conveying pain stimuli to the brain 43 .…”

Section: Mechanisms/pathophysiologymentioning

confidence: 73%

Irritable bowel syndrome

Enck¹,

Aziz

Barbara

et al. 2016

Nat Rev Dis Primers

781

774

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Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with a high population prevalence. The disorder can be debilitating in some patients, whereas others may have mild or moderate symptoms. The most important single risk factors are female sex, younger age and preceding gastrointestinal infections. Clinical symptoms of IBS include abdominal pain or discomfort, stool irregularities and bloating, as well as other somatic, visceral and psychiatric comorbidities. Currently, the diagnosis of IBS is based on symptoms and the exclusion of other organic diseases, and therapy includes drug treatment of the predominant symptoms, nutrition and psychotherapy. Although the underlying pathogenesis is far from understood, aetiological factors include increased epithelial hyperpermeability, dysbiosis, inflammation, visceral hypersensitivity, epigenetics and genetics, and altered brain–gut interactions. IBS considerably affects quality of life and imposes a profound burden on patients, physicians and the health-care system. The past decade has seen remarkable progress in our understanding of functional bowel disorders such as IBS that will be summarized in this Primer.

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Section: Mechanisms/pathophysiologymentioning

confidence: 73%

Irritable bowel syndrome

Enck¹,

Aziz

Barbara

et al. 2016

Nat Rev Dis Primers

781

774

View full text Add to dashboard Cite

show abstract

“…151,152 Different proteases seems to be of importance in different clinical situations: serine proteases have been found to be elevated in IBS-D, 152 and cysteine proteases in patients with IBS-C. 151 Cysteine proteases have a degrading effect on occludin in mice and also in the human colonic epithelial T84 cell line, and this pathogenetic mechanism can be supported by the finding of decreased occludin levels in mucosal biopsy samples from patients with IBS-C. 151 A steadily increasing number of studies support that increased intestinal permeability in patients with IBS is linked to enhanced activity of the immune system, and a link with food allergy has been suggested. 153 Experiments in colon explants from mice have shown that the interaction between TNF and neuropeptide Y results in increased intestinal permeability.…”

Section: Putative Causes Of Altered Gut Permeabilitymentioning

confidence: 97%

Crosstalk at the mucosal border: importance of the gut microenvironment in IBS

Öhman

Törnblom

Simrén

2014

Nat Rev Gastroenterol Hepatol

155

145

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The aetiology and pathology of IBS, a functional bowel disorder thought to lack an organic cause, is largely unknown. However, studies suggest that various features, such as altered composition of the gut microbiota, together with increased intestinal permeability, a changed balance in the enteroendocrine system and a dysregulated immune system in the gut, most likely have an important role in IBS. Exactly how these entities act together and give rise to symptoms is still unknown, but an altered gut microbiota composition could lead to dysregulation of the intestinal barrier as well as the enteroendocrine and the immune systems, which (through interactions with the nervous system) might generate symptoms. This Review highlights the crosstalk between the gut microbiota, the enteroendocrine system, the immune system and the role of intestinal permeability in patients with IBS.

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“…Recently, the Spiller group published a paper demonstrating the human (and not bacterial) origin of the most abundant fecal serine proteases in IBS-D patients[52]. Cysteine protease activity was elevated in fecal samples of IBS-C patients[53], although this alteration could not be observed in colonic samples of post-infectious IBS mice[51]. Recently, concerns have been raised about the tests used to determine the protease activity.…”

Section: Proteases Protease-activated Receptors and Protease Inhibitmentioning

confidence: 99%

Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

Ceuleers

Spaendonk

Hanning

et al. 2016

WJG

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Proteases, enzymes catalyzing the hydrolysis of peptide bonds, are present at high concentrations in the gastrointestinal tract. Besides their well-known role in the digestive process, they also function as signaling molecules through the activation of protease-activated receptors (PARs). Based on their chemical mechanism for catalysis, proteases can be classified into several classes: serine, cysteine, aspartic, metallo- and threonine proteases represent the mammalian protease families. In particular, the class of serine proteases will play a significant role in this review. In the last decades, proteases have been suggested to play a key role in the pathogenesis of visceral hypersensitivity, which is a major factor contributing to abdominal pain in patients with inflammatory bowel diseases and/or irritable bowel syndrome. So far, only a few preclinical animal studies have investigated the effect of protease inhibitors specifically on visceral sensitivity while their effect on inflammation is described in more detail. In our accompanying review we describe their effect on gastrointestinal permeability. On account of their promising results in the field of visceral hypersensitivity, further research is warranted. The aim of this review is to give an overview on the concept of visceral hypersensitivity as well as on the physiological and pathophysiological functions of proteases herein.

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Luminal Cysteine-Proteases Degrade Colonic Tight Junction Structure and Are Responsible for Abdominal Pain in Constipation-Predominant IBS

Abstract: These data suggest that luminal CPs may represent a new factor contributing to the genesis of symptoms in IBS.

Cited by 80 publications

References 39 publications

Irritable bowel syndrome

Irritable bowel syndrome

Crosstalk at the mucosal border: importance of the gut microenvironment in IBS

Visceral hypersensitivity in inflammatory bowel diseases and irritable bowel syndrome: The role of proteases

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