Subjects with Diarrhea-Predominant IBS Have Increased Rectal Permeability Responsive to Tryptase
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Background and Aims
Patients with diarrhea-predominant irritable bowel syndrome (IBS-D) appear to have increased intestinal permeability; it has been suggested that activation of protease-activated receptor-2 (PAR-2) receptors is responsible for this alteration. The aims of this study are to evaluate (1) if rectal (large bowel) permeability is increased in IBS-D and (2) if tryptase plays a critical role in the altered permeability.
Rectal biopsies from 20 patients with IBS-D and 30 subjects without the condition (normal controls) were assessed for macromolecular permeability using horseradish peroxidase in Ussing chambers in the basal state and after addition of drugs to the basolateral side. Reverse-transcription polymerase chain reaction (RT-PCR) was performed using colonic biopsy tissues from patients with IBS-D and normal subjects.
When tryptase was added to the basolateral (not mucosal) side of normal rectal biopsy tissues, permeability appeared to be proportional to the increase in tryptase concentration (P < 0.05) and was abolished by the addition of tryptase inhibitor (100 μM nafamostat; 1.568 ± 0.874 ng/2 h/mm2 to 0.766 ± 0.661 ng/2 h/mm2, n = 14, respectively, P < 0.01). Intestinal permeability in patients with IBS-D was significantly increased compared with controls (0.848 ± 0.0.600 ng/2 h/mm2, n = 21, P < 0.01). Nafamostat significantly reduced the enhanced permeability in IBS-D (0.934 ± 0.589 ng/2 h/mm2 to 0.247 ± 0.263 ng/2 h/mm2, n = 14, respectively, P < 0.05). Transcription levels of PAR2 measured by RT-PCR did not differ between IBS-D and normal subjects.
Tryptase seems to play an important role in the control of human colonic mucosal permeability, and enhanced tryptase activity was responsible for the increased permeability of rectal mucosa in IBS patients.
- Marshall JK, Thabane M, Garg AX, Clark W, Meddings J, Collins SM. Investigators WEL: intestinal permeability in patients with irritable bowel syndrome after a waterborne outbreak of acute gastroenteritis in Walkerton, Ontario. Aliment Pharmacol Ther. 2004;20:1317–1322. CrossRef
- Dunlop SP, Hebden J, Campbell E, et al. Abnormal intestinal permeability in subgroups of diarrhea-predominant irritable bowel syndromes. Am J Gastroenterol. 2006;101:1288–1294. CrossRef
- Gecse K, Roka R, Ferrier L, et al. Increased faecal serine protease activity in diarrhoeic IBS patients: a colonic lumenal factor impairing colonic permeability and sensitivity. Gut. 2008;57:591–599. CrossRef
- Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 2004;126:693–702. CrossRef
- Jacob C, Yang PC, Darmoul D, et al. Mast cell tryptase controls paracellular permeability of the intestine. Role of protease-activated receptor 2 and beta-arrestins. J Biol Chem. 2005;280:31936–31948. CrossRef
- Miller HR, Pemberton AD. Tissue-specific expression of mast cell granule serine proteinases and their role in inflammation in the lung and gut. Immunology. 2002;105:375–390. CrossRef
- O’Sullivan M, Clayton N, Breslin NP, et al. Increased mast cells in the irritable bowel syndrome. Neurogastroenterol Motil. 2000;12:449–457. CrossRef
- Park JH, Rhee PL, Kim HS, et al. Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. J Gastroenterol Hepatol. 2006;21:71–78. CrossRef
- Hollander D. Intestinal permeability, leaky gut, and intestinal disorders. Curr Gastroenterol Rep. 1999;1:410–416. CrossRef
- Bajka BH, Gillespie CM, Steeb CB, Read LC, Howarth GS. Applicability of the using chamber technique to permeability determinations in functionally distinct regions of the gastrointestinal tract in the rat. Scand J Gastroenterol. 2003;38:732–741. CrossRef
- Deitch EA, Xu D, Naruhn MB, Deitch DC, Lu Q, Marino AA. Elemental diet and IV-TPN-induced bacterial translocation is associated with loss of intestinal mucosal barrier function against bacteria. Ann Surg. 1995;221:299–307. CrossRef
- Mishima S, Xu D, Lu Q, Deitch EA. Bacterial translocation is inhibited in inducible nitric oxide synthase knockout mice after endotoxin challenge but not in a model of bacterial overgrowth. Arch Surg. 1997;132:1190–1195.
- Langeler EG, van Hinsbergh VW. Characterization of an in vitro model to study the permeability of human arterial endothelial cell monolayers. Thromb Haemost. 1988;60:240–246.
