Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Immunological aspects of intestinal mucus and mucins

Nature Reviews Immunology volume 16, pages 639–649 (2016)Cite this article

Subjects

Key Points

  • Mucins are highly O-glycosylated molecules that have gel-like properties. The mucin family consists of transmembrane mucins and gel-forming mucins. The transmembrane mucins cover the apical surfaces of the enterocytes and form the glycocalyx. The gel-forming mucins are secreted from goblet cells as large multimers that form the mucus skeleton and cover all epithelial surfaces.

  • Mucus in the small intestine forms a diffusion barrier where antimicrobial substances keep the epithelium free from microorganism. Mucus in the colon forms a dense inner mucus layer that bacteria are unable to penetrate, creating a bacteria-free zone at the epithelial surface.

  • Some, but not all, bacteria stimulate the formation of a functional mucus system with removable mucus in the small intestine and a stratified impenetrable inner mucus layer in colon.

  • Mucus in the intestine creates a niche for bacteria, with digestible glycans providing a stable energy source, but mucus also traps and removes bacteria. Bacteria in loose mucus are planktonic and less virulent.

  • The small intestinal goblet cells can sample luminal material during mucus secretion and transfer the antigens to lamina propria dendritic cells, something that also happens in the colon if bacterial numbers are decreased. This communication with the immune system has tolerogenic effects.

  • Intestinal pathogens have mechanisms that allow them to circumvent the mucus protection to reach the epithelium. These include good motility and secretion of enzymes that can degrade the otherwise protease-resistant mucins.

Abstract

A number of mechanisms ensure that the intestine is protected from pathogens and also against our own intestinal microbiota. The outermost of these is the secreted mucus, which entraps bacteria and prevents their translocation into the tissue. Mucus contains many immunomodulatory molecules and is largely produced by the goblet cells. These cells are highly responsive to the signals they receive from the immune system and are also able to deliver antigens from the lumen to dendritic cells in the lamina propria. In this Review, we will give a basic overview of mucus, mucins and goblet cells, and explain how each of these contributes to immune regulation in the intestine.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A general overview of the mucus layers in small intestine and colon.
Figure 2: The domain structures of gel-forming and transmembrane intestinal mucins.
Figure 3: The mucin-release mechanism in the small intestine.
Figure 4: Goblet cell uptake of luminal material with transfer to dendritic cells.
Figure 5: Effects of mucus defects and how pathogens can circumvent the mucus protection in the intestine.

Similar content being viewed by others

References

  1. Ambort, D. et al. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc. Natl Acad. Sci. USA 109, 5645–5650 (2012).

    CAS  PubMed  Google Scholar 

  2. Lang, T., Hansson, G. C. & Samuelsson, T. Gel-forming mucins appeared early in metazoan evolution. Proc. Natl Acad. Sci. USA 104, 16209–16214 (2007).

    CAS  PubMed  Google Scholar 

  3. Hattrup, C. L. & Gendler, S. J. Structure and function of the cell surface (tethered) mucins. Annu. Rev. Physiol. 70, 431–457 (2008).

    CAS  PubMed  Google Scholar 

  4. Corfield, A. P. Mucins: a biologically relevant glycan barrier in mucosal protection. Biochim. Biophys. Acta 1850, 236–252 (2015).

    CAS  PubMed  Google Scholar 

  5. Linden, S. K., Florin, T. H. & McGuckin, M. A. Mucin dynamics in intestinal bacterial infection. PLoS ONE 3, e3952 (2008).

    PubMed  PubMed Central  Google Scholar 

  6. Shibahara, H. et al. Pathobiological implications of mucin (MUC) expression in the outcome of small bowel cancer. PLoS ONE 9, e86111 (2014).

    PubMed  PubMed Central  Google Scholar 

  7. Thathiah, A. & Carson, D. D. MT1-MMP mediates MUC1 shedding independent of TACE/ADAM17. Biochem. J. 382, 363–373 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Larsson, J. M. et al. Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm. Bowel. Dis. 17, 2299–2307 (2011).

    Google Scholar 

  9. Hasnain, S. Z., Gallagher, A. L., Grencis, R. K. & Thornton, D. J. A new role for mucins in immunity: insights from gastrointestinal nematode infection. Int. J. Biochem. Cell Biol. 45, 364–374 (2013).

