Intestinal mucosal barrier function in health and disease

Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.

[1]  M. Osterman IFN-γ-Induced TNFR2 Expression Is Required for TNF-Dependent Intestinal Epithelial Barrier DysfunctionWang F, Schwarz BT, Graham WV, et al (Third Military Med Univ, Chongqing, China; Univ of Chicago) Gastroenterology 131:1153–1163, 2006§ , 2007 .

[2]  M. Marinaro,et al.  A transient breach in the epithelial barrier leads to regulatory T-cell generation and resistance to experimental colitis. , 2008, Gastroenterology.

[3]  Michael M. Wang,et al.  Caveolae-mediated Internalization of Occludin and Claudin-5 during CCL2-induced Tight Junction Remodeling in Brain Endothelial Cells* , 2009, The Journal of Biological Chemistry.

[4]  W. V. Graham,et al.  Interferon-γ and Tumor Necrosis Factor-α Synergize to Induce Intestinal Epithelial Barrier Dysfunction by Up-Regulating Myosin Light Chain Kinase Expression , 2005 .

[5]  M. Zeitz,et al.  Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. , 2005, Gastroenterology.

[6]  M. Netea,et al.  A Crohn's disease–associated NOD2 mutation suppresses transcription of human IL10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1 , 2009, Nature Immunology.

[7]  E. Dejana,et al.  Unique role of junctional adhesion molecule-a in maintaining mucosal homeostasis in inflammatory bowel disease. , 2008, Gastroenterology.

[8]  Yasuo Tano,et al.  Differential expression patterns of claudins, tight junction membrane proteins, in mouse nephron segments. , 2002, Journal of the American Society of Nephrology : JASN.

[9]  E. Severson,et al.  JAM-A regulates permeability and inflammation in the intestine in vivo , 2007, The Journal of experimental medicine.

[10]  J. Meddings,et al.  Intestinal glucose transport using perfused rat jejunum in vivo: model analysis and derivation of corrected kinetic constants. , 1989, Clinical science.

[11]  Y. Belkaid,et al.  A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism , 2007, The Journal of experimental medicine.

[12]  P. Verkade,et al.  Clostridium difficile Toxins Disrupt Epithelial Barrier Function by Altering Membrane Microdomain Localization of Tight Junction Proteins , 2001, Infection and Immunity.

[13]  J. Genschel,et al.  Genetic basis for increased intestinal permeability in families with Crohn’s disease: role of CARD15 3020insC mutation? , 2005, Gut.

[14]  Le Shen,et al.  Actin depolymerization disrupts tight junctions via caveolae-mediated endocytosis. , 2005, Molecular biology of the cell.

[15]  Lena Holm,et al.  The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria , 2010, Gut microbes.

[16]  C. V. Van Itallie,et al.  The density of small tight junction pores varies among cell types and is increased by expression of claudin-2 , 2008, Journal of Cell Science.

[17]  A. Sjöqvist,et al.  Permeability of the rat small intestinal epithelium along the villus-crypt axis: effects of glucose transport. , 2000, Gastroenterology.

[18]  K. Madsen,et al.  Interleukin-10 gene-deficient mice develop a primary intestinal permeability defect in response to enteric microflora. , 1999, Inflammatory bowel diseases.

[19]  S. Lees-Miller,et al.  Intestinal infection with Giardia spp. reduces epithelial barrier function in a myosin light chain kinase-dependent fashion. , 2002, Gastroenterology.

[20]  D. Rubin,et al.  Claudin-1 and claudin-2 expression is elevated in inflammatory bowel disease and may contribute to early neoplastic transformation , 2008, Laboratory Investigation.

[21]  O. Baker,et al.  Proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma alter tight junction structure and function in the rat parotid gland Par-C10 cell line. , 2008, American Journal of Physiology - Cell Physiology.

[22]  Hidde L Ploegh,et al.  CX3CR1-Mediated Dendritic Cell Access to the Intestinal Lumen and Bacterial Clearance , 2005, Science.

[23]  R Balfour Sartor,et al.  Microbial influences in inflammatory bowel diseases. , 2008, Gastroenterology.

[24]  H. Lochs,et al.  Intestinal permeability and the prediction of relapse in Crohri's disease , 1993, The Lancet.

[25]  Hilde Cheroutre,et al.  Reciprocal TH17 and Regulatory T Cell Differentiation Mediated by Retinoic Acid , 2007, Science.

[26]  P. Rutgeerts,et al.  Anti-tumor necrosis factor treatment restores the gut barrier in Crohn's disease , 2002, American Journal of Gastroenterology.

[27]  T. Sakaguchi,et al.  Claudins regulate the intestinal barrier in response to immune mediators. , 2000, Gastroenterology.

[28]  Tomohiro Watanabe,et al.  Muramyl dipeptide activation of nucleotide-binding oligomerization domain 2 protects mice from experimental colitis. , 2008, The Journal of clinical investigation.

[29]  R. Ricketts Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in crohn's ileocolitis: F.J. Baert, G.R. D'Haens, M. Peelers, et al. Gastroenterology 116:22–28 (January), 1999 , 2000 .

[30]  Kozo Kaibuchi,et al.  Regulation of Myosin Phosphatase by Rho and Rho-Associated Kinase (Rho-Kinase) , 1996, Science.

[31]  Jun Hee Lee,et al.  Energy-dependent regulation of cell structure by AMP-activated protein kinase , 2007, Nature.

[32]  A. Pedram,et al.  Mechanism of TNF-{alpha} modulation of Caco-2 intestinal epithelial tight junction barrier: role of myosin light-chain kinase protein expression. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[33]  K. Kurokawa,et al.  Effect of phosphorylation of myosin light chain by myosin light chain kinase and protein kinase C on conformational change and ATPase activities of human platelet myosin. , 1991, Blood.

[34]  D. Balkovetz,et al.  Downregulation of claudin-2 expression in renal epithelial cells by metabolic acidosis. , 2009, American journal of physiology. Renal physiology.

[35]  K. Madsen,et al.  Reducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse , 2008, Gut.

[36]  A. Ridley,et al.  Roles of Rho/ROCK and MLCK in TNF‐α‐induced changes in endothelial morphology and permeability , 2007, Journal of cellular physiology.

[37]  T. Noda,et al.  Complex phenotype of mice lacking occludin, a component of tight junction strands. , 2000, Molecular biology of the cell.

[38]  C. Bertrand,et al.  LPS-induced lung inflammation is linked to increased epithelial permeability: role of MLCK , 2005, European Respiratory Journal.

[39]  K. Madsen,et al.  The role of antibiotic and probiotic therapies in current and future management of inflammatory Bowel disease , 2006, Current gastroenterology reports.

[40]  E. Cario,et al.  Barrier-protective function of intestinal epithelial Toll-like receptor 2 , 2008, Mucosal Immunology.

[41]  J. Rotter,et al.  Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. , 1986, Annals of internal medicine.

[42]  M. Montrose,et al.  Regulated alkali secretion acts in tandem with unstirred layers to regulate mouse gastric surface pH. , 2004, Gastroenterology.

[43]  A. Prince,et al.  TLR2-induced calpain cleavage of epithelial junctional proteins facilitates leukocyte transmigration. , 2009, Cell host & microbe.

[44]  A. Craft,et al.  Intestinal permeability in children with Crohn's disease and coeliac disease. , 1982, British medical journal.

[45]  Sarah L. Brown,et al.  Myd88-dependent positioning of Ptgs2-expressing stromal cells maintains colonic epithelial proliferation during injury. , 2007, The Journal of clinical investigation.

[46]  K. Barrett,et al.  Epithelial dysfunction associated with the development of colitis in conventionally housed mdr1a-/- mice. , 2005, American journal of physiology. Gastrointestinal and liver physiology.

[47]  J. Madara,et al.  Interferon-gamma directly affects barrier function of cultured intestinal epithelial monolayers. , 1989, The Journal of clinical investigation.

[48]  M. Washington,et al.  Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. , 2005, The Journal of clinical investigation.

[49]  J. Turner,et al.  Epithelial myosin light chain kinase expression and activity are upregulated in inflammatory bowel disease , 2006, Laboratory Investigation.

[50]  W. Lencer,et al.  Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure , 2006, Journal of Cell Science.

[51]  F. Powrie,et al.  Dendritic cells in intestinal immune regulation , 2008, Nature Reviews Immunology.

[52]  L. Zeef,et al.  Early molecular and functional changes in colonic epithelium that precede increased gut permeability during colitis development in mdr1a(−/−) mice , 2008, Inflammatory bowel diseases.

[53]  J. Turner,et al.  Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na(+)-glucose cotransport. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[54]  D. Duerksen,et al.  Intestinal Permeability in Long-Term Follow-up of Patients with Celiac Disease on a Gluten-Free Diet , 2005, Digestive Diseases and Sciences.

[55]  J. Marshall,et al.  Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. , 2000, Gastroenterology.

[56]  L. M. Russo,et al.  Modulation of tumor necrosis factor-induced increase in renal (LLC-PK1) transepithelial permeability. , 1992, The American journal of physiology.

[57]  E. Chang,et al.  Akt2 Phosphorylates Ezrin to Trigger NHE3 Translocation and Activation* , 2005, Journal of Biological Chemistry.

[58]  R. Peek,et al.  Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. , 2009, Gastroenterology.

[59]  A. Hopkins,et al.  Interferon‐γ induces internalization of epithelial tight junction proteins via a macropinocytosis‐like process , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[60]  J. Lebreton,et al.  Gut ischemia and mesenteric synthesis of inflammatory cytokines after hemorrhagic or endotoxic shock. , 1997, The American journal of physiology.

[61]  M. Rescigno,et al.  Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning , 2009, Mucosal Immunology.

[62]  A. Malik,et al.  Synergistic effects of tumor necrosis factor-alpha and thrombin in increasing endothelial permeability. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[63]  J. Pilewski,et al.  Role of CFTR in airway disease. , 1999, Physiological reviews.

[64]  G. Corazza,et al.  Measurements of the jejunal unstirred layer in normal subjects and patients with celiac disease. , 1996, The American journal of physiology.

[65]  Jason X. Cheng,et al.  Tumor Necrosis Factor-induced Long Myosin Light Chain Kinase Transcription Is Regulated by Differentiation-dependent Signaling Events , 2006, Journal of Biological Chemistry.

[66]  C. Goodnow,et al.  Aberrant Mucin Assembly in Mice Causes Endoplasmic Reticulum Stress and Spontaneous Inflammation Resembling Ulcerative Colitis , 2008, PLoS medicine.

[67]  J. Nougayrède,et al.  Translocated EspF protein from enteropathogenic Escherichia coli disrupts host intestinal barrier function. , 2001, The Journal of clinical investigation.

[68]  R. Mrsny,et al.  A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. , 2002, Gastroenterology.

[69]  D. Artis Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut , 2008, Nature Reviews Immunology.

[70]  M. H. Cheng,et al.  Molecular Basis for Cation Selectivity in Claudin-2–based Paracellular Pores: Identification of an Electrostatic Interaction Site , 2009, The Journal of general physiology.

[71]  R. Sartor,et al.  Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice , 1998, Infection and Immunity.

[72]  J. Frank,et al.  Claudin-4 augments alveolar epithelial barrier function and is induced in acute lung injury. , 2009, American journal of physiology. Lung cellular and molecular physiology.

[73]  D. Sachar,et al.  Decrease in net stool output in cholera during intestinal perfusion with glucose-containing solutions. , 1968, The New England journal of medicine.

[74]  J. Meijerink,et al.  Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. , 2006, Gastroenterology.

[75]  C. V. Van Itallie,et al.  Claudin extracellular domains determine paracellular charge selectivity and resistance but not tight junction fibril architecture. , 2003, American journal of physiology. Cell physiology.

[76]  J. Gordon,et al.  In vivo analysis of cadherin function in the mouse intestinal epithelium: essential roles in adhesion, maintenance of differentiation, and regulation of programmed cell death , 1995, The Journal of cell biology.

[77]  yang-xin fu,et al.  LIGHT signals directly to intestinal epithelia to cause barrier dysfunction via cytoskeletal and endocytic mechanisms. , 2007, Gastroenterology.

[78]  W. Nelson,et al.  Structural and Functional Regulation of Tight Junctions by RhoA and Rac1 Small GTPases , 1998, The Journal of cell biology.

[79]  V. Théodorou,et al.  Myosin light chain kinase is involved in lipopolysaccharide-induced disruption of colonic epithelial barrier and bacterial translocation in rats. , 2005, The American journal of pathology.

[80]  S. Targan,et al.  Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. , 1997, Journal of immunology.

[81]  R. Sartor,et al.  Enhanced survival and mucosal repair after dextran sodium sulfate-induced colitis in transgenic mice that overexpress growth hormone. , 2001, Gastroenterology.

[82]  R. Mrsny,et al.  Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. , 1997, The American journal of physiology.

[83]  Liping Su,et al.  Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. , 2009, Gastroenterology.

[84]  E. Mazzon,et al.  Role of TNF-α in lung tight junction alteration in mouse model of acute lung inflammation , 2007, Respiratory research.

[85]  B. Beutler,et al.  Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease. , 1999, Gastroenterology.

[86]  R. Mrsny,et al.  Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo. , 2005, The Journal of clinical investigation.

[87]  R. Lifton,et al.  Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. , 1999, Science.

[88]  R. Mrsny,et al.  Mechanism of IFN-gamma-induced endocytosis of tight junction proteins: myosin II-dependent vacuolarization of the apical plasma membrane. , 2005, Molecular biology of the cell.

[89]  U Wahnschaffe,et al.  Changes in expression and distribution of claudin 2, 5 and 8 lead to discontinuous tight junctions and barrier dysfunction in active Crohn’s disease , 2006, Gut.

[90]  G. Warhurst,et al.  Interferon-γ selectively increases epithelial permeability to large molecules by activating different populations of paracellular pores , 2005, Journal of Cell Science.

[91]  L. Mayer,et al.  Evidence for a genetic defect in oral tolerance induction in inflammatory bowel disease , 2006, Inflammatory bowel diseases.

[92]  K. Czymmek,et al.  Deletion of JAM-A causes morphological defects in the corneal epithelium. , 2007, The international journal of biochemistry & cell biology.

[93]  A. Andoh,et al.  Increased expression of interleukin 17 in inflammatory bowel disease , 2003, Gut.

[94]  Klaus Ley,et al.  The primary defect in experimental ileitis originates from a nonhematopoietic source , 2006, The Journal of experimental medicine.

[95]  R. Coffman,et al.  Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. , 1994, Immunity.

[96]  C. Chabo,et al.  Gastrointestinal , Hepatobiliary and Pancreatic Pathology Impairment of the Intestinal Barrier by Ethanol Involves Enteric Microflora and Mast Cell Activation in Rodents , 2006 .

[97]  M. Leitges,et al.  Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo. , 2006, The Journal of clinical investigation.

[98]  G. Dalmasso,et al.  Temporal and Spatial Analysis of Clinical and Molecular Parameters in Dextran Sodium Sulfate Induced Colitis , 2009, PloS one.

[99]  A. Amiot,et al.  Presentation and long-term follow-up of refractory celiac disease: comparison of type I with type II. , 2009, Gastroenterology.

[100]  Yoshiharu Matsuura,et al.  Phosphorylation and Activation of Myosin by Rho-associated Kinase (Rho-kinase)* , 1996, The Journal of Biological Chemistry.

[101]  D. Ye,et al.  Mechanism of IL-1β-Induced Increase in Intestinal Epithelial Tight Junction Permeability1 , 2008, The Journal of Immunology.

[102]  R. Germain,et al.  Dynamic imaging of dendritic cell extension into the small bowel lumen in response to epithelial cell TLR engagement , 2006, The Journal of experimental medicine.

[103]  K. Barrett,et al.  AMP-activated Protein Kinase Mediates the Interferon-γ-induced Decrease in Intestinal Epithelial Barrier Function* , 2009, The Journal of Biological Chemistry.

[104]  J. Gordon,et al.  Inflammatory Bowel Disease and Adenomas in Mice Expressing a Dominant Negative N-Cadherin , 1995, Science.

[105]  O. Benada,et al.  Segmented filamentous bacteria in a defined bacterial cocktail induce intestinal inflammation in SCID mice reconstituted with CD45RBhigh CD4+ T cells , 2007, Inflammatory bowel diseases.

[106]  R. Xu,et al.  Cox-2 is regulated by Toll-like receptor-4 (TLR4) signaling: Role in proliferation and apoptosis in the intestine. , 2006, Gastroenterology.

[107]  Xiao-pei Gao,et al.  Nonmuscle myosin light-chain kinase mediates neutrophil transmigration in sepsis-induced lung inflammation by activating β2 integrins , 2008, Nature Immunology.

[108]  D. Hollander,et al.  Crohn's disease--a permeability disorder of the tight junction? , 1988, Gut.

[109]  A. Yu,et al.  Structure-Function Studies of Claudin Extracellular Domains by Cysteine-scanning Mutagenesis* , 2009, The Journal of Biological Chemistry.

[110]  P. Kozlowski,et al.  Mucosal vaccines: the promise and the challenge , 2006, Nature Reviews Immunology.

[111]  J. Pappenheimer,et al.  Structural basis for physiological regulation of paracellular pathways in intestinal epithelia , 2005, The Journal of Membrane Biology.

[112]  C. V. Van Itallie,et al.  ZO-1 stabilizes the tight junction solute barrier through coupling to the perijunctional cytoskeleton. , 2009, Molecular biology of the cell.

[113]  Torsten Schöneberg,et al.  Claudin-2 expression induces cation-selective channels in tight junctions of epithelial cells , 2002, Journal of Cell Science.

[114]  H. Tilg,et al.  XBP1 Links ER Stress to Intestinal Inflammation and Confers Genetic Risk for Human Inflammatory Bowel Disease , 2008, Cell.

[115]  Tomohiro Watanabe,et al.  NOD2 transgenic mice exhibit enhanced MDP-mediated down-regulation of TLR2 responses and resistance to colitis induction. , 2007, Gastroenterology.

[116]  Alastair Forbes,et al.  Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease , 2008, Nature Genetics.

[117]  Judy H. Cho,et al.  Chronic stimulation of Nod2 mediates tolerance to bacterial products , 2007, Proceedings of the National Academy of Sciences.

[118]  S. Colgan,et al.  Autocrine regulation of epithelial permeability by hypoxia: role for polarized release of tumor necrosis factor alpha. , 1998, Gastroenterology.