Skip to main content
SpringerLink
Log in

Genetically determined epithelial dysfunction and its consequences for microflora–host interactions

  • Multi-author review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The intestinal epithelium forms a highly active functional interface between the relatively sterile internal body surfaces and the enormously complex and diverse microbiota that are contained within the lumen. Genetic models that allow for manipulation of genes specifically in the intestinal epithelium have provided an avenue to understand the diverse set of pathways whereby intestinal epithelial cells (IECs) direct the immune state of the mucosa associated with homeostasis versus either productive or non-productive inflammation as occurs during enteropathogen invasion or inflammatory bowel disease (IBD), respectively. These pathways include the unfolded protein response (UPR) induced by stress in the endoplasmic reticulum (ER), autophagy, a self-cannibalistic pathway important for intracellular bacterial killing and proper Paneth cell function as well as the interrelated functions of NOD2/NF-κB signaling which also regulate autophagy induction. Multiple genes controlling these IEC pathways have been shown to be genetic risk factors for human IBD. This highlights the importance of these pathways not only for proper IEC function but also suggesting that IECs may be one of the cellular originators of organ-specific and systemic inflammation as in IBD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Kaser A, Zeissig S, Blumberg RS (2010) Inflammatory bowel disease. Annu Rev Immunol 28:573–621

    Article  PubMed  CAS  Google Scholar 

  2. Garrett WS, Gordon JI, Glimcher LH (2010) Homeostasis and inflammation in the intestine. Cell 140:859–870

    Article  PubMed  CAS  Google Scholar 

  3. Chow J, Lee SM, Shen Y, Khosravi A, Mazmanian SK (2010) Host-bacterial symbiosis in health and disease. Adv Immunol 107:243–274

    Article  PubMed  CAS  Google Scholar 

  4. Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789

    Article  PubMed  Google Scholar 

  5. Todd DJ, Lee AH, Glimcher LH (2008) The endoplasmic reticulum stress response in immunity and autoimmunity. Nat Rev Immunol 8:663–674

    Article  PubMed  CAS  Google Scholar 

  6. van der Flier LG, Clevers H (2009) Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71:241–260

    Article  PubMed  Google Scholar 

  7. Ouellette AJ (2010) Paneth cells and innate mucosal immunity. Curr Opin Gastroenterol 26:547–553

    Article  PubMed  Google Scholar 

  8. Sato T, van Es JH, Snippert HJ, Stange DE, Vries RG, van den Born M, Barker N, Shroyer NF, van de Wetering M, Clevers H (2010) Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature

  9. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  PubMed  CAS  Google Scholar 

  10. Kaser A, Lee AH, Franke A, Glickman JN, Zeissig S, Tilg H, Nieuwenhuis EE, Higgins DE, Schreiber S, Glimcher LH et al (2008) XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134:743–756

    Article  PubMed  CAS  Google Scholar 

  11. Salzman NH, Hung K, Haribhai D, Chu H, Karlsson-Sjoberg J, Amir E, Teggatz P, Barman M, Hayward M, Eastwood D et al (2010) Enteric defensins are essential regulators of intestinal microbial ecology. Nat Immunol 11:76–83

    Article  PubMed  CAS  Google Scholar 

  12. Garabedian EM, Roberts LJ, McNevin MS, Gordon JI (1997) Examining the role of Paneth cells in the small intestine by lineage ablation in transgenic mice. J Biol Chem 272:23729–23740

    Article  PubMed  CAS  Google Scholar 

  13. Wilson CL, Ouellette AJ, Satchell DP, Ayabe T, Lopez-Boado YS, Stratman JL, Hultgren SJ, Matrisian LM, Parks WC (1999) Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science 286:113–117

    Article  PubMed  CAS  Google Scholar 

  14. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nunez G, Flavell RA (2005) Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307:731–734

    Article  PubMed  CAS  Google Scholar 

  15. Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R et al (2005) Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. Proc Natl Acad Sci USA 102:18129–18134

    Article  PubMed  CAS  Google Scholar 

  16. Biswas A, Liu YJ, Hao L, Mizoguchi A, Salzman NH, Bevins CL, Kobayashi KS (2010) Induction and rescue of Nod2-dependent Th1-driven granulomatous inflammation of the ileum. Proc Natl Acad Sci USA 107:14739–14744

    Article  PubMed  CAS  Google Scholar 

  17. Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M et al (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603

    Article  PubMed  CAS  Google Scholar 

  18. Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH et al (2001) A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 411:603–606

    Article  PubMed  CAS  Google Scholar 

  19. Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S, Frenzel H, King K, Hasselmeyer A, MacPherson AJ et al (2001) Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations. Lancet 357:1925–1928

    Article  PubMed  CAS  Google Scholar 

  20. Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O’Morain C, Gassull M, Binder V et al (2002) CARD15/NOD2 mutational analysis and genotype–phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845–857

    Article  PubMed  CAS  Google Scholar 

  21. Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T, Lees CW, Balschun T, Lee J, Roberts R et al (2010) Genome-wide meta-analysis increases to 71 the number of confirmed Crohn’s disease susceptibility loci. Nat Genet 42:1118–1125

    Article  PubMed  CAS  Google Scholar 

  22. Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson DJ, Campbell BJ, Jewell D, Simmons A (2010) NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med 16:90–97

    Article  PubMed  CAS  Google Scholar 

  23. Travassos LH, Carneiro LA, Ramjeet M, Hussey S, Kim YG, Magalhaes JG, Yuan L, Soares F, Chea E, Le Bourhis L et al (2010) Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat Immunol 11:55–62

    Article  PubMed  CAS  Google Scholar 

  24. Homer CR, Richmond AL, Rebert NA, Achkar JP, McDonald C (2010) ATG16L1 and NOD2 interact in an autophagy-dependent antibacterial pathway implicated in Crohn’s disease pathogenesis. Gastroenterology 139:1630–1641, e1631–e1632

    Article  PubMed  CAS  Google Scholar 

  25. Hampe J, Franke A, Rosenstiel P, Till A, Teuber M, Huse K, Albrecht M, Mayr G, De La Vega FM, Briggs J et al (2007) A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39:207–211

    Article  PubMed  CAS  Google Scholar 

  26. Rioux JD, Xavier RJ, Taylor KD, Silverberg MS, Goyette P, Huett A, Green T, Kuballa P, Barmada MM, Datta LW et al (2007) Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nat Genet 39:596–604

    Article  PubMed  CAS  Google Scholar 

  27. Parkes M, Barrett JC, Prescott NJ, Tremelling M, Anderson CA, Fisher SA, Roberts RG, Nimmo ER, Cummings FR, Soars D et al (2007) Sequence variants in the autophagy gene IRGM and multiple other replicating loci contribute to Crohn’s disease susceptibility. Nat Genet 39:830–832

    Article  PubMed  CAS  Google Scholar 

  28. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451:1069–1075

    Article  PubMed  CAS  Google Scholar 

  29. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132:27–42

    Article  PubMed  CAS  Google Scholar 

  30. Cadwell K, Liu JY, Brown SL, Miyoshi H, Loh J, Lennerz JK, Kishi C, Kc W, Carrero JA, Hunt S et al (2008) A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature 456:259–263

    Article  PubMed  CAS  Google Scholar 

  31. Cadwell K, Patel KK, Maloney NS, Liu TC, Ng AC, Storer CE, Head RD, Xavier R, Stappenbeck TS, Virgin HW (2010) Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141:1135–1145

    Article  PubMed  CAS  Google Scholar 

  32. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G (2001) Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 276:4812–4818

    Article  PubMed  CAS  Google Scholar 

  33. Abbott DW, Yang Y, Hutti JE, Madhavarapu S, Kelliher MA, Cantley LC (2007) Coordinated regulation of Toll-like receptor and NOD2 signaling by K63-linked polyubiquitin chains. Mol Cell Biol 27:6012–6025

    Article  PubMed  CAS  Google Scholar 

  34. Abbott DW, Wilkins A, Asara JM, Cantley LC (2004) The Crohn’s disease protein, NOD2, requires RIP2 in order to induce ubiquitinylation of a novel site on NEMO. Curr Biol 14:2217–2227

    Article  PubMed  CAS  Google Scholar 

  35. Yeretssian G, Correa RG, Doiron K, Fitzgerald P, Dillon CP, Green DR, Reed JC, Saleh M. (2011). Non-apoptotic role of BID in inflammation and innate immunity. Nature

  36. Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27:693–733

    Article  PubMed  CAS  Google Scholar 

  37. Watanabe T, Kitani A, Murray PJ, Strober W (2004) NOD2 is a negative regulator of Toll-like receptor 2-mediated T helper type 1 responses. Nat Immunol 5:800–808

    Article  PubMed  CAS  Google Scholar 

  38. Hedl M, Li J, Cho JH, Abraham C (2007) Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci USA 104:19440–19445

    Article  PubMed  CAS  Google Scholar 

  39. Zaph C, Troy AE, Taylor BC, Berman-Booty LD, Guild KJ, Du Y, Yost EA, Gruber AD, May MJ, Greten FR et al (2007) Epithelial-cell-intrinsic IKK-beta expression regulates intestinal immune homeostasis. Nature 446:552–556

    Article  PubMed  CAS  Google Scholar 

  40. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, Huth M, Nikolaev A, Neufert C, Madison B et al (2007) Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557–561

    Article  PubMed  CAS  Google Scholar 

  41. Rimoldi M, Chieppa M, Salucci V, Avogadri F, Sonzogni A, Sampietro GM, Nespoli A, Viale G, Allavena P, Rescigno M (2005) Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells. Nat Immunol 6:507–514

    Article  PubMed  CAS  Google Scholar 

  42. Herbert DR, Yang JQ, Hogan SP, Groschwitz K, Khodoun M, Munitz A, Orekov T, Perkins C, Wang Q, Brombacher F et al (2009) Intestinal epithelial cell secretion of RELM-beta protects against gastrointestinal worm infection. J Exp Med 206:2947–2957

    Article  PubMed  CAS  Google Scholar 

  43. He W, Wang ML, Jiang HQ, Steppan CM, Shin ME, Thurnheer MC, Cebra JJ, Lazar MA, Wu GD (2003) Bacterial colonization leads to the colonic secretion of RELM-beta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology 125:1388–1397

    Article  PubMed  CAS  Google Scholar 

  44. Artis D, Wang ML, Keilbaugh SA, He W, Brenes M, Swain GP, Knight PA, Donaldson DD, Lazar MA, Miller HR et al (2004) RELM-beta/FIZZ2 is a goblet cell-specific immune-effector molecule in the gastrointestinal tract. Proc Natl Acad Sci USA 101:13596–13600

    Article  PubMed  CAS  Google Scholar 

  45. Ziegler SF, Artis D (2010) Sensing the outside world: TSLP regulates barrier immunity. Nat Immunol 11:289–293

    Article  PubMed  CAS  Google Scholar 

  46. Taylor BC, Zaph C, Troy AE, Du Y, Guild KJ, Comeau MR, Artis D (2009) TSLP regulates intestinal immunity and inflammation in mouse models of helminth infection and colitis. J Exp Med 206:655–667

    Article  PubMed  CAS  Google Scholar 

  47. Biton M, Levin A, Slyper M, Alkalay I, Horwitz E, Mor H, Kredo-Russo S, Avnit-Sagi T, Cojocaru G, Zreik F et al (2011) Epithelial microRNAs regulate gut mucosal immunity via epithelium-T cell crosstalk. Nat Immunol 12:239–246

    Article  PubMed  CAS  Google Scholar 

  48. Ivanov II, Atarashi K, Manel N, Brodie EL, Shima T, Karaoz U, Wei D, Goldfarb KC, Santee CA, Lynch SV et al (2009) Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139:485–498

    Article  PubMed  CAS  Google Scholar 

  49. Gaboriau-Routhiau V, Rakotobe S, Lecuyer E, Mulder I, Lan A, Bridonneau C, Rochet V, Pisi A, De Paepe M, Brandi G et al (2009) The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31:677–689

    Article  PubMed  CAS  Google Scholar 

  50. Mazmanian SK, Liu CH, Tzianabos AO, Kasper DL (2005) An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122:107–118

    Article  PubMed  CAS  Google Scholar 

  51. Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625

    Article  PubMed  CAS  Google Scholar 

  52. Round JL, Lee SM, Li J, Tran G, Jabri B, Chatila TA, Mazmanian SK (2011) The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332:974–977

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Work in the authors’ laboratories is supported by NIH RO1 grants DK44319, DK51362, DK53056 and DK08819 (R.S.B.), Innsbruck Medical University (MFI 2007-407, A.K.), the Austrian Science Fund and Ministry of Science P21530 and START Y446 (A.K.), the European Research Council under the European Community’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant agreement no. 260961 (A.K.) and the National Institute for Health Research Cambridge Biomedical Research Centre (A.K.).

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Addenbrooke’s Hospital, Level 5, Box 157, Hills Road, Cambridge, CB2 0QQ, UK

    Arthur Kaser & Lukas Niederreiter

  2. Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, USA

    Richard S. Blumberg

Authors
  1. Arthur Kaser
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lukas Niederreiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard S. Blumberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Arthur Kaser or Richard S. Blumberg.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaser, A., Niederreiter, L. & Blumberg, R.S. Genetically determined epithelial dysfunction and its consequences for microflora–host interactions. Cell. Mol. Life Sci. 68, 3643–3649 (2011). https://doi.org/10.1007/s00018-011-0827-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0827-y

Keywords

Search

Navigation