Mucus layers in inflammatory bowel disease

Inflammatory Bowel Diseases

Volumn 20, Issue 11, 2014, Pages 2124-2131

  Johansson, Malin E V ^a  

^a UNIVERSITY OF GOTHENBURG   (Sweden)

Author keywords

Bacteria penetration; Colon; Crohn's disease; Inflammatory bowel disease; Intestinal barrier; MUC2; Mucin; Mucus; Small intestine; Ulcerative colitis

Indexed keywords

INTERLEUKIN 10; MUCIN 2;

ARTICLE; COLONIC MUCUS; DYSBIOSIS; GLYCOSYLATION; HUMAN; IMMUNE RESPONSE; INFLAMMATORY BOWEL DISEASE; MUCUS; NONHUMAN; PRIORITY JOURNAL; PROTEIN SYNTHESIS; SMALL INTESTINAL MUCUS; SMALL INTESTINE; ULCERATIVE COLITIS; ANIMAL; METABOLISM; MUCOSA; PATHOLOGY;

ANIMALS; HUMANS; INFLAMMATORY BOWEL DISEASES; MUCOUS MEMBRANE; MUCUS;

EID: 84924703317     PISSN: 10780998     EISSN: 15364844     Source Type: Journal    
DOI: 10.1097/MIB.0000000000000117     Document Type: Article

References (85)

1. Lang T, Hansson GC, Samuelsson T. Gel-forming mucins appeared early in metazoan evolution. Proc Natl Acad Sci U S A. 2007;104:16209-16214.
2. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009; 361:2066-2078.
3. Xavier RJ, Podolsky DK. Unravelling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427-434.
4. Chassaing B, Darfeuille-Michaud A. The commensal microbiota and enteropathogens in the pathogenesis of inflammatory bowel diseases. Gastroenterology. 2011;140:1720-1728.
5. Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. 2014;20:91-99.
6. Allen A, Leonard AJ, Sellers LA. The mucus barrier. Its role in gastroduodenal mucosal protection. J Clin Gastroenterol. 1988;10(suppl 1): S93-S98.
7. Johansson ME, Sjovall H, Hansson GC. The gastrointestinal mucus system in health and disease. Nat Rev Gastroenterol Hepatol. 2013;10:352-361.
8. Pelaseyed T, Ermund A, Gustafsson JK, et al. The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system. Immunol Rev. 2014;in press.
9. Bennett EP, Mandel U, Clausen H, et al. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology. 2012;22:736-756.
10. Holmen Larsson JM, Thomsson KA, Rodriguez-Pineiro AM, et al. Studies of mucus in mouse stomach, small intestine, and colon. III. Gastrointestinal Muc5ac and Muc2 mucin O-glycan patterns reveal a regiospecific distribution. Am J Physiol Gastrointest Liver Physiol. 2013;305:G357-G363.
11. Larsson JM, Karlsson H, Sjovall H, et al. A complex, but uniform O-glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nanoLC/MSn. Glycobiology. 2009;19:756-766.
12. Sheng YH, Hasnain SZ, Florin TH, et al. Mucins in inflammatory bowel diseases and colorectal cancer. J Gastroenterol Hepatol. 2012;27:28-38.
13. Backstrom M, Ambort D, Thomsson E, et al. Increased understanding of the biochemistry and biosynthesis of MUC2 and other gel-forming mucins through the recombinant expression of their protein domains. Mol Biotechnol. 2013;54:250-256.
14. van der Flier LG, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol. 2009;71:241-260.
15. Park SW, Zhen G, Verhaeghe C, et al. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci U S A. 2009;106:6950-6955.
16. Tsuru A, Fujimoto N, Takahashi S, et al. Negative feedback by IRE1beta optimizes mucin production in goblet cells. Proc Natl Acad Sci U S A. 2013;110:2864-2869.
17. Asker N, Axelsson MAB, Olofsson SO, et al. Dimerization of the human MUC2 mucin in the endoplasmic reticulum is followed by a N-glycosylationdependent transfer of the mono-and dimers to the Golgi apparatus. J Biol Chem. 1998;273:18857-18863.
18. Godl K, Johansson MEV, Karlsson H, et al. The N-termini of the MUC2 mucin form trimers that are held together within a trypsin-resistant core fragment. J Biol Chem. 2002;277:47248-47256.
19. Ambort D, Johansson ME, Gustafsson JK, et al. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc Natl Acad Sci U S A. 2012;109:5645-5650.
20. Gustafsson JK, Ermund A, Ambort D, et al. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J Exp Med. 2012;209:1263-1272.
21. Adler KB, Tuvim MJ, Dickey BF. Regulated mucin secretion from Airway epithelial cells. Front Endocrinol (Lausanne). 2013;4:129.
22. Specian RD, Neutra MR. The surface topography of the colonic crypt in rabbit and monkey. Am J Anat. 1981;160:461-472.
23. Larsson JM, Karlsson H, Crespo JG, et al. Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm Bowel Dis. 2011;17: 2299-2307.
24. Rodriguez-Pineiro AM, Bergstrom JH, Ermund A, et al. Studies of mucus in mouse stomach, small intestine, and colon. II. Gastrointestinal mucus proteome reveals Muc2 and Muc5ac accompanied by a set of core proteins. Am J Physiol Gastrointest Liver Physiol. 2013;305:G348-G356.
25. Van Klinken BJ, Dekker J, van Gool SA, et al. MUC5B is the prominent mucin in human gallbladder and is also expressed in a subset of colonic goblet cells. Am J Physiol. 1998;274:G871-G878.
26. Johansson ME, Thomsson KA, Hansson GC. Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 mucin, is strongly bound to the Fcgbp protein. J Proteome Res. 2009;8:3549-3557.
27. Gruber AD, Elble RC, Ji HL, et al. Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl-channel proteins. Genomics. 1998;54:200-214.
28. Kumazawa-Inoue K, Mimura T, Hosokawa-Tamiya S, et al. ZG16p, an animal homolog of beta-prism fold plant lectins, interacts with heparan sulfate proteoglycans in pancreatic zymogen granules. Glycobiology. 2012;22:258-266.
29. Tateno H, Yabe R, Sato T, et al. Human ZG16p recognizes pathogenic fungi through non-self polyvalent mannose in the digestive system. Glycobiology. 2012;22:210-220.
30. Johansson ME, Phillipson M, Petersson J, et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A. 2008;105:15064-15069.
31. Mashimo H, Wu DC, Podolsky DK, et al. Impaired defense of intestinal mucosa in mice lacking intestinal trefoil factor. Science. 1996;274:262-265.
32. Artis D, Wang ML, Keilbaugh SA, et al. RELMbeta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci U S A. 2004;101:13596-13600.
33. Hooper LV, Macpherson AJ. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat Rev Immunol. 2010; 10:159-169.
34. Atuma C, Strugula V, Allen A, et al. The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo. Am J Physiol Gastrointest Liver Physiol. 2001;280:G922-G929.
35. Ermund A, Schutte A, Johansson ME, et al. Studies of mucus in mouse stomach, small intestine, and colon. I. Gastrointestinal mucus layers have different properties depending on location as well as over the Peyer's patches. Am J Physiol Gastrointest Liver Physiol. 2013;305: G341-G347.
36. Vaishnava S, Yamamoto M, Severson KM, et al. The antibacterial lectin RegIIIgamma promotes the spatial segregation of microbiota and host in the intestine. Science. 2011;334:255-258.
37. McDole JR, Wheeler LW, McDonald KG, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature. 2012;483:345-349.
38. Knoop KA, Miller MJ, Newberry RD. Transepithelial antigen delivery in the small intestine: different paths, different outcomes. Curr Opin Gastroenterol. 2013;29:112-118.
39. Shan M, Gentile M, Yeiser JR, et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science. 2013;342: 447-453.
40. Allan-Wojtas P, Farnworth ER, Modler HW, et al. A solvent-based fixative for electron microscopy to improve retention and visualization of the intestinal mucus blanket for probiotics studies. Microsc Res Tech. 1997;36:390-399.
41. Backhed F, Ley RE, Sonnenburg JL, et al. Host-bacterial mutualism in the human intestine. Science. 2005;307:1915-1920.
