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

被引：80

作者：

Annahazi, Anita ^{[1
,2
,3
]}

Ferrier, Laurent ^{[1
,2
]}

Bezirard, Valerie ^{[1
,2
]}

Leveque, Mathilde ^{[1
,2
]}

Eutamene, Helene ^{[1
,2
]}

Ait-Belgnaoui, Afifa ^{[1
,2
]}

Coeffier, Moise ^{[4
,5
]}

Ducrotte, Philippe ^{[4
,6
]}

Roka, Richard ^{[3
]}

Inczefi, Orsolya ^{[3
]}

Gecse, Krisztina ^{[3
]}

Rosztoczy, Andras ^{[3
]}

Molnar, Tamas ^{[3
]}

Ringel-Kulka, Tamar ^{[7
]}

Ringel, Yehuda ^{[8
]}

Piche, Thierry ^{[9
]}

Theodorou, Vassilia ^{[1
,2
]}

Wittmann, Tibor ^{[3
]}

Bueno, Lionel ^{[1
,2
]}

机构：

[1] INRA, UMR1331, Neurogastroenterol & Nutr Grp, F-31027 Toulouse 3, France

[2] Neurogastroenterol & Nutr Grp, INP, EI Purpan, UMR1331, Toulouse, France

[3] Univ Szeged, Dept Internal Med 1, Szeged, Hungary

[4] Univ Rouen, INSERM, UMR1073, Rouen, France

[5] Rouen Univ Hosp, Nutr Unit, Rouen, France

[6] Rouen Univ Hosp, Dept Gastroenterol, Rouen, France

[7] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Maternal & Child Hlth, Chapel Hill, NC USA

[8] Univ N Carolina, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Chapel Hill, NC USA

[9] Hop Archet II, INSERM, Dept Gastroenterol, U576, Nice, France

来源：

AMERICAN JOURNAL OF GASTROENTEROLOGY | 2013年 / 108卷 / 08期

关键词：

IRRITABLE-BOWEL-SYNDROME; INTESTINAL PERMEABILITY; CARE-SEEKING; GUT; SERINE; INFLAMMATION; PROTEINASES; PREVALENCE; MICROBIOTA; MECHANISM;

D O I：

10.1038/ajg.2013.152

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

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.

引用

页码：1322 / 1331

页数：10

共 45 条

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