Increased small intestinal permeability in ulcerative colitis: Rather genetic than environmental and a risk factor for extensive disease?†
Corresponding Author
Carsten Büning MD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Schumannstr. 20/21, 10117 Berlin, GermanySearch for more papers by this authorNora Geissler MD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Search for more papers by this authorMatthias Prager MD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Search for more papers by this authorAndreas Sturm Prof
Department of Gastroenterology and Hepatology, Charité, Campus Virchow-Klinikum, Berlin, Germany
Search for more papers by this authorDaniel C. Baumgart Prof
Department of Gastroenterology and Hepatology, Charité, Campus Virchow-Klinikum, Berlin, Germany
Search for more papers by this authorJanine Büttner PhD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Search for more papers by this authorSabine Bühner PhD
Department of Human Biology, University of Technology, Munich, Germany
Search for more papers by this authorVerena Haas PhD
Franz-Volhard Clinical Research Center, Charité, Campus Buch, Berlin, Germany
Search for more papers by this authorHerbert Lochs Prof
Rectorate, Medical University Innsbruck, Innsbruck, Austria
Search for more papers by this authorCorresponding Author
Carsten Büning MD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Schumannstr. 20/21, 10117 Berlin, GermanySearch for more papers by this authorNora Geissler MD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Search for more papers by this authorMatthias Prager MD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Search for more papers by this authorAndreas Sturm Prof
Department of Gastroenterology and Hepatology, Charité, Campus Virchow-Klinikum, Berlin, Germany
Search for more papers by this authorDaniel C. Baumgart Prof
Department of Gastroenterology and Hepatology, Charité, Campus Virchow-Klinikum, Berlin, Germany
Search for more papers by this authorJanine Büttner PhD
Department of Gastroenterology, Hepatology & Endocrinology, Charité, Campus Mitte, Berlin, Germany
Search for more papers by this authorSabine Bühner PhD
Department of Human Biology, University of Technology, Munich, Germany
Search for more papers by this authorVerena Haas PhD
Franz-Volhard Clinical Research Center, Charité, Campus Buch, Berlin, Germany
Search for more papers by this authorHerbert Lochs Prof
Rectorate, Medical University Innsbruck, Innsbruck, Austria
Search for more papers by this authorSupported by a grant from the Eli and Edythe Broad Foundation (to C.B., BMRP Proposal No. IBD-0164R) and by the Charité, Universitätsmedizin Berlin. The work is part of the doctoral thesis of Nora Geissler.
Abstract
Background:
A disturbed epithelial barrier could play a pivotal role in ulcerative colitis (UC). We performed a family-based study analyzing in vivo gastrointestinal permeability in patients with UC, their healthy relatives, spouses, and controls.
Methods:
In total, 89 patients with UC in remission, 35 first-degree relatives (UC-R), 24 nonrelated spouses (UC-NR), and 99 healthy controls (HC) were studied. Permeability was assessed by a sugar-drink test using sucrose (gastroduodenal permeability), lactulose/mannitol (intestinal permeability), and sucralose (colonic permeability). Data were correlated with clinical characteristics including medical treatment.
Results:
Increased intestinal permeability was detected significantly more often in UC patients in remission (25/89, 28.1%) compared with HC (6/99, 6.1%; P < 0.001). Similar results were obtained in UC-R (7/35, 20.0%; P = 0.01 compared with HC) regardless of sharing the same household with the patients or not. No difference was found between UC-NR (3/24, 12.5%) and HC. Notably, in UC patients increased intestinal permeability was found in 12/28 patients (42.9%) with pancolitis, 7/30 (23.3%) patients with left-sided colitis, and in 2/19 (10.5%) patients with proctitis (P = 0.04). Gastroduodenal and colonic permeability were similar in all groups. Among patients on azathioprine, increased intestinal permeability was only seen in 1/18 (5.6%) patients. In contrast, in 24/70 (34.3%) patients without azathioprine, an increased intestinal permeability was found (P = 0.005).
Conclusions:
An increased intestinal but not colonic permeability was found in UC patients in clinical remission that could mark a new risk factor for extensive disease location. Similar findings in healthy relatives but not spouses suggest that this barrier defect is genetically determined. (Inflamm Bowel Dis 2012)
REFERENCES
- 1 Teahon K, Smethurst P, Levi AJ, et al. Intestinal permeability in patients with Crohn's disease and their first degree relatives. Gut. 1992; 33: 320–323.
- 2 Söderholm JD, Olaison G, Lindberg E, et al. Different intestinal permeability patterns in relatives and spouses of patients with Crohn's disease: an inherited defect in mucosal defence? Gut. 1999; 44: 96–100.
- 3 Peeters M, Geypens B, Claus D, et al. Clustering of increased small intestinal permeability in families with Crohn's disease. Gastroenterology. 1997; 113: 802–807.
- 4 D'Incà R, Annese V, di Leo V, et al. Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease. Aliment Pharmacol Ther. 2006; 23: 1455–1461.
- 5 Fries W, Renda MC, Lo Presti MA, et al. Intestinal permeability and genetic determinants in patients, first-degree relatives, and controls in a high-incidence area of Crohn's disease in southern Italy. Am J Gastroenterol. 2005; 100: 2730–2736.
- 6 Irvine EJ, Marshall JK. Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterology. 2000; 119: 1740–1744.
- 7 Wyatt J, Vogelsang H, Hübl W, et al. Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet. 1993; 341: 1437–1439.
- 8 Buhner S, Buning C, Genschel J, et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut. 2006; 55: 342–347.
- 9 Stange EF, Travis S, Vermeire S. European evidence-based Consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. J Crohns Colitis. 2008; 2: 1–23.
- 10 Silverberg MS, Satsangi J, Ahmad T, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005; 19( Suppl A): 5–36.
- 11 Haas V, Büning C, Buhner S, et al. Clinical relevance of measuring colonic permeability. Eur J Clin Invest. 2009; 39: 139–144.
- 12 Arslan G, Atasever T, Cindoruk M, et al. (51)CrEDTA colonic permeability and therapy response in patients with ulcerative colitis. Nucl Med Commun. 2001; 22: 997–1001.
- 13 Casellas F, Aguadé S, Soriano B, et al. Intestinal permeability to 99mTc-diethylenetriaminopentaacetic acid in inflammatory bowel disease. Am J Gastroenterol. 1986; 81: 767–770.
- 14 Issenman RM, Jenkins RT, Radoja C. Intestinal permeability compared in pediatric and adult patients with inflammatory bowel disease. Clin Invest Med. 1993; 16: 187–196.
- 15 Jenkins RT, Jones DB, Goodacre RL, et al. Reversibility of increased intestinal permeability to 51Cr-EDTA in patients with gastrointestinal inflammatory diseases. Am J Gastroenterol. 1987; 82: 1159–1164
- 16 Jenkins AP, Nukajam WS, Menzies IS, et al. Simultaneous administration of lactulose and 51Cr-ethylenediaminetetraacetic acid. A test to distinguish colonic from small-intestinal permeability change. Scand J Gastroenterol. 1992; 27: 769–773.
- 17 Miki K, Moore D, Butler R, et al. The sugar permeability test reflects disease activity in children and adolescents with inflammatory bowel disease. J Pediatr. 1998; 133: 750–754.
- 18 Resnick RH, Royal H, Marshall W, et al. Intestinal permeability in gastrointestinal disorders. Use of oral [99mTc]DTPA. Dig Dis Sci. 1990; 35: 205–211.
- 19 Teahon K, Somasundaram S, Smith T, et al. Assessing the site of increased intestinal permeability in coeliac and inflammatory bowel disease. Gut. 1996; 38: 864–869.
- 20 Welcker K, Martin A, Kölle P, et al. Increased intestinal permeability in patients with inflammatory bowel disease. Eur J Med Res. 2004; 9: 456–460.
- 21 Jenkins R, Goodacre R, Rooney P, et al. Studies of intestinal diseases using permeability in inflammatory bowel diseases using polyethylene glycol 400. Clin Biochem. 1986; 19: 298–302.
- 22 Lobley RW, Burrows PC, Warwick R, et al. Simultaneous assessment of intestinal permeability and lactose tolerance with orally administered raffinose, lactose and L-arabinose. Clin Sci (Lond). 1990; 79: 175–183.
- 23 Munkholm, P, Langholz E, Hollander D, et al. Intestinal permeability in patients with Crohn's disease and ulcerative colitis and their first degree relatives. Gut. 1994; 35: 68–72.
- 24 Peled Y, Watz C, Gilat T. Measurement of intestinal permeability using 51Cr-EDTA. Am J Gastroenterol. 1985; 80: 770–773.
- 25 Gursoy S, Guven K, Kula M, et al. Subclinical alveolar involvement in ulcerative colitis. Inflamm Bowel Dis. 2005; 11: 372–375.
- 26 Miele E, Pascarella F, Quaglietta L, et al. Altered intestinal permeability is predictive of early relapse in children with steroid-responsive ulcerative colitis. Aliment Pharmacol Ther. 2001; 25: 933–939.
- 27 Røseth AG, Aadland E, Jahnsen J, et al. Assessment of disease activity in ulcerative colitis by faecal calprotectin, a novel granulocyte marker protein. Digestion. 1997; 58: 176–180.
- 28 Silberer H, Küppers B, Mickisch O, et al. Fecal leukocyte proteins in inflammatory bowel disease and irritable bowel syndrome. Clin Lab. 2005; 51: 117–126.
- 29 Langhorst J, Elsenbruch S, Kolezer J, et al. Noninvasive markers in the assessment of intestinal inflammation in inflammatory bowel diseases: pPerformance of fecal lactoferrin, calprotectin, and PMN-Elastase, CRP, and clinical indices. Am J Gastroenterol. 2008; 103: 162–169.
- 30 Schoepfer A, Beglinger C, Straumann A, et al. Fecal calprotectin correlates more closely with the simple endoscopic score for Crohn's disease (SES-CD) than CRP, blood leukocytes, and the CDAI. Am J Gastroenterol. 2010; 105: 162–169.
- 31 Walkiewicz D, Werlin SL, Fish D, et al. Fecal calprotectin is useful in predicting disease relapse in pediatric inflammatory bowel disease. Inflamm Bowel Dis. 2008; 14: 669–673.
- 32 D'Incà R, Dal Pont E, Di Leo V, et al. Can calprotectin predict relapse risk in inflammatory bowel disease? Am J Gastroenterol. 2008; 103: 2007–2014.
- 33 Etchevers M, Aceituno M, Garcia-Bosch O, et al. Risk factors and characteristics of extent progression in ulcerative colitis. Inflamm Bowel Dis. 2009; 15: 1320–1325.
- 34 Pierik M, Joossens S, Vermiere S, et al. Toll-like receptor-1, -2 and -6 polymorphisms influence disease extension in inflammatory bowel diseases. Inflamm Bowel Dis. 2006; 12: 1–8.
- 35 Arrieta MC, Madsen K, Doyle J, et al. Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse. Gut. 2009; 58: 41–48.
- 36 Mazzon E, Cuzzocrea S. Thalidomide treatment reduces the alteration of paracellular barrier function in mice ileum during experimental colitis. Shock. 2006; 25: 515–521.
- 37 Mazzon E, Cuzzocrea S. Absence of functional peroxisome proliferator-activated receptor-alpha enhanced ileum permeability during experimental colitis. Shock. 2007; 28: 192–201.
- 38 Suenaert P, Bulteel V, Lemmens L, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's Disease. Am J Gastroenterol. 2002; 97: 2000–2004.
- 39 Teahon K, Smethurst P, Levi AJ, et al. The effect of elemental diet on intestinal permeability and inflammation in Crohn's disease. Gastroenterology. 1991; 101: 84–89.
- 40 Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992; 43: 329–339.
- 41 Ben-Horin S, Goldstein I, Fudim E, et al. Early preservation of effector functions followed by eventual T cell memory depletion: a model for the delayed onset of the effect of thiopurines. Gut. 2009; 58: 398–403.
- 42 Swidsinski A, Loening-Baucke V, Bengmrak S, et al. Azathioprine and mesalazine-induced effects on the mucosal flora in patients with IBD colitis. Inflamm Bowel Dis. 2007; 13: 51–56.
- 43 Jenkins RT, Ramage JK, Jones DB, et al. Small bowel and colonic permeability to 51Cr-EDTA in patients with active inflammatory bowel disease. Clin Invest Med. 1988; 11: 151–155.
- 44 Schulzke J, Ploeger S, Amasheh M, et al. Epithelial tight junctions in intestinal inflammation. Ann N Y Acad Sci. 2009; 1165: 294–300.
- 45 Schurmann G, Bruwer M, Klotz A, et al. Transepithelial transport processes at the intestinal mucosa in inflammatory bowel disease. Int J Colorectal Dis. 1999; 14: 41–46.
- 46 Nejdfors P, Wang Q, Ekelund M, et al. Increased colonic permeability in patients with ulcerative colitis: an in vitro study. Scand J Gastroenterol. 1998; 33: 749–753.
- 47 Wallon C, Persborn M, Jönsson M, et al. Eosinophils express muscarinic receptors and corticotropin-releasing factor to disrupt the mucosal barrier in ulcerative colitis. Gastroenterology. 2011; 140: 1597–1607.
- 48 Fisher S, Tremelling M, Anderson C, et al. Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease. Nat Genet. 2008; 40: 710–712.
- 49 The UK IBD Genetics Consortium & the Wellcome Trust Case Control Consortium. Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet. 2009; 41: 1330–1336.
- 50 Wapenaar MC, Monsuur AJ, van Bodegraven AA, et al. Associations with tight junction genes PARD3 and MAGI2 in Dutch patients point to a common barrier defect for coeliac disease and ulcerative colitis. Gut. 2008; 57: 463–467.
- 51 McGovern D, Taylor K, Landers C, et al. MAGI2 genetic variation and inflammatory bowel disease. Inflamm Bowel Dis. 2009; 15: 75–83.