- Brun P, Castagliuolo I, Di Leo V, et al. Increased intestinal permeability in obese mice: new evidence in the pathogenesis of nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol. 2007;292:G518–G525. CrossRef
- Willemsen LE, Hoetjes JP, van Deventer SJ, van Tol EA. Abrogation of IFN-gamma mediated epithelial barrier disruption by serine protease inhibition. Clin Exp Immunol. 2005;142:275–284. CrossRef
- Park JH, Rhee PL, Lee JH, et al. Segmental heterogeneity of electrogenic secretions in human ascending colon and rectum. Int J Colorectal Dis. 2006;21:357–364. CrossRef
- Egan WJ, Lauri G, Egan WJ, Lauri G. Prediction of intestinal permeability. Adv Drug Deliv Rev. 2002;54:273–289. CrossRef
- Cenac N, Chin AC, Garcia-Villar R, et al. PAR2 activation alters colonic paracellular permeability in mice via IFN-gamma-dependent and -independent pathways. J Physiol. 2004;558:913–925. CrossRef
- Cenac N, Garcia-Villar R, Ferrier L, et al. Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability. J Immunol. 2003;170:4296–4300.
- Talley NJ, Spiller R. Irritable bowel syndrome: a little understood organic bowel disease? Lancet. 2002;360:555–564. CrossRef
- Dunlop SP, Jenkins D, Spiller RC. Distinctive histological patterns of chronic inflammtory cells in rectal biopsies of patients with different clinical subtypes of IBS. Gastroenterology. 2002;122:A136.
- Dunlop SP, Jenkins D, Spiller RC. Distinctive clinical, psychological, and histological features of postinfective irritable bowel syndrome. Am J Gastroenterol. 2003;98:1578–1583. CrossRef
- Cenac N, Andrews CN, Holzhausen M, et al. Role for protease activity in visceral pain in irritable bowel syndrome. J Clin Invest. 2007;117:636–647. CrossRef
- Barbara G. Proteases in irritable bowel syndrome: a lot more than just digestive enzymes. Clin Gastroenterol Hepatol. 2007;5:548–549. CrossRef
- Roka R, Ait-Belgnaoui A, Salvador-Cartier C, et al. Dexamethasone prevents visceral hyperalgesia but not colonic permeability increase induced by luminal protease-activated receptor-2 agonist in rats. Gut. 2007;56:1072–1078. CrossRef
- Cenac N, Coelho AM, Nguyen C, et al. Induction of intestinal inflammation in mouse by activation of proteinase-activated receptor-2. Am J Pathol. 2002;161:1903–1915.
- Chin AC, Vergnolle N, MacNaughton WK, Wallace JL, Hollenberg MD, Buret AG. Proteinase-activated receptor 1 activation induces epithelial apoptosis and increases intestinal permeability. Proc Natl Acad Sci USA. 2003;100:11104–11109. CrossRef
- Coelho AM, Vergnolle N, Guiard B, Fioramonti J, Bueno L. Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats. Gastroenterology. 2002;122:1035–1047. CrossRef
- Schmidlin F, Amadesi S, Dabbagh K, et al. Protease-activated receptor 2 mediates eosinophil infiltration and hyperreactivity in allergic inflammation of the airway. J Immunol. 2002;169:5315–5321.
- Mori S, Itoh Y, Shinohata R, Sendo T, Oishi R, Nishibori M. Nafamostat mesilate is an extremely potent inhibitor of human tryptase. J Pharmacol Sci. 2003;92:420–423. CrossRef
- Sendo T, Itoh Y, Goromaru T, et al. A potent tryptase inhibitor nafamostat mesilate dramatically suppressed pulmonary dysfunction induced in rats by a radiographic contrast medium. Br J Pharmacol. 2003;138:959–967. CrossRef
- Spiller RC, Jenkins D, Thornley JP, et al. Increased rectal mucosal enteroendocrine cells, T lymphocytes, and increased gut permeability following acute campylobacter enteritis and in post-dysenteric irritable bowel syndrome. Gut. 2000;47:804–811. CrossRef
- Kingham JG, Loehry CA. Permeability of the small intestine after intra-arterial injection of histamine-type mediators and irradiation. Gut. 1976;17:517–526. CrossRef
- Wallon C, Braaf Y, Wolving M, Olaison G, Soderholm JD. Endoscopic biopsies in ussing chambers evaluated for studies of macromolecular permeability in the human colon. Scand J Gastroenterol. 2005;40:586–595. CrossRef
- Weston AP, Biddle WL, Bhatia PS, Miner PB Jr. Terminal ileal mucosal mast cells in irritable bowel syndrome. Dig Dis Sci. 1993;38:1590–1595. CrossRef
- Subjects with Diarrhea-Predominant IBS Have Increased Rectal Permeability Responsive to Tryptase
Digestive Diseases and Sciences
Volume 55, Issue 10 , pp 2922-2928
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- Irritable bowel syndrome
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- 1. Department of Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
- 2. Department of BioNano Technology and Gaehon BioNano Research Institute, Kyungwon University, Seongnam, Gyeonggi-Do, 461-701, Republic of Korea