Intestinal epithelium in inflammatory bowel disease

Mehmet Coskun, Mehmet Coskun

Abstract

The intestinal epithelium has a strategic position as a protective physical barrier to luminal microbiota and actively contributes to the mucosal immune system. This barrier is mainly formed by a monolayer of specialized intestinal epithelial cells (IECs) that are crucial in maintaining intestinal homeostasis. Therefore, dysregulation within the epithelial layer can increase intestinal permeability, lead to abnormalities in interactions between IECs and immune cells in underlying lamina propria, and disturb the intestinal immune homeostasis, all of which are linked to the clinical disease course of inflammatory bowel disease (IBD). Understanding the role of the intestinal epithelium in IBD pathogenesis might contribute to an improved knowledge of the inflammatory processes and the identification of potential therapeutic targets.

Keywords: Crohn’s disease; barrier dysfunction; inflammatory bowel disease; intestinal epithelium; tight junctions; ulcerative colitis.

Figures

Figure 1
Figure 1
Genetics, gut microbiota, and an uncontrolled immune response cause defects in epithelial barrier function by affecting the barrier integrity, increasing tissue destruction and mucosal inflammation.

References

    1. Ordás I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Ulcerative colitis. Lancet (2012) 380:1606–19.10.1016/S0140-6736(12)60150-0
    1. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet (2012) 380:1590–605.10.1016/S0140-6736(12)60026-9
    1. Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol (2010) 28:573–621.10.1146/annurev-immunol-030409-101225
    1. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol (2006) 3:390–407.10.1038/ncpgasthep0528
    1. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet (2010) 42:1118–25.10.1038/ng.717
    1. Anderson CA, Boucher G, Lees CW, Franke A, D’Amato M, Taylor KD, et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat Genet (2011) 43:246–52.10.1038/ng.764
    1. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature (2011) 474:307–1710.1038/nature10209
    1. Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature (2012) 491:119–24.10.1038/nature11582
    1. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med (2009) 361:2066–7810.1056/NEJMra0804647
    1. Frank DN, Robertson CE, Hamm CM, Kpadeh Z, Zhang T, Chen H, et al. Disease phenotype and genotype are associated with shifts in intestinal-associated microbiota in inflammatory bowel diseases. Inflamm Bowel Dis (2011) 17:179–84.10.1002/ibd.21339
    1. Nagalingam NA, Lynch SV. Role of the microbiota in inflammatory bowel diseases. Inflamm Bowel Dis (2012) 18:968–84.10.1002/ibd.21866
    1. Manichanh C, Borruel N, Casellas F, Guarner F. The gut microbiota in IBD. Nat Rev Gastroenterol Hepatol (2012) 9:599–608.10.1038/nrgastro.2012.152
    1. Brown EM, Sadarangani M, Finlay BB. The role of the immune system in governing host-microbe interactions in the intestine. Nat Immunol (2013) 14:660–7.10.1038/ni.2611
    1. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology (2014) 146:1489–99.10.1053/j.gastro.2014.02.009
    1. Maloy KJ, Powrie F. Intestinal homeostasis and its breakdown in inflammatory bowel disease. Nature (2011) 474:298–306.10.1038/nature10208
    1. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol (2009) 71:241–60.10.1146/annurev.physiol.010908.163145
    1. Noah TK, Donahue B, Shroyer NF. Intestinal development and differentiation. Exp Cell Res (2011) 317:2702–1010.1016/j.yexcr.2011.09.006
    1. Dupaul-Chicoine J, Dagenais M, Saleh M. Crosstalk between the intestinal microbiota and the innate immune system in intestinal homeostasis and inflammatory bowel disease. Inflamm Bowel Dis (2013) 19:2227–37.10.1097/MIB.0b013e31828dcac7