42. Swidsinski A, Sydora BC, Doerffel Y, et al. Viscosity gradient within the mucus layer determines the mucosal barrier function and the spatial organization of the intestinal microbiota. Inflamm Bowel Dis. 2007;13: 963-970.
43. van der Waaij LA, Harmsen HJ, Madjipour M, et al. Bacterial population analysis of human colon and terminal ileum biopsies with 16S rRNA-based fluorescent probes: commensal bacteria live in suspension and have no direct contact with epithelial cells. Inflamm Bowel Dis. 2005; 11:865-871.
44. Johansson ME, Gustafsson JK, Holmen-Larsson J, et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut. 2014;63: 281-291.
45. Johansson ME. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS One. 2012;7:e41009.
46. Sonnenburg JL, Xu J, Leip DD, et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science. 2005;307:1955-1959.
47. Petersson J, Schreiber O, Hansson GC, et al. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am J Physiol Gastrointest Liver Physiol. 2011;300:G327-G333.
48. Grootjans J, Hundscheid IH, Lenaerts K, et al. Ischaemia-induced mucus barrier loss and bacterial penetration are rapidly counteracted by increased goblet cell secretory activity in human and rat colon. Gut. 2013;62:250-258.
49. Gustafsson JK, Navabi N, Rodriguez-Pineiro AM, et al. Dynamic changes in mucus thickness and ion secretion during Citrobacter rodentium infection and clearance. PLoS One. 2013;8:e84430.
50. Khan WI, Collins SM. Immune-mediated alteration in gut physiology and its role in host defence in nematode infection. Parasite Immunol. 2004;26:319-326.
51. Pullan RD, Thomas GA, Rhodes M, et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut. 1994; 35:353-359.
52. Cadwell K, Liu JY, Brown SL, et al. A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008;456:259-263.
53. Liu B, Gulati AS, Cantillana V, et al. Irgm1-deficient mice exhibit Paneth cell abnormalities and increased susceptibility to acute intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2013;305:G573-G584.
54. Wehkamp J, Harder J, Weichenthal M, et al. NOD2 (CARD15) mutations in Crohn's disease are associated with diminished mucosal alpha-defensin expression. Gut. 2004;53:1658-1664.
55. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell. 2008;134:743-756.
56. Patel KK, Miyoshi H, Beatty WL, et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J. 2013;32:3130-3144.
57. An G, Wei B, Xia B, et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J Exp Med. 2007;204:1417-1429.
58. Fu J, Wei B, Wen T, et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J Clin Invest. 2011;121:1657-1666.
59. Corfield AP, Myerscough N, Bradfield N, et al. Colonic mucins in ulcerative colitis: evidence for loss of sulfation. Glycoconj J. 1996;13:809-822.
60. Rhodes JM. Unifying hypothesis for inflammatory bowel disease and associated colon cancer: sticking the pieces together with sugar. Lancet. 1996;347:40-44.
61. Dawson PA, Huxley S, Gardiner B, et al. Reduced mucin sulfonation and impaired intestinal barrier function in the hyposulfataemic NaS1 null mouse. Gut. 2009;58:910-919.
62. Tobisawa Y, Imai Y, Fukuda M, et al. Sulfation of colonic mucins by N-acetylglucosamine 6-O-sulfotransferase-2 and its protective function in experimental colitis in mice. J Biol Chem. 2010;285:6750-6760.
63. McGuckin MA, Eri RD, Das I, et al. ER stress and the unfolded protein response in intestinal inflammation. Am J Physiol Gastrointest Liver Physiol. 2010;298:G820-G832.
64. Heazlewood CK, Cook MC, Eri R, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 2008;5:e54.
65. Hasnain SZ, Tauro S, Das I, et al. IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells. Gastroenterology. 2013;144:357-368.
66. Paul G, Khare V, Gasche C. Inflamed gut mucosa: downstream of interleukin-10. Eur J Clin Invest. 2012;42:95-109.
67. Franke A, Balschun T, Karlsen TH, et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319-1323.
68. Begue B, Verdier J, Rieux-Laucat F, et al. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol. 2011;106:1544-1555.
69. Glocker EO, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361: 2033-2045.
70. Moran CJ, Walters TD, Guo CH, et al. IL-10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis. 2013; 19:115-123.
71. Kominsky DJ, Campbell EL, Ehrentraut SF, et al. IFN-gamma-mediated induction of an apical IL-10 receptor on polarized intestinal epithelia. J Immunol. 2014;192:1267-1276.
72. Schwerbrock NM, Makkink MK, Van der SM, et al. Interleukin 10-deficient mice exhibit defective colonic Muc2 synthesis before and after induction of colitis by commensal bacteria. Inflamm Bowel Dis. 2004;10:811-823.
73. van der Sluis M, Bouma J, Vincent A, et al. Combined defects in epithelial and immunoregulatory factors exacerbate the pathogenesis of inflammation: mucin 2-interleukin 10-deficient mice. Lab Invest. 2008;88:634-642.
74. Forgue-Lafitte ME, Fabiani B, Levy PP, et al. Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer. Int J Cancer. 2007;121:1543-1549.
75. Van Klinken BJ, van der Wal JW, Einerhand AW, et al. Sulphation and secretion of the predominant secretory human colonic mucin MUC2 in ulcerative colitis. Gut. 1999;44:387-393.
76. Guo X, Zheng S, Dang H, et al. Genome reference and sequence variation in the large repetitive central exon of human MUC5AC. Am J Respir Cell Mol Biol. 2014;50:223-232.
77. Takaishi H, Matsuki T, Nakazawa A, et al. Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. Int J Med Microbiol. 2008;298:463-472.
78. Carvalho FA, Koren O, Goodrich JK, et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe. 2012;12:139-152.
79. van der Post S, Subramani DB, Backstrom M, et al. Site-specific O-glycosylation on the MUC2 mucin protein inhibits cleavage by the Porphyromonas gingivalis secreted cysteine protease (RgpB). J Biol Chem. 2013;288:14636-14646.
80. Van der SM, de Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology. 2006;131:117-129.
81. Velcich A, Yang WC, Heyer J, et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science. 2002;295:1726-1729.
82. Bergstrom KS, Kissoon-Singh V, Gibson DL, et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. 2010;6: e1000902.
83. Hasnain SZ, Wang H, Ghia JE, et al. Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology. 2010;138:1763-1771.
84. Johansson ME, Gustafsson JK, Sjoberg KE, et al. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLoS One. 2010;5.
85. Laubitz D, Larmonier CB, Bai A, et al. Colonic gene expression profile in NHE3-deficient mice: evidence for spontaneous distal colitis. Am J Physiol Gastrointest Liver Physiol. 2008;295:G63-G77.