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:

Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier

Nature Reviews Microbiology volume 16, pages 457–470 (2018)Cite this article

Subjects

Abstract

The intestinal mucosal barrier is composed of epithelial cells that are protected by an overlying host-secreted mucous layer and functions as the first line of defence against pathogenic and non-pathogenic microorganisms. Some microorganisms have evolved strategies to either survive in the mucosal barrier or circumvent it to establish infection. In this Review, we discuss the current state of knowledge of the complex interactions of commensal microorganisms with the intestinal mucosal barrier, and we discuss strategies used by pathogenic microorganisms to establish infection by either exploiting different epithelial cell lineages or disrupting the mucous layer, as well as the role of defects in mucus production in chronic disease.

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

Fig. 1: Structure, function and production of the gut mucosal barrier.
Fig. 2: Microbial pathways involved in the metabolism of colonic mucus.
Fig. 3: Interactions of pathogens with the mucosal barrier in the small intestine.
Fig. 4: Pathogen adaptations that promote colonization and invasion of the mucosal barrier in the large intestine.

Similar content being viewed by others

References

  1. Savage, D. C. Microbial ecology of the gastrointestinal tract. Annu. Rev. Microbiol. 31, 107–133 (1977).

    Article  PubMed  CAS  Google Scholar 

  2. Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Koenig, J. E. et al. Succession of microbial consortia in the developing infant gut microbiome. Proc. Natl Acad. Sci. USA 108, 4578–4585 (2011).

    Article  PubMed  CAS  Google Scholar 

  4. Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A. & Brown, P. O. Development of the human infant intestinal microbiota. PLoS Biol. 5, e177 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Yassour, M. et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci. Transl. Med. 8, 343ra81–343ra81 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. David, L. A. et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559–563 (2014). This study demonstrates that the gut microbiota reacts quickly to shifts in diet that alter the amount of plant material versus animal protein and that similar taxa are responsive to diet across individual humans.

    Article  PubMed  CAS  Google Scholar 

  7. Sonnenburg, E. D. et al. Diet-induced extinctions in the gut microbiota compound over generations. Nature 529, 212–215 (2016). This proof-of-principle study demonstrates that prolonged dietary fibre starvation in mice results in reduced diversity within a generation, and this loss of diversity becomes irreparable and more severe over multiple generations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. El Kaoutari, A., Armougom, F., Gordon, J. I., Raoult, D. & Henrissat, B. The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nat. Rev. Microbiol. 11, 497–504 (2013).

    Article  PubMed  CAS  Google Scholar 

  9. Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013). This study demonstrates that the bacterial metabolite butyrate induces the differentiation of T reg cells and, furthermore, is able to ameliorate colitis in mice, providing novel insight into the interactions between the microbiota and host immune homeostasis.

    Article  PubMed  CAS  Google Scholar 

  10. Kim, M. H., Kang, S. G., Park, J. H., Yanagisawa, M. & Kim, C. H. Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145, 396–406 (2013).

    Article  PubMed  CAS  Google Scholar 

  11. Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1708–1720 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. den Besten, G. et al. The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J. Lipid Res. 54, 2325–2340 (2013).

    Article  CAS  Google Scholar 

  13. Louis, P., Hold, G. L. & Flint, H. J. The gut microbiota, bacterial metabolites and colorectal cancer. Nat. Rev. Microbiol. 12, 661–672 (2014).

    Article  PubMed  CAS  Google Scholar 

  14. Turner, J. R. Intestinal mucosal barrier function in health and disease. Nat. Rev. Immunol. 9, 799–809 (2009).

    Article  PubMed  CAS  Google Scholar 

  15. Peterson, L. W. & Artis, D. Intestinal epithelial cells: regulators of barrier function and immune homeostasis. Nat. Rev. Immunol. 14, 141–153 (2014).

    Article  PubMed  CAS  Google Scholar 

  16. Johansson, M. E. V. & Hansson, G. C. Immunological aspects of intestinal mucus and mucins. Nat. Rev. Immunol. 16, 639–649 (2016).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Gerbe, F., Legraverend, C. & Jay, P. The intestinal epithelium tuft cells: specification and function. Cell. Mol. Life Sci. 69, 2907–2917 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Pabst, O. New concepts in the generation and functions of IgA. Nat. Rev. Immunol. 12, 821–832 (2012).