    1. Koch S, Nusrat A. The life and death of epithelia during inflammation: lessons learned from the gut. Annu Rev Pathol (2012) 7:35–60.10.1146/annurev-pathol-011811-120905
    1. Ahn SH, Shah YM, Inoue J, Morimura K, Kim I, Yim S, et al. Hepatocyte nuclear factor 4alpha in the intestinal epithelial cells protects against inflammatory bowel disease. Inflamm Bowel Dis (2008) 14:908–20.10.1002/ibd.20413
    1. Zheng X, Tsuchiya K, Okamoto R, Iwasaki M, Kano Y, Sakamoto N, et al. Suppression of hath1 gene expression directly regulated by hes1 via notch signaling is associated with goblet cell depletion in ulcerative colitis. Inflamm Bowel Dis (2011) 17:2251–60.10.1002/ibd.21611
    1. Coskun M, Olsen AK, Holm TL, Kvist PH, Nielsen OH, Riis LB, et al. TNF-alpha-induced down-regulation of CDX2 suppresses MEP1A expression in colitis. Biochim Biophys Acta (2012) 1822:843–51.10.1016/j.bbadis.2012.01.012
    1. Peterson LW, Artis D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat Rev Immunol (2014) 14:141–5310.1038/nri3608
    1. Zeissig S, Bürgel N, Günzel D, Richter J, Mankertz J, Wahnschaffe U, et al. Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease. Gut (2007) 56:61–72.10.1136/gut.2006.094375
    1. Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterology (2005) 129:550–64.10.1016/j.gastro.2005.05.002
    1. Schmitz H, Barmeyer C, Fromm M, Runkel N, Foss HD, Bentzel CJ, et al. Altered tight junction structure contributes to the impaired epithelial barrier function in ulcerative colitis. Gastroenterology (1999) 116:301–9.10.1016/S0016-5085(99)70126-5
    1. Marini M, Bamias G, Rivera-Nieves J, Moskaluk CA, Hoang SB, Ross WG, et al. TNF-alpha neutralization ameliorates the severity of murine Crohn’s-like ileitis by abrogation of intestinal epithelial cell apoptosis. Proc Natl Acad Sci U S A (2003) 100:8366–71.10.1073/pnas.1432897100
    1. Su L, Nalle SC, Shen L, Turner ES, Singh G, Breskin LA, et al. TNFR2 activates MLCK-dependent tight junction dysregulation to cause apoptosis-mediated barrier loss and experimental colitis. Gastroenterology (2013) 145:407–15.10.1053/j.gastro.2013.04.011
    1. Nava P, Koch S, Laukoetter MG, Lee WY, Kolegraff K, Capaldo CT, et al. Interferon-gamma regulates intestinal epithelial homeostasis through converging beta-catenin signaling pathways. Immunity (2010) 32:392–402.10.1016/j.immuni.2010.03.001
    1. Mankertz J, Schulzke JD. Altered permeability in inflammatory bowel disease: pathophysiology and clinical implications. Curr Opin Gastroenterol (2007) 23:379–83.10.1097/MOG.0b013e32816aa392
    1. Suenaert P, Bulteel V, Lemmens L, Noman M, Geypens B, Van Assche G, et al. Anti-tumor necrosis factor treatment restores the gut barrier in Crohn’s disease. Am J Gastroenterol (2002) 97:2000–4.10.1111/j.1572-0241.2002.05914.x
    1. Toedter G, Li K, Sague S, Ma K, Marano C, Macoritto M, et al. Genes associated with intestinal permeability in ulcerative colitis: changes in expression following infliximab therapy. Inflamm Bowel Dis (2012) 18:1399–410.10.1002/ibd.22853
    1. Pastorelli L, De Salvo C, Mercado JR, Vecchi M, Pizarro TT. Central role of the gut epithelial barrier in the pathogenesis of chronic intestinal inflammation: lessons learned from animal models and human genetics. Front Immunol (2013) 4:280.10.3389/fimmu.2013.00280
    1. Pizarro TT, Pastorelli L, Bamias G, Garg RR, Reuter BK, Mercado JR, et al. SAMP1/YitFc mouse strain: a spontaneous model of Crohn’s disease-like ileitis. Inflamm Bowel Dis (2011) 17:2566–84.10.1002/ibd.21638
    1. Sundberg JP, Elson CO, Bedigian H, Birkenmeier EH. Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice. Gastroenterology (1994) 107:1726–35.
    1. Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology (2006) 131:117–29.10.1053/j.gastro.2006.04.020
    1. Boltin D, Perets TT, Vilkin A, Niv Y. Mucin function in inflammatory bowel disease: an update. J Clin Gastroenterol (2013) 47:106–11.10.1097/MCG.0b013e3182688e73
    1. Wehkamp J, Stange EF. Paneth’s disease. J Crohns Colitis (2010) 4:523–31.10.1016/j.crohns.2010.05.010
    1. Muniz LR, Knosp C, Yeretssian G. Intestinal antimicrobial peptides during homeostasis, infection, and disease. Front Immunol (2012) 3:310.10.3389/fimmu.2012.00310
    1. Ostaff MJ, Stange EF, Wehkamp J. Antimicrobial peptides and gut microbiota in homeostasis and pathology. EMBO Mol Med (2013) 5:1465–8310.1002/emmm.201201773
    1. Arijs I, De Hertogh G, Lemaire K, Quintens R, Van Lommel L, Van Steen K, et al. Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment. PLoS One (2009) 4:e7984.10.1371/journal.pone.0007984
    1. Wehkamp J, Harder J, Weichenthal M, Mueller O, Herrlinger KR, Fellermann K, et al. Inducible and constitutive beta-defensins are differentially expressed in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis (2003) 9:215–23.10.1097/00054725-200307000-00001
    1. Wehkamp J, Schmid M, Fellermann K, Stange EF. Defensin deficiency, intestinal microbes, and the clinical phenotypes of Crohn’s disease. J Leukoc Biol (2005) 77:460–5.10.1189/jlb.0904543
    1. Mokry M, Middendorp S, Wiegerinck CL, Witte M, Teunissen H, Meddens CA, et al. Many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the intestinal epithelium. Gastroenterology (2013) 146:1040–7.10.1053/j.gastro.2013.12.003
    1. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci (2008) 65:3756–88.10.1007/s00018-008-8281-1
    1. Muise AM, Walters TD, Glowacka WK, Griffiths AM, Ngan BY, Lan H, et al. Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn’s disease. Gut (2009) 58:1121–7.10.1136/gut.2008.175117
    1. Banerjee S, Oneda B, Yap LM, Jewell DP, Matters GL, Fitzpatrick LR, et al. MEP1A allele for meprin A metalloprotease is a susceptibility gene for inflammatory bowel disease. Mucosal Immunol (2009) 2:220–31.10.1038/mi.2009.3
    1. Bertenshaw GP, Turk BE, Hubbard SJ, Matters GL, Bylander JE, Crisman JM, et al. Marked differences between metalloproteases meprin A and B in substrate and peptide bond specificity. J Biol Chem (2001) 276:13248–55.10.1074/jbc.M011414200
    1. Kruse MN, Becker C, Lottaz D, Köhler D, Yiallouros I, Krell HW, et al. Human meprin alpha and beta homo-oligomers: cleavage of basement membrane proteins and sensitivity to metalloprotease inhibitors. Biochem J (2004) 378:383–9.10.1042/BJ20031163
    1. Broder C, Becker-Pauly C. The metalloproteases meprin alpha and meprin beta: unique enzymes in inflammation, neurodegeneration, cancer and fibrosis. Biochem J (2013) 450:253–64.10.1042/BJ20121751
    1. Bao J, Yura RE, Matters GL, Bradley SG, Shi P, Tian F, et al. Meprin A impairs epithelial barrier function, enhances monocyte migration, and cleaves the tight junction protein occludin. Am J Physiol Renal Physiol (2013) 305:F714–26.10.1152/ajprenal.00179.2012
    1. Banerjee S, Jin G, Bradley SG, Matters GL, Gailey RD, Crisman JM, et al. Balance of meprin A and B in mice affects the progression of experimental inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol (2011) 300:G273–82.10.1152/ajpgi.00504.2009
    1. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhães JG, et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol (2010) 11:55–62.10.1038/ni.1823
    1. Hoefkens E, Nys K, John JM, Van Steen K, Arijs I, Van der Goten J, et al. Genetic association and functional role of Crohn disease risk alleles involved in microbial sensing, autophagy, and endoplasmic reticulum (ER) stress. Autophagy (2013) 9:2046–55.10.4161/auto.26337
    1. Goto Y, Kiyono H. Epithelial barrier: an interface for the cross-communication between gut flora and immune system. Immunol Rev (2012) 245:147–63.10.1111/j.1600-065X.2011.01078.x
    1. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature (2008) 456:259–63.10.1038/nature07416
    1. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science (2005) 307:731–4.10.1126/science.1104911
    1. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell (2008) 134:743–56.10.1016/j.cell.2008.07.021
    1. Adolph TE, Tomczak MF, Niederreiter L, Ko HJ, Böck J, Martinez-Naves E, et al. Paneth cells as a site of origin for intestinal inflammation. Nature (2013) 503:272–6.10.1038/nature12599
    1. Deuring JJ, Fuhler GM, Konstantinov SR, Peppelenbosch MP, Kuipers EJ, de Haar C, et al. Genomic ATG16L1 risk allele-restricted Paneth cell ER stress in quiescent Crohn’s disease. Gut (2014) 63:1081–91.10.1136/gutjnl-2012-303527
    1. Coskun M, Olsen J, Seidelin JB, Nielsen OH. MAP kinases in inflammatory bowel disease. Clin Chim Acta (2011) 412:513–20.10.1016/j.cca.2010.12.020
    1. Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res (2013) 76C:1–8.10.1016/j.phrs.2013.06.007
    1. Willson TA, Jurickova I, Collins M, Denson LA. Deletion of intestinal epithelial cell STAT3 promotes T-lymphocyte STAT3 activation and chronic colitis following acute dextran sodium sulfate injury in mice. Inflamm Bowel Dis (2013) 19:512–25.10.1097/MIB.0b013e31828028ad
    1. Nielsen OH, Coskun M, Steenholdt C, Rogler G. The role and advances of immunomodulator therapy for inflammatory bowel disease. Expert Rev Gastroenterol Hepatol (2014).10.1586/17474124.2014.945914
    1. Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med (2013) 369:754–6210.1056/NEJMct1209614
    1. Nielsen OH, Ainsworth MA. Which biological agents are most appropriate for ulcerative colitis? Ann Intern Med (2014) 160:733–410.7326/M14-0605
    1. Pedersen J, Coskun M, Soendergaard C, Salem M, Nielsen OH. Inflammatory pathways of importance for management of inflammatory bowel disease. World J Gastroenterol (2014) 20:64–77.10.3748/wjg.v20.i1.64
    1. Seidelin JB, Coskun M, Nielsen OH. Mucosal healing in ulcerative colitis: pathophysiology and pharmacology. Adv Clin Chem (2013) 59:101–2310.1016/B978-0-12-405211-6.00004-8
    1. Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases: a systematic review. Gut (2012) 61:1619–35.10.1136/gutjnl-2012-302830
    1. De Cruz P, Kamm MA, Prideaux L, Allen PB, Moore G. Mucosal healing in Crohn’s disease: a systematic review. Inflamm Bowel Dis (2013) 19:429–44.10.1002/ibd.22977
    1. Vaughn BP, Shah S, Cheifetz AS. The role of mucosal healing in the treatment of patients with inflammatory bowel disease. Curr Treat Options Gastroenterol (2014) 12:103–17.10.1007/s11938-013-0008-1
    1. Bamias G, Dahman MI, Arseneau KO, Guanzon M, Gruska D, Pizarro TT, et al. Intestinal-specific TNFalpha overexpression induces Crohn’s-like ileitis in mice. PLoS One (2013) 8:e72594.10.1371/journal.pone.0072594
    1. Hassan C, Ierardi E, Burattini O, De Francesco V, Zullo A, Stoppino G, et al. Tumour necrosis factor alpha down-regulation parallels inflammatory regression in ulcerative colitis patients treated with infliximab. Dig Liver Dis (2007) 39:811–7.10.1016/j.dld.2007.06.003
    1. Fischer A, Gluth M, Pape UF, Wiedenmann B, Theuring F, Baumgart DC. Adalimumab prevents barrier dysfunction and antagonizes distinct effects of TNF on tight junction proteins and signaling pathways in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol (2013) 304:G970–9.10.1152/ajpgi.00183.2012
    1. Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology (2011) 141:1762–72.10.1053/j.gastro.2011.07.050

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner