Mechanisms of Disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases

  • Nature Clinical Practice Gastroenterology & Hepatology 2, 416422 (2005)
  • doi:10.1038/ncpgasthep0259
  • Download Citation
Published online:


The primary functions of the gastrointestinal tract have traditionally been perceived to be limited to the digestion and absorption of nutrients and electrolytes, and to water homeostasis. A more attentive analysis of the anatomic and functional arrangement of the gastrointestinal tract, however, suggests that another extremely important function of this organ is its ability to regulate the trafficking of macromolecules between the environment and the host through a barrier mechanism. Together with the gut-associated lymphoid tissue and the neuroendocrine network, the intestinal epithelial barrier, with its intercellular tight junctions, controls the equilibrium between tolerance and immunity to nonself-antigens. When the finely tuned trafficking of macromolecules is dysregulated in genetically susceptible individuals, both intestinal and extraintestinal autoimmune disorders can occur. This new paradigm subverts traditional theories underlying the development of autoimmunity, which are based on molecular mimicry and/or the bystander effect, and suggests that the autoimmune process can be arrested if the interplay between genes and environmental triggers is prevented by re-establishing intestinal barrier function. Understanding the role of the intestinal barrier in the pathogenesis of gastrointestinal disease is an area of translational research that encompasses many fields and is currently receiving a great deal of attention. This review is timely given the increased interest in the role of a 'leaky gut' in the pathogenesis of gastrointestinal diseases and the advent of novel treatment strategies, such as the use of probiotics.

  • Subscribe to Nature Reviews Gastroenterology & Hepatology for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.


  1. 1.

    and (2003) The epidemiology of autoimmune diseases. Autoimmun Rev 2: 119–125

  2. 2.

    (2004) Pathogenesis and spectrum of autoimmunity. Methods Mol Med 102: 1–8

  3. 3.

    and (2004) Induction, acceleration or prevention of autoimmunity by molecular mimicry. Mol Immunol 40: 1113–1120

  4. 4.

    et al. (1991) Antigen-driven bystander suppression after oral administration of antigens. J Exp Med 174: 791–798

  5. 5.

    and (2005) Microbes, immunoregulation, and the gut. Gut 54: 317–320

  6. 6.

    et al. (2002) An oral introduction of intestinal bacteria prevents the development of a long-term TH2-skewed immunological memory induced by neonatal antibiotic treatment in mice. Clin Exp Allergy 32: 1112–1116

  7. 7.

    et al. (2002) The possible link between de-worming and the emergence of immunological disease. J Lab Clin Med 139: 334–338

  8. 8.

    and (2005) A worm's eye view of the immune system: consequences for evolution of human autoimmune disease. Nat Rev Immunol 5: 420–426

  9. 9.

    and (2002) T helper cell subclasses and clinical disease states. Curr Opin Gast 18: 711–716

  10. 10.

    et al. (1993) Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123: 1777–1788

  11. 11.

    et al. (1998) Claudin-1 and -2: Novel Integral Membrane Proteins Localizing at Tight Junctions with No Sequence Similarity to Occludin. J Cell Biol 141: 1539–1550

  12. 12.

    et al. (1998) Junctional Adhesion Molecule, a Novel Member of the Immunoglobulin Superfamily That Distributes at Intercellular Junctions and Modulates Monocyte Transmigration. J Cell Biol 142: 117–127

  13. 13.

    et al. (2000) Molecular Physiology and Pathophysiology of Tight Junctions I. Tight junction structure and function: lessons from mutant animals and proteins. Am J Physiol Gastrointest Liver Physiol 279: G250–G254

  14. 14.

    et al. (1999) Manner of Interaction of Heterogeneous Claudin Species Within and Between Tight Junction Strands. J Cell Biol 147: 891–903

  15. 15.

    et al. (2004) A porous defense: the leaky epithelial barrier in intestinal disease. Lab Invest 84: 282–291

  16. 16.

    et al. (2000) Human zonulin, a potential modulator of intestinal tight junctions. J Cell Sci 113: 4435–4440

  17. 17.

    et al. (2002) Host-dependent zonulin secretion causes the impairment of the small intestine barrier function after bacterial exposure. Gastroenterology 123: 1607–1615

  18. 18.

    and (2004) Isolated Lymphoid Follicles Can Function as Sites for Induction of Mucosal Immune Responses. Ann NY Acad Sci 1029: 44–57

  19. 19.

    et al. (2003) Isolated Lymphoid Follicle Formation Is Inducible and Dependent Upon Lymphotoxin-Sufficient B Lymphocytes, Lymphotoxin β Receptor, and TNF Receptor I Function. J Immunol 170: 5475–5482

  20. 20.

    et al. (1987) The Foreign Antigen-Binding Site and T-Cell Recognition Regions of Class-I Histocompatibility Antigens. Nature 329: 512–518

  21. 21.

    et al. (1987) Histopathology of Intestinal Inflammation Related to Reactive Arthritis. Gut 28: 394–401

  22. 22.

    et al. (2004) Intestinal villous M cells: An antigen entry site in the mucosal epithelium. PNAS 101: 6110–6115

  23. 23.

    and (2000) The ins and outs of body surface immunology. Science 290: 97–100

  24. 24.

    and (2004) Gastrointestinal dendritic cells play a role in immunity, tolerance, and disease. Gastroenterology 127: 300–309

  25. 25.

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

  26. 26.

    and (2001) Dendritic Cells: Specialized and Regulated Antigen Processing Machines. Cell 106: 255–258

  27. 27.

    et al. (2004) 'Educated' dendritic cells act as messengers from memory to naive T helper cells. Nat Immunol 5: 615–622

  28. 28.

    et al. (2004) Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis. Cell 118: 229–241

  29. 29.

    et al. (2004) Toll-like receptor 2 enhances ZO-1-associated intestinal epithelial barrier integrity via protein kinase C. Gastroenterology 127: 224–238

  30. 30.

    et al. (2004) Degranulation of Paneth Cells via Toll-Like Receptor 9. Am J Pathol 165: 373–381

  31. 31.

    et al. (2004) Mechanisms of cross hyporesponsiveness to toll-like receptor bacterial ligands in intestinal epithelial cells. Gastroenterology 126: 1054–1070

  32. 32.

    and (2004) Toll-Dependent Control Mechanisms of CD4 T Cell Activation. Immunity 21: 733–741

  33. 33.

    et al. (2004) Toll-Like Receptor 4 Signaling by Intestinal Microbes Influences Susceptibility to Food Allergy. J Immunol 172: 6978–6987

  34. 34.

    et al. (2004) Lactobacillus acidophilus protects tight junctions from aspirin damage in HT-29 cells. Digestion 69: 225–228

  35. 35.

    et al. (2004) Effect of probiotics on gastrointestinal symptoms and small intestinal permeability in children with atopic dermatitis. J Pediatr 145: 612–616

  36. 36.

    et al. (2004) Probiotics partly reverse increased bacterial translocation after simultaneous liver resection and colonic anastomosis in rats. J Surg Res 117: 262–271

  37. 37.

    et al. (2004) Enteric Nematodes Induce Stereotypic STAT6-Dependent Alterations in Intestinal Epithelial Cell Function. J Immunol 172: 5616–5621

  38. 38.

    et al. (2002) Role of STAT6 and Mast Cells in IL-4- and IL-13-Induced Alterations in Murine Intestinal Epithelial Cell Function. J Immunol 169: 4417–4422

  39. 39.

    et al. (2001) The Role of IL-4 in Heligmosomoides polygyrus-Induced Alterations in Murine Intestinal Epithelial Cell Function. J Immunol 167: 2234–2239

  40. 40.

    et al. (2005) Mechanism of TNF-α modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. Am J Physiol Gastrointest Liver Physiol 288: G422–G430

  41. 41.

    et al. (2005) Interferon-γ and Tumor Necrosis Factor-α Synergize to Induce Intestinal Epithelial Barrier Dysfunction by Up-Regulating Myosin Light Chain Kinase Expression. Am J Pathol 166: 409–419

  42. 42.

    et al. (2004) The G.U.T. of gut. Scand J Gastroenterol 39: 807–815

  43. 43.