    Article  PubMed  CAS  Google Scholar 

  20. Kommineni, S. et al. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526, 719–722 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Tailford, L. E., Crost, E. H., Kavanaugh, D. & Juge, N. Mucin glycan foraging in the human gut microbiome. Front. Genet. 6, 81 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. McGuckin, M. A., Lindén, S. K., Sutton, P. & Florin, T. H. Mucin dynamics and enteric pathogens. Nat. Rev. Microbiol. 9, 265–278 (2011).

    Article  PubMed  CAS  Google Scholar 

  23. Cameron, E. & Sperandio, V. Frenemies: signaling and nutritional integration in pathogen-microbiota-host interactions. Cell Host Microbe 18, 275–284 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Tanoue, T., Atarashi, K. & Honda, K. Development and maintenance of intestinal regulatory T cells. Nat. Rev. Immunol. 16, 295–309 (2016).

    Article  PubMed  CAS  Google Scholar 

  25. Iliev, I. D. & Leonardi, I. Fungal dysbiosis: immunity and interactions at mucosal barriers. Nat. Rev. Immunol. 17, 635–646 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  26. Darwich, A. S., Aslam, U., Ashcroft, D. M. & Rostami-Hodjegan, A. Meta-analysis of the turnover of intestinal epithelia in preclinical animal species and humans. Drug Metab. Dispos. 42, 2016–2022 (2014).

    Article  PubMed  CAS  Google Scholar 

  27. Johansson, M. E. V., Larsson, J. M. H. & Hansson, G. C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host-microbial interactions. Proc. Natl Acad. Sci. USA 108, 4659–4665 (2011).

    Article  PubMed  CAS  Google Scholar 

  28. Li, H. et al. The outer mucus layer hosts a distinct intestinal microbial niche. Nat. Commun. 6, 8292 (2015). This study separates the microbial populations and physiological responses of mucus-associated and luminal bacteria, demonstrating distinct microbiota and behaviours in these niches.

    Article  PubMed  CAS  Google Scholar 

  29. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Birchenough, G. M. H., Nystrom, E. E. L., 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 is a novel study that reveals differentiation of crypt goblet cells into distinct roles, including a TLR-expressing sentinel goblet cell that senses microbial pathogen-associated molecular patterns.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Velcich, A. et al. Colorectal cancer in mice genetically deficient in the mucin Muc2. Science 295, 1726–1729 (2002). This is a foundational study in which MUC2 was eliminated in mice to demonstrate that deficiency of MUC2 leads to development of colorectal cancer.

    Article  PubMed  CAS  Google Scholar 

  33. 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).

    Article  PubMed  CAS  Google Scholar 

  34. Johansson, M. E. V., Sjövall, H. & Hansson, G. C. The gastrointestinal mucus system in health and disease. Nat. Rev. Gastroenterol. Hepatol. 10, 352–361 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Earle, K. A. et al. Quantitative imaging of gut microbiota spatial organization. Cell Host Microbe 18, 478–488 (2015). This is a seminal study that both innovates microscopic techniques for visualizing gut bacteria and shows low fibre-induced thinning of the colonic mucous layer.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Desai, M. S. et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 167, 1339–1353 (2016). This study demonstrates that dietary fibre deprivation leads to mucus thinning and increased pathogen susceptibility in mice.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Porter, N. T. & Martens, E. C. The critical roles of polysaccharides in gut microbial ecology and physiology. Annu. Rev. Microbiol. 71, 349–369 (2017).

    Article  PubMed  CAS  Google Scholar 

  38. Koropatkin, N. M., Cameron, E.a & Martens, E. C. How glycan metabolism shapes the human gut microbiota. Nat. Rev. Microbiol. 10, 323–335 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Hutkins, R. W. et al. Prebiotics: why definitions matter. Curr. Opin. Biotechnol. 37, 1–7 (2016).

    Article  PubMed  CAS  Google Scholar 

  40. Martens, E. C. et al. Recognition and degradation of plant cell wall polysaccharides by two human gut symbionts. PLoS Biol. 9, e1001221 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Cuskin, F. et al. Human gut bacteroidetes can utilize yeast mannan through a selfish mechanism. Nature 517, 165–169 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Larsbrink, J. et al. A discrete genetic locus confers xyloglucan metabolism in select human gut bacteroidetes. Nature 506, 498–502 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Ndeh, D. et al. Complex pectin metabolism by gut bacteria reveals novel catalytic functions. Nature 544, 65–70 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Sonnenburg, E. D. et al. Specificity of polysaccharide use in intestinal bacteroides species determines diet-induced microbiota alterations. Cell 141, 1241–1252 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Nihira, T. et al. Discovery of β-1,4-d-mannosyl- N-acetyl-d-glucosamine phosphorylase involved in the metabolism of N-glycans. J. Biol. Chem. 288, 27366–27374 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Martens, E. C., Kelly, A. G., Tauzin, A. S. & Brumer, H. The devil lies in the details: how variations in polysaccharide fine-structure impact the physiology and evolution of gut microbes. J. Mol. Biol. 426, 3851–3865 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Martens, E. C., Chiang, H. C. & Gordon, J. I. Mucosal glycan foraging enhances fitness and transmission of a saccharolytic human gut bacterial symbiont. Cell Host Microbe 4, 447–457 (2008). This is a study that initially probes the Bacteroides mechanisms of host O -linked and N -linked glycan degradation, linking these functions to colonization and transmission between generations.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Nakjang, S., Ndeh, D. A., Wipat, A., Bolam, D. N. & Hirt, R. P. A novel extracellular metallopeptidase domain shared by animal host-associated mutualistic and pathogenic microbes. PLoS ONE 7, e30287 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Noach, I. et al. Recognition of protein-linked glycans as a determinant of peptidase activity. Proc. Natl Acad. Sci. USA 114, 1–10 (2017).

    Article  CAS  Google Scholar 

  50. Owen, C. D. et al. Unravelling the specificity and mechanism of sialic acid recognition by the gut symbiont Ruminococcus gnavus. Nat. Commun. 8, 2196 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Crost, E. H. et al. The mucin-degradation strategy of Ruminococcus gnavus: the importance of intramolecular trans-sialidases. Gut Microbes 7, 302–312 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Davis, C. P. & Savage, D. C. Habitat, succession, attachment, and morphology of segmented, filamentous microbes indigenous to the murine gastrointestinal tract. Infect. Immun. 10, 948–956 (1974).

    PubMed  PubMed Central  CAS  Google Scholar 

  53. Lee, S. M. et al. Bacterial colonization factors control specificity and stability of the gut microbiota. Nature 501, 426–429 (2013). This is a novel study showing that the order of gut colonization affects the ability to compete, even among isogenic strains of the same species, and that functions that govern crypt colonization contribute to colonization advantage.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Whitaker, W. R., Shepherd, E. S. & Sonnenburg, J. L. Tunable expression tools enable single-cell strain distinction in the gut microbiome. Cell 169, 538–546.e12 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Pedron, T. et al. A crypt-specific core microbiota resides in the mouse colon. mBio 3, e00116–e00112 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011). This paper demonstrates the importance of the antimicrobial protein REG3γ to avoid close bacterial contact with small intestinal epithelium.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Hase, K. et al. Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response. Nature 462, 226–230 (2009).

    Article  PubMed  CAS  Google Scholar 

  59. Clark, M. A., Jepson, M. A., Simmons, N. L. & Hirts, B. H. Preferential interaction of Salmonella typhimurium with mouse Peyer's patch M cells. Res. Microbiol. 145, 543–552 (1994).

    Article  PubMed  CAS  Google Scholar 

  60. Rescigno, M. et al. Dendritic cells express tight junction proteins and penetrate gut epithelial monolayers to sample bacteria. Nat. Immunol. 2, 361–367 (2001).

    Article  PubMed  CAS  Google Scholar 

  61. Marra, A. & Isberg, R. R. Invasin-dependent and invasin-independent pathways for translocation of Yersinia pseudotuberculosis across the Peyer’s patch intestinal epithelium. Infect. Immun. 65, 3412–3421 (1997).

    PubMed  PubMed Central  CAS  Google Scholar 

  62. Rankin, S., Isberg, R. R. & Leong, J. M. The integrin-binding domain of invasin is sufficient to allow bacterial entry into mammalian cells. Infect. Immun. 60, 3909–3912 (1992).

    PubMed  PubMed Central  CAS  Google Scholar 

  63. Clark, M. A., Hirst, B. H. & Jepson, M. A. M-Cell surface β1 integrin expression and invasin-mediated targeting of Yersinia pseudotuberculosis to mouse Peyer’s patch M cells. Infect. Immun. 66, 1237–1243 (1998).

    PubMed  PubMed Central  CAS  Google Scholar 

  64. Secott, T. E., Lin, T. L. & Wu, C. C. Mycobacterium avium subsp. paratuberculosis fibronectin attachment protein facilitates M-cell targeting and invasion through a fibronectin bridge with host integrins. Infect. Immun. 72, 3724–3732 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Shen, Y., Naujokas, M., Park, M. & Ireton, K. InIB-dependent internalization of Listeria is mediated by the Met receptor tyrosine kinase. Cell 103, 501–510 (2000).

    Article  PubMed  CAS  Google Scholar 

  66. Mengaud, J., Ohayon, H., Gounon, P., Mege, R. M. & Cossart, P. E-Cadherin is the receptor for internalin, a surface protein required for entry of L. monocytogenes into epithelial cells. Cell 84, 923–932 (1996).

    Article  PubMed  CAS  Google Scholar 

  67. Sousa, S. et al. Src, cortactin and Arp2/3 complex are required for E-cadherin-mediated internalization of Listeria into cells. Cell. Microbiol. 9, 2629–2643 (2007).

    Article  PubMed  CAS  Google Scholar 

  68. Kocks, C. et al. L. monocytogenes-induced actin assembly requires the actA gene product, a surface protein. Cell 68, 521–531 (1992).

    Article  PubMed  CAS  Google Scholar 

  69. 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).

    Article  PubMed  CAS  Google Scholar 

  70. Wu, Z., Nybom, P. & Magnusson, K.-E. Distinct effects of Vibrio cholerae haemagglutinin/protease on the structure and localization of the tight junction-associated proteins occludin and ZO-1. Cell. Microbiol. 2, 11–17 (2000).

    Article  PubMed  CAS  Google Scholar 

  71. Fasano, A. et al. Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc. Natl Acad. Sci. USA 88, 5242–5246 (1991).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  72. Saitoh, Y. et al. Tight junctions. Structural insight into tight junction disassembly by Clostridium perfringens enterotoxin. Science 347, 775–778 (2015).

    Article  PubMed  CAS  Google Scholar 

  73. Amat, C. B., Motta, J.-P., Chadee, K. & Buret, A. G. Giardia duodenalis directly depletes mucins in intestinal goblet cells. FASEB J 30, 162.1–162.1 (2016).

    Google Scholar 

  74. Maia-Brigagão, C., Morgado-Díaz, J. A. & De Souza, W. Giardia disrupts the arrangement of tight, adherens and desmosomal junction proteins of intestinal cells. Parasitol. Int. 61, 280–287 (2012).

    Article  PubMed  CAS  Google Scholar 

  75. Teoh, Da, Kamieniecki, D., Pang, G. & Buret, A. G. Giardia lamblia rearranges F-actin and alpha-actinin in human colonic and duodenal monolayers and reduces transepithelial electrical resistance. J. Parasitol. 86, 800–806 (2000).

    PubMed  CAS  Google Scholar 

  76. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Zhou, Z. et al. Lipid A modifications in polymyxin-resistant Salmonella typhimurium: PmrA-dependent 4-amino-4-deoxy- L-arabinose, and phosphoethanolamine incorporation. J. Biol. Chem. 276, 43111–43121 (2001).

    Article  PubMed  CAS  Google Scholar 

  78. Gunn, J. S. et al. PmrA-PmrB-regulated genes necessary for 4-aminoarabinose lipid A modification and polymyxin resistance. Mol. Microbiol. 27, 1171–1182 (1998).

    Article  PubMed  CAS  Google Scholar 

  79. Vaara, M. et al. Characterization of the lipopolysaccharide from the polymyxin-resistant pmrA mutants of Salmonella typhimurium. FEBS Lett. 129, 145–149 (1981).

    Article  PubMed  CAS  Google Scholar 

  80. Peschel, A. How do bacteria resist human antimicrobial peptides? Trends Microbiol. 10, 179–186 (2002).

    Article  PubMed  CAS  Google Scholar 

  81. Llobet, E., Tomas, J. M. & Bengoechea, J. A. Capsule polysaccharide is a bacterial decoy for antimicrobial peptides. Microbiology 154, 3877–3886 (2008).

    Article  PubMed  CAS  Google Scholar 

  82. Tan, Y., Zanoni, I., Cullen, T. W., Goodman, A. L. & Kagan, J. C. Mechanisms of toll-like receptor 4 endocytosis reveal a common immune-evasion strategy used by pathogenic and commensal bacteria. Immunity 43, 909–922 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Cullen, T. W. et al. Antimicrobial peptide resistance mediates resilience of prominent gut commensals during inflammation. Scince 347, 170–175 (2015).

    Article  CAS  Google Scholar 

  84. Kim, Y. G. et al. Neonatal acquisition of Clostridia species protects against colonization by bacterial pathogens. Science 356, 315–319 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  85. Byndloss, M. X. et al. Microbiota-activated PPAR-γ signaling inhibits dysbiotic Enterobacteriaceae expansion. Science 357, 570–575 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Hasnain, S. Z. et al. Mucin gene deficiency in mice impairs host resistance to an enteric parasitic infection. Gastroenterology 138, 1763–1771 (2010).

    Article  PubMed  CAS  Google Scholar 

  88. Turner, J. E., Stockinger, B. & Helmby, H. IL-22 mediates goblet cell hyperplasia and worm expulsion in intestinal helminth infection. PLoS Pathog. 9, 1–7 (2013).

    Article  CAS  Google Scholar 

  89. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat. Med. 14, 282–289 (2008).

    Article  PubMed  CAS  Google Scholar 

  90. Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Erdem, A. L., Avelino, F., Xicohtencatl-Cortes, J. & Girón, J. A. Host protein binding and adhesive properties of H6 and H7 flagella of attaching and effacing Escherichia coli. J. Bacteriol. 189, 7426–7435 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Lawley, T. D. et al. Antibiotic treatment of Clostridium difficile carrier mice triggers a supershedder state, spore-mediated transmission, and severe disease in immunocompromised hosts. Infect. Immun. 77, 3661–3669 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Tasteyre, A., Barc, M. C., Collignon, A., Boureau, H. & Karjalainen, T. Role of FliC and FliD flagellar proteins of Clostridium difficile in adherence and gut colonization. Infect. Immun. 69, 7937–7940 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Purcell, E. B., McKee, R. W., McBride, S. M., Waters, C. M. & Tamayo, R. Cyclic diguanylate inversely regulates motility and aggregation in Clostridium difficile. J. Bacteriol. 194, 3307–3316 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Li, S., Konstantinov, S. R., Smits, R. & Peppelenbosch, M. P. Bacterial biofilms in colorectal cancer initiation and progression. Trends Mol. Med. 23, 18–30 (2017).

    Article  PubMed  Google Scholar 

  96. Dejea, C. M. et al. Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359, 592–597 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Grys, T. E., Siegel, M. B., Lathem, W. W. & Welch, R. A. The StcE protease contributes to intimate adherence of enterohemorrhagic Escherichia coli O157:H7 to host cells. Infect. Immun. 73, 1295–1303 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Hews, C. L. et al. The StcE metalloprotease of enterohaemorrhagic Escherichia coli reduces the inner mucus layer and promotes adherence to human colonic epithelium ex vivo. Cell. Microbiol. 19, e12717 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  99. Valeri, M. et al. Pathogenic E. coli exploits SslE mucinase activity to translocate through the mucosal barrier and get access to host cells. PLoS One 10, 1–14 (2015).

    Google Scholar 

  100. Moncada, D., Keller, K. & Chadee, K. Entamoeba histolytica cysteine proteinases disrupt the polymeric structure of colonic mucin and alter its protective function. Infect. Immun. 71, 838–844 (2003). This is a study that reveals that pathogens can target critical sites in the MUC2 network to dissolve its important barrier function.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  102. Chadee, K., Petri, W. A., Innes, D. J. & Ravdin, J. I. Rat and human colonic mucins bind to and inhibit adherence lectin of Entamoeba histolytica. J. Clin. Invest. 80, 1245–1254 (1987).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Hasnain, S. Z., McGuckin, M. A., Grencis, R. K. & Thornton, D. J. Serine protease(s) secreted by the nematode Trichuris muris degrade the mucus barrier. PLoS Negl. Trop. Dis. 6, e1856 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Nusrat, A. Turner, J. R., Verkade, P., Madara, L. & Parkos, C. A. Clostridium difficile toxins disrupt epithelial barrier function by altering membrane microdomain localization of tight junction proteins. Infect. Immun. 69, 1329–1336 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Guttman, J. A. et al. Attaching and effacing pathogen-induced tight junction disruption in vivo. Cell Microbiol 8, 634–645 (2006).

    Article  PubMed  CAS  Google Scholar 

  106. Simonovic, I., Rosenberg, J., Koutsouris, A. & Hecht, G. Enteropathogenic Escherichia coli dephosphorylates and dissociates occludin from intestinal epithelial tight junctions. Cell. Microbiol. 2, 305–315 (2000).

    Article  PubMed  CAS  Google Scholar 

  107. Elmi, A. et al. Campylobacter jejuni outer membrane vesicle-associated proteolytic activity promotes bacterial invasion by mediating cleavage of intestinal epithelial cell E-cadherin and occludin. Cell. Microbiol. 18, 561–572 (2016).

    Article  PubMed  CAS  Google Scholar 

  108. Ng, K. M. et al. Microbiota-liberated host sugars facilitate post-antibiotic expansion of enteric pathogens. Nature 502, 96–99 (2013). This study connects the mucin-foraging activity of commensal B. thetaiotaomicron with the release of sialic acid, which benefits the pathogens C. difficile and S . Typhimurium.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Pacheco, A. R. et al. Fucose sensing regulates bacterial intestinal colonization. Nature 492, 113–117 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Bry, L., Falk, P. G., Midtvedt, T. & Gordon, J. I. A model of host-microbial interactions in an open mammalian ecosystem. Science 273, 1380–1383 (1996).

    Article  PubMed  CAS  Google Scholar 

  111. Engevik, M. A. et al. Loss of NHE3 alters gut microbiota composition and influences bacteroides thetaiotaomicron growth. Am. J. Physiol. Gastrointest. Liver Physiol. 305, G697–G711 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Schumann, M., Siegmund, B., Schulzke, J. D. & Fromm, M. Celiac disease: role of the epithelial barrier. Cell. Mol. Gastroenterol. Hepatol. 3, 150–162 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Wang, Y. et al. Cosmc is an essential chaperone for correct protein O-glycosylation. Proc. Natl Acad. Sci. USA 107, 9228–9233 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  114. Bergstrom, K. et al. Core 1– and 3–derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. Mucosal Immunol. 10, 91–103 (2017).

    Article  PubMed  CAS  Google Scholar 

  115. Fu, J. et al. Loss of intestinal core 1–derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666 (2011). This is a critical study that demonstrates that defects in MUC2 glycosylation in mice, which are similar to those observed in some humans, promote spontaneous inflammation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Johansson, M. E. V. 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).

    Article  PubMed  CAS  Google Scholar 

  117. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Schroeder, B. O. et al. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe 23, 27–40.e7 (2017). This study demonstrates that a low-fibre, Western-style diet promotes increased permeability of the inner mucous layer that can be reversed by prebiotics and probiotics.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  119. Palm, N. W. et al. Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease. Cell 158, 1000–1010 (2014). This is an important study establishing that a subset of microbiota species is coated with IgA and that these species elicit increased host inflammatory responses when separately introduced into germ-free mice.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Bergstrom, K. S. B. & Xia, L. Mucin-type O-glycans and their roles in intestinal homeostasis. Glycobiology 23, 1026–1037 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Ju, T. et al. Human tumor antigens Tn and sialyl Tn arise from mutations in Cosmc. Cancer Res. 68, 1636–1646 (2008).

    Article  PubMed  CAS  Google Scholar 

  122. An, G. et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3–derived O-glycans. J. Exp. Med. 204, 1417–1429 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Sommer, F. et al. Altered mucus glycosylation in core 1 O-glycan-deficient mice affects microbiota composition and intestinal architecture. PLoS One 9, e85254 (2014).

  124. Zhu, W. et al. Precision editing of the gut microbiota ameliorates colitis. Nature 553, 208–211 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Zou, J. et al. Fiber-mediated nourishment of gut microbiota protects against diet-induced obesity by restoring IL-22-mediated colonic health. Cell Host Microbe 23, 41–53 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  127. Moor, K. et al. High-avidity IgA protects the intestine by enchaining growing bacteria. Nature 544, 498–502 (2017).

    Article  PubMed  CAS  Google Scholar 

  128. Okumura, R. et al. Lypd8 promotes the segregation of flagellated microbiota and colonic epithelia. Nature 532, 117–121 (2016).

    Article  PubMed  CAS  Google Scholar 

  129. Propheter, D. C., Chara, A. L., Harris, T. A., Ruhn, K. A. & Hooper, L. V. Resistin-like molecule β is a bactericidal protein that promotes spatial segregation of the microbiota and the colonic epithelium. Proc. Natl Acad. Sci. 114, 11027–11033 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  130. Akira, S. & Takeda, K. Toll-like receptor signalling. Nat. Rev. Immunol. 4, 499–511 (2004).

    Article  PubMed  CAS  Google Scholar 

  131. Fukata, M. Toll-like receptor-4 is required for intestinal response to epithelial injury and limiting bacterial translocation in a murine model of acute colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 288, G1055–G1065 (2005).

    Article  PubMed  CAS  Google Scholar 

  132. Danne, C. et al. A large polysaccharide produced by helicobacter hepaticus induces an anti-inflammatory gene signature in macrophages. Cell Host Microbe 22, 733–745.e5 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Chung, L. et al. Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells. Cell Host Microbe 23, 203–214.e5 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  134. 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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Xie, L. et al. Targeting of MyD88 homodimerization by novel synthetic inhibitor TJ-M2010-5 in preventing colitis-associated colorectal cancer. J. Natl Cancer Inst. 108, 1–12 (2016).

    Article  CAS  Google Scholar 

  136. Carvalho, F. A. et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139–152 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  137. Zhan, Y. et al. Gut microbiota protects against gastrointestinal tumorigenesis caused by epithelial injury. Cancer Res. 73, 7199–7210 (2013).

    Article  PubMed  CAS  Google Scholar 

  138. Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013).

    Article  PubMed  CAS  Google Scholar 

  139. Singh, N. et al. Activation of the receptor (Gpr109a) for niacin and the commensal metabolite butyrate suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Zhang, M. et al. Butyrate inhibits interleukin-17 and generates Tregs to ameliorate colorectal colitis in rats. BMC Gastroenterol. 16, 84 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  141. Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Fukuda, S. et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 469, 543–547 (2011).

    Article  PubMed  CAS  Google Scholar 

  143. Howitt, M. R. et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351, 1329–1333 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  145. 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).

    Article  CAS  Google Scholar 

  146. Holmén Larsson, J. M., Thomsson, K. A., Rodríguez-Piñeiro, A. M., Karlsson, H. & Hansson, G. C. 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. 305, G357–G363 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Bennett, E. P. et al. Control of mucin-type O-glycosylation: a classification of the polypeptide GalNAc-transferase gene family. Glycobiology 22, 736–756 (2012).

    Article  PubMed  CAS  Google Scholar 

  148. Brockhausen, I., Schachter, H., S. P. Essentials of Glycobiology (Cold Spring Harbor Laboratory Press, 2009).

  149. Lawhon, S. D., Maurer, R., Suyemoto, M. & Altier, C. Intestinal short-chain fatty acids alter Salmonella typhimurium invasion gene expression and virulence through BarA/SirA. Mol. Microbiol. 46, 1451–1464 (2002).

    Article  PubMed  CAS  Google Scholar 

  150. Gantois, I. et al. Butyrate specifically down-regulates Salmonella pathogenicity island 1 gene expression. Appl. Environ. Microbiol. 72, 946–949 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Hung, C. C. et al. The intestinal fatty acid propionate inhibits Salmonella invasion through the post-translational control of HilD. Mol. Microbiol. 87, 1045–1060 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Ferreyra, J. A. et al. Gut microbiota-produced succinate promotes C. difficile infection after antibiotic treatment or motility disturbance. Cell Host Microbe 16, 770–777 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  153. Curtis, M. M. et al. The gut commensal Bacteroides thetaiotaomicron exacerbates enteric infection through modification of the metabolic landscape. Cell Host Microbe 16, 759–769 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  154. Tobe, T., Nakanishi, N. & Sugimoto, N. Activation of motility by sensing short-chain fatty acids via two steps in a flagellar gene regulatory cascade in enterohemorrhagic Escherichia coli. Infect. Immun. 79, 1016–1024 (2011).

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

Work in the authors’ laboratories was supported by National Institutes of Health R01 and R21 (GM099513 and AI128120) awards (to E.C.M.) and an Innovator Award from the Kenneth Rainin Foundation. Work in their laboratories was also supported by the following grants (to M.S.D.): Luxembourg National Research Fund (FNR) CORE (C15/BM/10318186); FNR AFR Bilateral (11228353); Luxembourg Ministry of Higher Education and Research support (DM-Muc); and Personalized Medicine Consortium of Luxembourg Pump Prime (Die-IBD).

Author information

Authors and Affiliations

  1. University of Michigan Medical School, Ann Arbor, MI, USA

    Eric C. Martens

  2. Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg

    Mareike Neumann & Mahesh S. Desai

  3. Odense Research Center for Anaphylaxis, Department of Dermatology and Allergy Center, Odense University Hospital, University of Southern Denmark, Odense, Denmark

    Mahesh S. Desai

Authors
  1. Eric C. Martens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mareike Neumann
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mahesh S. Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.C.M., M.N. and M.S.D. researched data for the article, discussed the content, wrote the article, and reviewed and edited the manuscript before submission.

Corresponding authors

Correspondence to Eric C. Martens or Mahesh S. Desai.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Commensal

Refers to symbiotic microorganisms that do not seem to harm (pathogens) or benefit (mutualists) their host. Commensal is arguably an imprecise term to apply to a microorganism, especially considering that any microorganism may display behaviours that are both beneficial and detrimental.

Microbiota

A community of microorganisms, such as the taxonomically diverse and densely populated assemblage of species that inhabits the human gut.

Inflammatory bowel disease

(IBD). A group of chronic diseases characterized by episodes of relapsing and remitting inflammation. Crohn’s disease and ulcerative colitis are the most common types of IBDs and are thought to develop from a combination of host genetic predisposition, including defects in the gut mucosal and immunological barriers, and environmental factors, such as diet and the microbiota.

Tight junctions

Multi-protein complexes that form near the apical ends of intestinal epithelial cells, providing tight, water-impermeable and ion-impermeable seals between cells. Proteins that are included in tight junctions include claudins and occludins, which span the membrane and are anchored together outside the cell and are connected to the intracellular cytoskeleton.

Mucous layer

Mucus, composed mostly of secreted mucin glycoproteins and other substances, is secreted by goblet cells and overlies the intestinal epithelium, forming an adherent and insoluble inner layer and a looser outer layer in the colon.

Tuft cells

Taste-chemosensory cells that are present in the intestinal epithelium and have an important role in initiating a type 2 immune response to clear parasitic infection. They have a unique appearance that includes a tubulovesicular system and an apical bundle of microfilaments that are attached to a tuft of long, lumen-facing microvilli.

Glycoproteins

Class of proteins comprising oligosaccharide chains connected to a backbone polypeptide, sometimes thousands of amino acids long, which is modified with glycans in the endoplasmic reticulum. Mucins and other glycoproteins contain O-linked and N-linked glycans attached to serine or threonine and asparagine, respectively.

Secretory IgA

Immunoglobulin A (IgA) is the most abundant antibody isotype in the human body and occurs in two subtypes: IgA1 and IgA2, which are distinguished by their heavy chains. IgA1 is predominant in the serum, and IgA2 is most abundant in the intestinal tract to bind pathogens by reducing mobility and decreasing proliferation.

Carbohydrate-active enzymes

(CAZymes). This term encompasses several different groups of enzymes: glycoside hydrolases, polysaccharide lyases, carbohydrate esterases and glycosyltransferases. These groups, and hundreds of more specific enzyme families that they collectively contain, are involved in building and degrading polysaccharides and glycans.

Prebiotics

Dietary supplements (most often oligosaccharide or polysaccharide fibres) that selectively increase certain taxonomic groups in the gut microbiota and also exert a positive impact on host health.

Hidden Markov models

A statistical approach that is often used in bioinformatics to identify hidden, but meaningful, amino acid sequence signals in proteins and can be used to group them into families with similar function.

Interleukin-22

(IL-22). A cytokine that is part of the IL-10 cytokine family that is produced by activated natural killer and T cells and, in the gut, is responsible for activating epithelial cell regeneration, mucin production and antimicrobial peptide secretion.

Innate lymphoid cells

(ILCs). A group of innate immune cells that are characterized by the absence of antigen-specific B or T cell receptors.

Colonization resistance

A phenomenon by which the presence of a healthy microbiota inhibits invasion by external pathogens. In the gut, this state has been ascribed to the inhibition of many enteric pathogens, which are more adept at gaining an infection foothold after a major perturbation, such as antibiotic treatment.

Lectin

A broad family of plant, animal and bacterial proteins defined by their ability to bind to certain carbohydrates with moderate to high affinity.

Type III secretion systems

(T3SSs). Needle-like complexes related to the bacterial flagellum that are an important virulence factor of Gram-negative bacteria. They enable pathogenic bacteria to inject effector proteins into the cytoplasm of the host target cell and modify a variety of cellular responses.

Molecular chaperone

Type of protein that assists in the folding and unfolding of other proteins. They prevent aggregation by binding to non-native structures and therefore support the folding process.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Martens, E.C., Neumann, M. & Desai, M.S. Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier. Nat Rev Microbiol 16, 457–470 (2018). https://doi.org/10.1038/s41579-018-0036-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41579-018-0036-x

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