    CAS  PubMed  Google Scholar 

  10. Ridley, C. et al. Assembly of the respiratory mucin MUC5B: a new model for a gel-forming mucin. J. Biol. Chem. 289, 16409–16420 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Gum, J. R., Crawley, S. C., Hicks, J. W., Szymkowski, D. E. & Kim, Y. S. MUC17, a novel membrane-tethered mucin. Biochem. Biophys. Res. Commun. 291, 466–475 (2002).

    CAS  PubMed  Google Scholar 

  12. Williams, S. J. et al. Two novel mucin genes down-regulated in colorectal cancer identified by differential display. Cancer Res. 59, 4083–4089 (1999).

    CAS  PubMed  Google Scholar 

  13. Pelaseyed, T., Gustafsson, J. K., Gustafsson, I. J., Ermund, A. & Hansson, G. C. Carbachol-induced MUC17 endocytosis is concomitant with NHE3 internalization and CFTR membrane recruitment in enterocytes. Am. J. Physiol. Cell Physiol. 305, C457–C467 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Sheng, Y. H. et al. The MUC13 cell-surface mucin protects against intestinal inflammation by inhibiting epithelial cell apoptosis. Gut 60, 1661–1670 (2011).

    CAS  PubMed  Google Scholar 

  15. Gregorieff, A. et al. The Ets-domain transcription factor Spdef promotes maturation of goblet and Paneth cells in the intestinal epithelium. Gastroenterology 137, 1333–1345 (2009). This study shows that the transcription factor SPDEF is a major regulator of goblet and Paneth cell maturation and controls goblet cell-specific gene expression.

    CAS  PubMed  Google Scholar 

  16. Park, S. W. et al. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc. Natl Acad. Sci. USA 106, 6950–6955 (2009).

    CAS  PubMed  Google Scholar 

  17. Tsuru, A. et al. Negative feedback by IRE1β optimizes mucin production in goblet cells. Proc. Natl Acad. Sci. USA 110, 2864–2869 (2013).

    CAS  PubMed  Google Scholar 

  18. Johansson, M. E. Fast renewal of the distal colonic mucus layers by the surface goblet cells as measured by in vivo labeling of mucin glycoproteins. PLoS ONE 7, e41009 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Neutra, M. & Leblond, C. P. Synthesis of the carbohydrate of mucus in the Golgi complex as shown by electron microscope radioautography of goblet cells from rats injected with glucose-H3. J. Cell Biol. 30, 119–136 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Davis, C. W. & Dickey, B. F. Regulated airway goblet cell mucin secretion. Annu. Rev. Physiol. 70, 487–512 (2008).

    CAS  PubMed  Google Scholar 

  21. Specian, R. D. & Neutra, M. R. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. J. Cell Biol. 85, 626–640 (1980).

    CAS  PubMed  Google Scholar 

  22. Sato, T. et al. Single Lgr5 stem cells build crypt–villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).

    CAS  PubMed  Google Scholar 

  23. Tran, D. T., Masedunskas, A., Weigert, R. & Ten Hagen, K. G. Arp2/3-mediated F-actin formation controls regulated exocytosis in vivo. Nat. Commun. 6, 10098 (2015).

    PubMed  PubMed Central  Google Scholar 

  24. Patel, K. K. et al. Autophagy proteins control goblet cell function by potentiating reactive oxygen species production. EMBO J. 32, 3130–3144 (2013). This study shows that goblet cell secretion can be initiated via endocytosis and requires activation of autophagy proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Birchenough, G. M. H., Nystrom, E. L. N., Johansson, M. E. V. & Hansson, G. C. A sentinel goblet cell guards the colonic crypt by triggering Nlrp6- dependent Muc2 secretion. Science 352, 1535–1542 (2016). This study describes a sentinel goblet cell that guards the colonic crypt opening and defends this region by stimulating mucus secretion.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gustafsson, J. K. et al. Bicarbonate and functional CFTR channel are required for proper mucin secretion and link cystic fibrosis with its mucus phenotype. J. Exp. Med. 209, 1263–1272 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Schutte, A. et al. Microbial-induced meprin β cleavage in MUC2 mucin and a functional CFTR channel are required to release anchored small intestinal mucus. Proc. Natl Acad. Sci. USA 111, 12396–12401 (2014).