    (1992) Role of the intestine in the physiopathology of inflammatory rheumatism. Rev Rhum Mal Osteoartic 59: 389–392

  44. 44.

    et al. (2005) Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. PNAS 102: 2916–2921

  45. 45.

    and (1980) Structural abnormalities of jejunal epithelial cell membranes in celiac sprue. Lab Invest 43: 254–261

  46. 46.

    et al. (1998) Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatric Research 43: 435–441

  47. 47.

    et al. (2000) Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 355: 1518–1519

  48. 48.

    et al. (2003) Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 52: 218–223

  49. 49.

    et al. (2004) Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol 173: 1925–1933

  50. 50.

    et al.: Gliadin Stimulation of Murine Macrophage Inflammatory Gene Expression and Intestinal Permeability are Myd88-Dependent. J Immunol, in revision

  51. 51.

    et al. (2004) Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev 3: 394–400

  52. 52.

    et al. (1999) Intestinal permeability test as a predictor of clinical course in Crohn's disease. Am J Gastroenterol 94: 2956–2960

  53. 53.

    et al. (1993) Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet 341: 1437–1439

  54. 54.

    et al. (2004) Mechanisms of diarrhea in the interleukin-2-deficient mouse model of colonic inflammation. Am J Physiol Gastrointest Liver Physiol 286: G244–G252

  55. 55.

    et al. (2004) Endocytosis of Epithelial Apical Junctional Proteins by a Clathrin-mediated Pathway into a Unique Storage Compartment. Mol Biol Cell 15: 176–188

  56. 56.

    et al. (1999) Altered intestinal permeability to mannitol in diabetes mellitus type I. J Pediatr Gastroenterol Nutr 28: 264–269

  57. 57.

    et al. (1987) Intestinal permeability in diabetic diarrhoea. Diabet Med 4: 49–52

  58. 58.

    et al. (1986) Abnormal intestinal permeability to sugars in diabetes mellitus. Diabetologia 29: 221–224

  59. 59.

    et al. (1988) Increased intestinal permeability to (51 Cr) EDTA is correlated with IgA immune complex-plasma levels in children with IgA-associated nephropathies. Acta Paediatr Scand 77: 118–124

  60. 60.

    et al. (1993) Mucosal immunity in primary glomerulonephritis. III. Study of intestinal permeability. Nephron 63: 286–290

  61. 61.

    et al. (2001) The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor α in the pathogenesis of non-alcoholic steatohepatitis. Gut 48: 206–211

  62. 62.

    et al. (1996) Multiple sclerosis patients have peripheral blood CD45RO+ B cells and increased intestinal permeability. Dig Dis Sci 41: 2493–2498

Download references


Work by the authors was supported in parts by grants from the National Institutes of Health: DK-48373 and DK-66630 (AF) and AI/DK49316 (TSD).

Author information


  1. A Fasano is Professor of Pediatrics, Medicine, and Physiology, and Director of the Mucosal Biology Research Center and the Center for Celiac Research, and T Shea-Donohue is Professor of Medicine and Physiology and a member of the Mucosal Biology Research Center, at the University of Maryland School of Medicine, Baltimore, MD, USA.

    • Alessio Fasano
    •  & Terez Shea-Donohue


  1. Search for Alessio Fasano in:

  2. Search for Terez Shea-Donohue in:

Competing interests

AF has economic interests in Alba Therapeutics, a company that works on the treatment of autoimmune diseases, including type 1 diabetes and celiac disease.

Corresponding author

Correspondence to Alessio Fasano.