    CAS  PubMed  Google Scholar 

  29. Ermund, A., Schutte, A., Johansson, M. E., Gustafsson, J. K. & Hansson, G. C. 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. 305, G341–G347 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nat. Rev. Immunol. 10, 159–169 (2010).

    CAS  PubMed  Google Scholar 

  31. Meyer-Hoffert, U. et al. Secreted enteric antimicrobial activity localises to the mucus surface layer. Gut 57, 764–771 (2008).

    CAS  PubMed  Google Scholar 

  32. van der Waaij, L. A. 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. 11, 865–871 (2005).

    PubMed  Google Scholar 

  33. Bevins, C. L. & Salzman, N. H. Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis. Nat. Rev. Microbiol. 9, 356–368 (2011).

    CAS  PubMed  Google Scholar 

  34. Swidsinski, A., Loening-Baucke, V., Lochs, H. & Hale, L. P. Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J. Gastroenterol. 11, 1131–1140 (2005).

    PubMed  PubMed Central  Google Scholar 

  35. Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008). This study describes the well-structured inner mucus layer of the two-layered mucus system that separates the colonic bacteria from the epithelium.

    CAS  PubMed  Google Scholar 

  36. Kato, A. & Romero, M. F. Regulation of electroneutral NaCl absorption by the small intestine. Annu. Rev. Physiol. 73, 261–281 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Swidsinski, A., Loening-Baucke, V., Verstraelen, H., Osowska, S. & Doerffel, Y. Biostructure of fecal microbiota in healthy subjects and patients with chronic idiopathic diarrhea. Gastroenterology 135, 568–579 (2008).

    PubMed  Google Scholar 

  38. Li, H. et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun. 6, 8292 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Derrien, M., Collado, M. C., Ben-Amor, K., Salminen, S. & de Vos, W. M. The Mucin degrader Akkermansia muciniphila is an abundant resident of the human intestinal tract. Appl. Environ. Microbiol. 74, 1646–1648 (2008).

    CAS  PubMed  Google Scholar 

  40. Robertson, B. R. et al. Mucispirillum schaedleri gen. nov., sp. nov., a spiral-shaped bacterium colonizing the mucus layer of the gastrointestinal tract of laboratory rodents. Int. J. Syst. Evol. Microbiol. 55, 1199–1204 (2005).

    CAS  PubMed  Google Scholar 

  41. Macpherson, A. J., McCoy, K. D., Johansen, F. E. & Brandtzaeg, P. The immune geography of IgA induction and function. Mucosal Immunol. 1, 11–22 (2008).

    CAS  PubMed  Google Scholar 

  42. Jakobsson, H. E. et al. The composition of the gut microbiota shapes the colon mucus barrier. EMBO Rep. 16, 164–177 (2015).

    CAS  PubMed  Google Scholar 

  43. Slack, E., Balmer, M. L. & Macpherson, A. J. B cells as a critical node in the microbiota–host immune system network. Immunol. Rev. 260, 50–66 (2014).

    CAS  PubMed  Google Scholar 

  44. Rogier, E. W., Frantz, A. L., Bruno, M. E. & Kaetzel, C. S. Secretory IgA is concentrated in the outer layer of colonic mucus along with gut bacteria. Pathog. 3, 390–403 (2014).

    CAS  Google Scholar 

  45. Frantz, A. L. et al. Targeted deletion of MyD88 in intestinal epithelial cells results in compromised antibacterial immunity associated with downregulation of polymeric immunoglobulin receptor, mucin-2, and antibacterial peptides. Mucosal Immunol. 5, 501–512 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Loonen, L. M. et al. REG3γ-deficient mice have altered mucus distribution and increased mucosal inflammatory responses to the microbiota and enteric pathogens in the ileum. Mucosal Immunol. 7, 939–947 (2014).

    CAS  PubMed  Google Scholar 

  48. Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Earle, K. A. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 18, 478–488 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sommer, F. & Backhed, F. The gut microbiota engages different signaling pathways to induce Duox2 expression in the ileum and colon epithelium. Mucosal Immunol. 8, 372–379 (2015).

    CAS  PubMed  Google Scholar 

  51. Barr, J. J. et al. Bacteriophage adhering to mucus provide a non-host-derived immunity. Proc. Natl Acad. Sci. USA 110, 10771–10776 (2013).

    CAS  PubMed  Google Scholar 

  52. Rodriguez-Pineiro, A. M. 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. 305, G348–G356 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. McDole, J. R. et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 483, 345–349 (2012). A report showing that small intestinal goblet cells take up lumenal material during secretion and deliver this material to lamina propria DCs.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Shan, M. et al. Mucus enhances gut homeostasis and oral tolerance by delivering immunoregulatory signals. Science 342, 447–453 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kraehenbuhl, J. P. & Neutra, M. R. Epithelial M cells: differentiation and function. Annu. Rev. Cell Dev. Biol. 16, 301–332 (2000).

    CAS  PubMed  Google Scholar 

  56. Knoop, K. A., McDonald, K. G., McCrate, S., McDole, J. R. & Newberry, R. D. Microbial sensing by goblet cells controls immune surveillance of luminal antigens in the colon. Mucosal Immunol. 8, 198–210 (2015).

    CAS  PubMed  Google Scholar 

  57. Knoop, K. A., McDonald, K. G., Kulkarni, D. H. & Newberry, R. D. Antibiotics promote inflammation through the translocation of native commensal colonic bacteria. Gut 65, 1100–1109 (2015).

    PubMed  PubMed Central  Google Scholar 

  58. Rosen, S. D. Ligands for L-selectin: homing, inflammation, and beyond. Annu. Rev. Immunol. 22, 129–156 (2004).

    CAS  PubMed  Google Scholar 

  59. Khan, W. I. & Collins, S. M. Immune-mediated alteration in gut physiology and its role in host defence in nematode infection. Parasite Immunol. 26, 319–326 (2004).

    CAS  PubMed  Google Scholar 

  60. Oeser, K., Schwartz, C. & Voehringer, D. Conditional IL-4/IL-13-deficient mice reveal a critical role of innate immune cells for protective immunity against gastrointestinal helminths. Mucosal Immunol. 8, 672–682 (2015).

    CAS  PubMed  Google Scholar 

  61. Finkelman, F. D. et al. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol. Rev. 201, 139–155 (2004).

    CAS  PubMed  Google Scholar 

  62. Steenwinckel, V. et al. IL-9 promotes IL-13-dependent paneth cell hyperplasia and up-regulation of innate immunity mediators in intestinal mucosa. J. Immunol. 182, 4737–4743 (2009).

    CAS  PubMed  Google Scholar 

  63. von Moltke, J., Ji, M., Liang, H. E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit. Nature 529, 221–225 (2016).

    CAS  PubMed  Google Scholar 

  64. Gerbe, F. et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature 529, 226–230 (2016).

    CAS  PubMed  Google Scholar 

  65. Rajavelu, P. et al. Airway epithelial SPDEF integrates goblet cell differentiation and pulmonary Th2 inflammation. J. Clin. Invest. 125, 2021–2031 (2015).

    PubMed  PubMed Central  Google Scholar 

  66. Turner, J. E., Stockinger, B. & Helmby, H. IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS Pathog. 9, e1003698 (2013).

    PubMed  PubMed Central  Google Scholar 

  67. Johansson, M. E. et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 63, 281–291 (2014). A study showing that colitic mice and patients with ulcerative colitis have a defect inner mucus layer that allows bacterial penetration.

    CAS  PubMed  Google Scholar 

  68. Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. El, A. S. et al. Temporal and spatial interplay of microbiota and intestinal mucosa drive establishment of immune homeostasis in conventionalized mice. Mucosal Immunol. 5, 567–579 (2012).

    Google Scholar 

  71. Johansson, M. E. et al. Normalization of host intestinal mucus layers requires long-term microbial colonization. Cell Host Microbe 18, 582–592 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Juge, N. Microbial adhesins to gastrointestinal mucus. Trends Microbiol. 20, 30–39 (2012).

    CAS  PubMed  Google Scholar 

  73. Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Rawls, J. F., Mahowald, M. A., Ley, R. E. & Gordon, J. I. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127, 423–433 (2006). This study shows that host mechanisms are important for the selection of a host-specific microbiota.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Marcobal, A., Southwick, A. M., Earle, K. A. & Sonnenburg, J. L. A refined palate: bacterial consumption of host glycans in the gut. Glycobiology 23, 1038–1046 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Pudlo, N. A. et al. Symbiotic human gut bacteria with variable metabolic priorities for host mucosal glycans. mBio 6, e01282–15 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Sonnenburg, J. L. et al. Glycan foraging in vivo by an intestine-adapted bacterial symbiont. Science 307, 1955–1959 (2005).

    CAS  PubMed  Google Scholar 

  78. Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Caldara, M. et al. Mucin biopolymers prevent bacterial aggregation by retaining cells in the free-swimming state. Curr. Biol. 22, 2325–2330 (2012). This study showed that bacteria can swim in freshly prepared mucus and remain in a planktonic state.

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Norkina, O., Burnett, T. G. & De Lisle, R. C. Bacterial overgrowth in the cystic fibrosis transmembrane conductance regulator null mouse small intestine. Infect. Immun. 72, 6040–6049 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002). This study shows that mice lacking MUC2 have no protective mucus and develop cancer.

    CAS  PubMed  Google Scholar 

  82. El, A. S. et al. Transient inflammatory-like state and microbial dysbiosis are pivotal in establishment of mucosal homeostasis during colonisation of germ-free mice. Benef. Microbes 5, 67–77 (2014).

    Google Scholar 

  83. Wrzosek, L. et al. Bacteroides thetaiotaomicron and Faecalibacterium prausnitzii influence the production of mucus glycans and the development of goblet cells in the colonic epithelium of a gnotobiotic model rodent. BMC Biol. 11, 61 (2013).

    PubMed  PubMed Central  Google Scholar 

  84. Willing, B. P., Russell, S. L. & Finlay, B. B. Shifting the balance: antibiotic effects on host-microbiota mutualism. Nat. Rev. Microbiol. 9, 233–243 (2011).

    CAS  PubMed  Google Scholar 

  85. Wlodarska, M. et al. Antibiotic treatment alters the colonic mucus layer and predisposes the host to exacerbated Citrobacter rodentium-induced colitis. Infect. Immun. 79, 1536–1545 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004).

    CAS  PubMed  Google Scholar 

  87. Vijay-Kumar, M. et al. Deletion of TLR5 results in spontaneous colitis in mice. J. Clin. Invest. 117, 3909–3921 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Bhinder, G. et al. Intestinal epithelium-specific MyD88 signaling impacts host susceptibility to infectious colitis by promoting protective goblet cell and antimicrobial responses. Infect. Immun. 82, 3753–3763 (2014).

    PubMed  PubMed Central  Google Scholar 

  89. Hamer, H. M. et al. The role of butyrate on colonic function. Aliment. Pharmacol. Ther. 27, 104–119 (2008).

    CAS  PubMed  Google Scholar 

  90. Gaudier, E. et al. Butyrate specifically modulates MUC gene expression in intestinal epithelial goblet cells deprived of glucose. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G1168–G1174 (2004).

    CAS  PubMed  Google Scholar 

  91. Artis, D. & Grencis, R. K. The intestinal epithelium: sensors to effectors in nematode infection. Mucosal Immunol. 1, 252–264 (2008).

    CAS  PubMed  Google Scholar 

  92. Stecher, B. et al. Flagella and chemotaxis are required for efficient induction of Salmonella enterica serovar Typhimurium colitis in streptomycin-pretreated mice. Infect. Immun. 72, 4138–4150 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Navarro-Garcia, F. et al. Pic, an autotransporter protein secreted by different pathogens in the Enterobacteriaceae family, is a potent mucus secretagogue. Infect. Immun. 78, 4101–4109 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Silva, A. J., Pham, K. & Benitez, J. A. Haemagglutinin/protease expression and mucin gel penetration in El Tor biotype Vibrio cholerae. Microbiology 149, 1883–1891 (2003).

    CAS  PubMed  Google Scholar 

  95. Nikitas, G. et al. Transcytosis of Listeria monocytogenes across the intestinal barrier upon specific targeting of goblet cell accessible E-cadherin. J. Exp. Med. 208, 2263–2277 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Bergstrom, K. S. et al. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog. 6, e1000902 (2010).

    PubMed  PubMed Central  Google Scholar 

  97. Bhullar, K. et al. The serine protease autotransporter pic modulates citrobacter rodentium pathogenesis and its innate recognition by the host. Infect. Immun. 83, 2636–2650 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lidell, M. E., Moncada, D. M., Chadee, K. & Hansson, G. C. Entamoeba histolytica cysteine proteases cleave the MUC2 mucin in its C-terminal part and dissolves the protective colonic mucus gel. Proc. Natl Acad. Sci. USA 103, 9298–9303 (2006).

    CAS  PubMed  Google Scholar 

  99. van der Sluis, M. et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 131, 117–129 (2006).

    CAS  PubMed  Google Scholar 

  100. Huang, E. Y. et al. Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. Inflamm. Bowel. Dis. 21, 963–972 (2015).

    PubMed  PubMed Central  Google Scholar 

  101. Liu, C. et al. NHE8 plays an important role in mucosal protection via its effect on bacterial adhesion. Am. J. Physiol. Cell Physiol. 305, C121–C128 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Xiao, F. et al. Slc26a3 deficiency is associated with loss of colonic HCO3− secretion, absence of a firm mucus layer and barrier impairment in mice. Acta Physiol. (Oxf) 211, 161–175 (2013).

    Google Scholar 

  103. Fu, J. et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Hickey, C. A. et al. Colitogenic bacteroides thetaiotaomicron antigens access host immune cells in a sulfatase-dependent manner via outer membrane vesicles. Cell Host Microbe 17, 672–680 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Johansson, M. E. et al. Bacteria penetrate the inner mucus layer before inflammation in the dextran sulfate colitis model. PLoS ONE 5, e12238 (2010).

    PubMed  PubMed Central  Google Scholar 

  106. Kuhn, R., Lohler, J., Rennick, D., Rajewsky, K. & Muller, W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75, 263–274 (1993).

    CAS  PubMed  Google Scholar 

  107. Bertolotti, A. et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice. J. Clin. Invest. 107, 585–593 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Bersudsky, M. et al. Non-redundant properties of IL-1α and IL-1β during acute colon inflammation in mice. Gut 63, 598–609 (2014).

    CAS  PubMed  Google Scholar 

  109. Imaeda, H. et al. Interleukin-33 suppresses Notch ligand expression and prevents goblet cell depletion in dextran sulfate sodium-induced colitis. Int. J. Mol. Med. 28, 573–578 (2011).

    CAS  PubMed  Google Scholar 

  110. Ito, R. et al. Involvement of IL-17A in the pathogenesis of DSS-induced colitis in mice. Biochem. Biophys. Res. Commun. 377, 12–16 (2008).

    CAS  PubMed  Google Scholar 

  111. Grootjans, J. 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 62, 250–258 (2013). This study proposed a conceptual model for how mucus secretion from the crypt can clear bacteria and reconstitute an inner mucus layer.

    PubMed  Google Scholar 

  112. Heazlewood, C. K. et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med. 5, e54 (2008).

    PubMed  PubMed Central  Google Scholar 

  113. Das, I. et al. Glucocorticoids alleviate intestinal ER stress by enhancing protein folding and degradation of misfolded proteins. J. Exp. Med. 210, 1201–1216 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Wang, R. et al. Neutralizing IL-23 is superior to blocking IL-17 in suppressing intestinal inflammation in a spontaneous murine colitis model. Inflamm. Bowel Dis. 21, 973–984 (2015).

    PubMed  Google Scholar 

  115. Pullan, R. D. et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 35, 353–359 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Heylen, M. et al. Of worms, mice and man: an overview of experimental and clinical helminth-based therapy for inflammatory bowel disease. Pharmacol. Ther. 143, 153–167 (2014).

    CAS  PubMed  Google Scholar 

  117. Audie, J. P. et al. Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. J. Histochem. Cytochem. 41, 1479–1485 (1993).

    CAS  PubMed  Google Scholar 

  118. Weiss, A. A., Babyatsky, M. W., Ogata, S., Chen, A. & Itzkowitz, S. H. Expression of MUC2 and MUC3 mRNA in human normal, malignant, and inflammatory intestinal tissues. J. Histochem. Cytochem. 44, 1161–1166 (1996).

    CAS  PubMed  Google Scholar 

  119. Williams, S. J. et al. MUC13, a novel human cell surface mucin expressed by epithelial and hemopoietic cells. J. Biol. Chem. 276, 18327–18336 (2001).

    CAS  PubMed  Google Scholar 

  120. Chang, S. K. et al. Localization of mucin (MUC2 and MUC3) messenger RNA and peptide expression in human normal intestine and colon cancer. Gastroenterology 107, 28–36 (1994).

    CAS  PubMed  Google Scholar 

  121. Ho, S. B. et al. Mucin gene expression in normal, preneoplastic, and neoplastic human gastric epithelium. Cancer Res. 55, 2681–2690 (1995).

    CAS  PubMed  Google Scholar 

  122. Gruber, A. D. 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 54, 200–214 (1998).

    CAS  PubMed  Google Scholar 

  123. Johansson, M. E., Thomsson, K. A. & Hansson, G. C. 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. 8, 3549–3557 (2009).

    CAS  PubMed  Google Scholar 

  124. Madsen, J., Nielsen, O., Tornoe, I., Thim, L. & Holmskov, U. Tissue localization of human trefoil factors 1, 2, and 3. J. Histochem. Cytochem. 55, 505–513 (2007).

    CAS  PubMed  Google Scholar 

  125. Tateno, H. et al. Human ZG16p recognizes pathogenic fungi through non-self polyvalent mannose in the digestive system. Glycobiology 22, 210–220 (2012).

    CAS  PubMed  Google Scholar 

  126. Kang, W. & Reid, K. B. DMBT1, a regulator of mucosal homeostasis through the linking of mucosal defense and regeneration? FEBS Lett. 540, 21–25 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The work of the authors was supported by the Swedish Research Council, the Swedish Cancer Foundation, the Knut and Alice Wallenberg Foundation, the IngaBritt and Arne Lundberg Foundation, Sahlgren's University Hospital (ALF), the National Institute of Allergy and Infectious Diseases (U01AI095473), the Hasselblad Foundation, and the Swedish Foundation for Strategic Research.

Author information

Authors and Affiliations

  1. Department of Medical Biochemistry, University of Gothenburg, Gothenburg, 405 30, Sweden

    Malin E. V. Johansson & Gunnar C. Hansson

Authors
  1. Malin E. V. Johansson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gunnar C. Hansson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gunnar C. Hansson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Glossary

SEA domain

(Sea urchin sperm protein, enterokinase, and agrin domain) A domain that is found on the outside of the membrane in several transmembrane mucins and autocatalytically cleaved during folding in the endoplasmic reticulum.

Cystic fibrosis transmembrane conductance regulator

(CFTR). An ion channel that transports chloride and bicarbonate ions. Defects in this channel cause cystic fibrosis.

Dextran sulfate sodium (DSS)-induced colitis

A model of colitis induced in rodents by the addition of DSS to drinking water; this causes the inner colon mucus layer to become penetrable to bacteria, disrupts the epithelial layer and leads to intestinal inflammation.

SAM pointed domain-containing Ets transcription factor

(SPDEF). A transcription factor that is a master regulator of goblet cell lineage differentiation and maturation.

Goblet cell theca

The cluster of large mucin-filled granulae that are typically observed in goblet cells.

Segmented filamentous bacteria

Bacteria that infect the small intestine of the mouse, but not humans, attaching to the enterocyte membranes; they support T helper 17 cell responses in the mouse intestine.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Johansson, M., Hansson, G. Immunological aspects of intestinal mucus and mucins. Nat Rev Immunol 16, 639–649 (2016). https://doi.org/10.1038/nri.2016.88

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2016.88

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing