Comprehensive Physiology Wiley Online Library

Epithelial Organization: The Gut and Beyond

Full Article on Wiley Online Library



ABSTRACT

Epithelial cells are essential to the survival and homeostasis of complex organisms. These cells cover the surfaces of all mucosae, the skin, and other compartmentalized structures essential to physiological function. In addition to maintenance of barriers that separate internal and external compartments, epithelia display a variety of organ‐specific differentiated functions. Function is reflected in overall epithelial structure and organization, shape of individual cells, and proteins expressed by these cells. More than one epithelial cell type is often present within a single organ and, in many cases, individual cells differentiate to change their functional behaviors as part of normal development or in response to extracellular stimuli. This article discusses the diversity of epithelial structure and function in general terms and explores representative tissues in greater depth to highlight organ specific functions and their contributions to physiology and disease. © 2017 American Physiological Society. Compr Physiol 7:1497‐1518, 2017.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images


Figure 1. Figure 1. Diversity of epithelial cell shape and function.
Figure 2. Figure 2. Epithelial cell architecture and organization. (A) Fluorescence micrograph of human small intestine labeled for E‐cadherin (green), F‐actin (purple), tight junction protein ZO‐1 (red), and DNA (blue). Note the localization of each protein: actin is present within the cortical actomyosin ring and microvillus brush border, ZO‐1 as bright puncta at tight junctions, and E‐cadherin along basolateral membranes. (B) The apical junctional complex of an intestinal epithelial cell. Tight junction proteins include claudins, zonula occludens 1 (ZO‐1), occludin, and F‐actin, while E‐cadherin, α‐catenin 1, β‐catenin, and F‐actin interact to form the adherens junction. Myosin light chain kinase (MLCK) is associated with the perijunctional actomyosin ring. Desmosomes are formed by interactions between desmoglein and desmocollin, which are bound to keratin filaments. Integrins form focal adhesions with the extracellular matrix proteins. (C) Transmission electron micrograph showing junctional complexes between two enterocytes. The tight junction (TJ) is just below the microvilli (Mv), followed by the adherens junction (AJ). The desmosomes (D) are located basolaterally. (D) Scanning electron micrograph showing microvilli, as viewed from above. (E) Confocal micrograph of cultured small intestinal epithelial cells labeled for F‐actin. In this apical view (from above the cell), microvilli (Mv) can be appreciated as small dot‐like structures due to their F‐actin core. The cortical actin ring that forms a belt around each epithelial cell can also be appreciated at the junction between the two cells shown. (F) Freeze‐fracture electron micrograph showing apical microvilli (Mv) and tight junction strands (TJ) in a cultured intestinal epithelial cell. [Part C from Nature Reviews Immunology () and part F from Annual Reviews of Physiology () with permission.]
Figure 3. Figure 3. Comparison of small intestinal and colonic mucosal architecture. (A) Low‐magnification image of hematoxylin and eosin‐stained section of normal human duodenum. The mucosa can be separated into villus, crypt, and muscularis mucosae (m. mucosae) and sits atop the submucosa. The villi greatly expand mucosal thickness. (B) Low‐magnification image of hematoxylin and eosin‐stained section of normal human distal colon. The mucosa can be separated into surface, crypt, and muscularis mucosae (m. mucosae) and, like the small intestinal mucosa, rests on the submucosa.
Figure 4. Figure 4. Segregation of epithelial transport proteins along the crypt:villus axis. Fluorescence micrographs of human small intestine labeled for E‐cadherin (red), F‐actin (purple), and DNA (blue). (A) Note the localization of CFTR (green) to the apical membrane of epithelial cells within the lower villus and crypt, the principal site of chloride secretion. (B) Note that NKCC1 (green) is expressed in the same population of cells that expressed CFTR but is localized to the basolateral membrane, where colocalizes with E‐cadherin. (C) NHE3 (green) is localized to the apical membrane and predominantly expressed on cells within the villus, where the bulk of absorption takes place. (D) Similar to NHE3, SGLT1 (green) is localized to the apical membrane of villous absorptive enterocytes. Bright autofluorescence (green) of red blood cells highlights villous capillaries that run just beneath the basement membrane is present in some images (particularly panel C). (E) These transporters are expressed throughout small intestine and colon; similar transporters are expressed within the nephron in a site‐specific manner.
Figure 5. Figure 5. Epithelial glucose transport as a model of Na+‐coupled nutrient absorption. (A) Glucose (Glu) absorption begins with transport across the apical, brush border membrane via SGLT1‐mediated Na+ cotransport. Both glucose and Na+ diffuse to the basolateral membranes where they exit the cell by way of GLUT2 and Na+K+ATPase, respectively. As described in the text, this and the many other Na+ absorptive pathways present can deplete Na+ from the lumen and thereby inhibit further absorption. Tight junction proteins claudin‐2 and claudin‐15 allow Na+ to diffuse, passively, across the tight junction according to the concentration gradient to replenish luminal stores and allow continued nutrient absorption. (B) Fluorescence micrograph of human small intestine labeled for Na+K+ATPase (green), E‐cadherin (red), F‐actin (purple), and DNA (blue). Note the localization of the Na+K+ATPase to the basolateral membranes of villus and crypt epithelial cells. (C) Claudin‐15 (green) is distributed in a dot‐like pattern at epithelial cell junctions. By light microscopy, claudin‐15 appears to colocalize with the very apical extent of E‐cadherin, which is otherwise restricted to the basolateral membrane as well as the dense cortical (perijunctional) F‐actin ring.
Figure 6. Figure 6. Molecular mechanisms of pore and leak pathway regulation by the immune system during disease. (A) IL‐13 results in transcriptional activation of claudin‐2 expression and resulting increases in pore pathway permeability. In contrast, TNF activates myosin light chain kinase transcription and enzymatic activity. These lead to endocytic removal of occludin from the tight junction and increased leak pathway permeability. (B) Transgenic, intestinal epithelial‐restricted expression of constitutively active‐MLCK restores sensitivity of long MLCK−/− mice to adoptive transfer colitis, an immune mediated experimental IBD induced by transfer of CD4+CD45RBhi T cells into Rag1−/− immunodeficient recipients. Long MLCK−/− mice are protected from disease‐associated MLC phosphorylation (green, upper panels) and claudin‐2 upregulation (green, lower panels). Tissue specific, intestinal epithelial expression of a constitutively active MLCK (CA‐MLCK) catalytic domain restores disease‐associated MLC phosphorylation and claudin‐2 upregulation. Thus, although inflammatory cytokines can specifically and differentially activate pore and leak pathways, the regulation of these paracellular flux routes is linked in disease. Bar = 10 um. [Part B adapted from Gastroenterology () with permission.]


Figure 1. Diversity of epithelial cell shape and function.


Figure 2. Epithelial cell architecture and organization. (A) Fluorescence micrograph of human small intestine labeled for E‐cadherin (green), F‐actin (purple), tight junction protein ZO‐1 (red), and DNA (blue). Note the localization of each protein: actin is present within the cortical actomyosin ring and microvillus brush border, ZO‐1 as bright puncta at tight junctions, and E‐cadherin along basolateral membranes. (B) The apical junctional complex of an intestinal epithelial cell. Tight junction proteins include claudins, zonula occludens 1 (ZO‐1), occludin, and F‐actin, while E‐cadherin, α‐catenin 1, β‐catenin, and F‐actin interact to form the adherens junction. Myosin light chain kinase (MLCK) is associated with the perijunctional actomyosin ring. Desmosomes are formed by interactions between desmoglein and desmocollin, which are bound to keratin filaments. Integrins form focal adhesions with the extracellular matrix proteins. (C) Transmission electron micrograph showing junctional complexes between two enterocytes. The tight junction (TJ) is just below the microvilli (Mv), followed by the adherens junction (AJ). The desmosomes (D) are located basolaterally. (D) Scanning electron micrograph showing microvilli, as viewed from above. (E) Confocal micrograph of cultured small intestinal epithelial cells labeled for F‐actin. In this apical view (from above the cell), microvilli (Mv) can be appreciated as small dot‐like structures due to their F‐actin core. The cortical actin ring that forms a belt around each epithelial cell can also be appreciated at the junction between the two cells shown. (F) Freeze‐fracture electron micrograph showing apical microvilli (Mv) and tight junction strands (TJ) in a cultured intestinal epithelial cell. [Part C from Nature Reviews Immunology () and part F from Annual Reviews of Physiology () with permission.]


Figure 3. Comparison of small intestinal and colonic mucosal architecture. (A) Low‐magnification image of hematoxylin and eosin‐stained section of normal human duodenum. The mucosa can be separated into villus, crypt, and muscularis mucosae (m. mucosae) and sits atop the submucosa. The villi greatly expand mucosal thickness. (B) Low‐magnification image of hematoxylin and eosin‐stained section of normal human distal colon. The mucosa can be separated into surface, crypt, and muscularis mucosae (m. mucosae) and, like the small intestinal mucosa, rests on the submucosa.


Figure 4. Segregation of epithelial transport proteins along the crypt:villus axis. Fluorescence micrographs of human small intestine labeled for E‐cadherin (red), F‐actin (purple), and DNA (blue). (A) Note the localization of CFTR (green) to the apical membrane of epithelial cells within the lower villus and crypt, the principal site of chloride secretion. (B) Note that NKCC1 (green) is expressed in the same population of cells that expressed CFTR but is localized to the basolateral membrane, where colocalizes with E‐cadherin. (C) NHE3 (green) is localized to the apical membrane and predominantly expressed on cells within the villus, where the bulk of absorption takes place. (D) Similar to NHE3, SGLT1 (green) is localized to the apical membrane of villous absorptive enterocytes. Bright autofluorescence (green) of red blood cells highlights villous capillaries that run just beneath the basement membrane is present in some images (particularly panel C). (E) These transporters are expressed throughout small intestine and colon; similar transporters are expressed within the nephron in a site‐specific manner.


Figure 5. Epithelial glucose transport as a model of Na+‐coupled nutrient absorption. (A) Glucose (Glu) absorption begins with transport across the apical, brush border membrane via SGLT1‐mediated Na+ cotransport. Both glucose and Na+ diffuse to the basolateral membranes where they exit the cell by way of GLUT2 and Na+K+ATPase, respectively. As described in the text, this and the many other Na+ absorptive pathways present can deplete Na+ from the lumen and thereby inhibit further absorption. Tight junction proteins claudin‐2 and claudin‐15 allow Na+ to diffuse, passively, across the tight junction according to the concentration gradient to replenish luminal stores and allow continued nutrient absorption. (B) Fluorescence micrograph of human small intestine labeled for Na+K+ATPase (green), E‐cadherin (red), F‐actin (purple), and DNA (blue). Note the localization of the Na+K+ATPase to the basolateral membranes of villus and crypt epithelial cells. (C) Claudin‐15 (green) is distributed in a dot‐like pattern at epithelial cell junctions. By light microscopy, claudin‐15 appears to colocalize with the very apical extent of E‐cadherin, which is otherwise restricted to the basolateral membrane as well as the dense cortical (perijunctional) F‐actin ring.


Figure 6. Molecular mechanisms of pore and leak pathway regulation by the immune system during disease. (A) IL‐13 results in transcriptional activation of claudin‐2 expression and resulting increases in pore pathway permeability. In contrast, TNF activates myosin light chain kinase transcription and enzymatic activity. These lead to endocytic removal of occludin from the tight junction and increased leak pathway permeability. (B) Transgenic, intestinal epithelial‐restricted expression of constitutively active‐MLCK restores sensitivity of long MLCK−/− mice to adoptive transfer colitis, an immune mediated experimental IBD induced by transfer of CD4+CD45RBhi T cells into Rag1−/− immunodeficient recipients. Long MLCK−/− mice are protected from disease‐associated MLC phosphorylation (green, upper panels) and claudin‐2 upregulation (green, lower panels). Tissue specific, intestinal epithelial expression of a constitutively active MLCK (CA‐MLCK) catalytic domain restores disease‐associated MLC phosphorylation and claudin‐2 upregulation. Thus, although inflammatory cytokines can specifically and differentially activate pore and leak pathways, the regulation of these paracellular flux routes is linked in disease. Bar = 10 um. [Part B adapted from Gastroenterology () with permission.]
References
 1.Acharya P, Beckel J, Ruiz WG, Wang E, Rojas R, Birder L, Apodaca G. Distribution of the tight junction proteins ZO‐1, occludin, and claudin‐4, ‐8, and ‐12 in bladder epithelium. Am J Physiol Renal Physiol 287: F305‐F318, 2004.
 2.Ait‐Omar A, Monteiro‐Sepulveda M, Poitou C, Le Gall M, Cotillard A, Gilet J, Garbin K, Houllier A, Chateau D, Lacombe A, Veyrie N, Hugol D, Tordjman J, Magnan C, Serradas P, Clement K, Leturque A, Brot‐Laroche E. GLUT2 accumulation in enterocyte apical and intracellular membranes: A study in morbidly obese human subjects and ob/ob and high fat‐fed mice. Diabetes 60: 2598‐2607, 2011.
 3.Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol 1: a002584, 2009.
 4.Andrianesis V, Glykofridi S, Doupis J. The renal effects of SGLT2 inhibitors and a mini‐review of the literature. Ther Adv Endocrinol Metab 7: 212‐228, 2016.
 5.Anitha M, Reichardt F, Tabatabavakili S, Nezami BG, Chassaing B, Mwangi S, Vijay‐Kumar M, Gewirtz A, Srinivasan S. Intestinal dysbiosis contributes to the delayed gastrointestinal transit in high‐fat diet fed mice. Cell Mol Gastroenterol Hepatol 2: 328‐339, 2016.
 6.Apodaca G, Gallo LI, Bryant DM. Role of membrane traffic in the generation of epithelial cell asymmetry. Nature Cell Biology 14: 1235‐1243, 2012.
 7.Ares GR, Caceres PS, Ortiz PA. Molecular regulation of NKCC2 in the thick ascending limb. Am J Physiol ‐ Renal Physiol 301: F1143‐F1159, 2011.
 8.Arnott ID, Kingstone K, Ghosh S. Abnormal intestinal permeability predicts relapse in inactive Crohn disease. Scand J Gastroenterol 35: 1163‐1169, 2000.
 9.Atisook K, Madara JL. An oligopeptide permeates intestinal tight junctions at glucose‐elicited dilatations. Gastroenterol 100: 719‐724, 1991.
 10.Baas AF, Kuipers J, van der Wel NN, Batlle E, Koerten HK, Peters PJ, Clevers HC. Complete polarization of single intestinal epithelial cells upon activation of LKB1 by STRAD. Cell 116: 457‐466, 2004.
 11.Bagnat M, Cheung ID, Mostov KE, Stainier DY. Genetic control of single lumen formation in the zebrafish gut. Nat Cell Biol 9: 954‐960, 2007.
 12.Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449: 1003‐1007, 2007.
 13.Barry AK, Tabdili H, Muhamed I, Wu J, Shashikanth N, Gomez GA, Yap AS, Gottardi CJ, de Rooij J, Wang N, Leckband DE. Alpha‐catenin cytomechanics–‐role in cadherin‐dependent adhesion and mechanotransduction. J Cell Sci 127: 1779‐1791, 2014.
 14.Beatch M, Jesaitis LA, Gallin WJ, Goodenough DA, Stevenson BR. The tight junction protein ZO‐2 contains three PDZ (PSD‐95/Discs‐Large/ZO‐1) domains and an alternatively spliced region. J Biol Chem 271: 25723‐25726, 1996.
 15.Beaulieu JF. Differential expression of the VLA family of integrins along the crypt‐villus axis in the human small intestine. J Cell Sci 102: 427‐436, 1992.
 16.Beggs AD, Latchford AR, Vasen HF, Moslein G, Alonso A, Aretz S, Bertario L, Blanco I, Bulow S, Burn J, Capella G, Colas C, Friedl W, Moller P, Hes FJ, Jarvinen H, Mecklin JP, Nagengast FM, Parc Y, Phillips RK, Hyer W, Ponz de Leon M, Renkonen‐Sinisalo L, Sampson JR, Stormorken A, Tejpar S, Thomas HJ, Wijnen JT, Clark SK, Hodgson SV. Peutz‐Jeghers syndrome: A systematic review and recommendations for management. Gut 59: 975‐986, 2010.
 17.Benharouga M, Sharma M, So J, Haardt M, Drzymala L, Popov M, Schwapach B, Grinstein S, Du K, Lukacs GL. The role of the C terminus and Na+/H+ exchanger regulatory factor in the functional expression of cystic fibrosis transmembrane conductance regulator in nonpolarized cells and epithelia. J Biol Chem 278: 22079‐22089, 2003.
 18.Berglund JJ, Riegler M, Zolotarevsky Y, Wenzl E, Turner JR. Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na(+)‐glucose cotransport. Am J Physiol Gastrointest Liver Physiol 281: G1487‐G1493, 2001.
 19.Bergstrom KS, Kissoon‐Singh V, Gibson DL, Ma C, Montero M, Sham HP, Ryz N, Huang T, Velcich A, Finlay BB, Chadee K, Vallance BA. Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa. PLoS Pathog 6: e1000902, 2010.
 20.Berx G, Cleton‐Jansen AM, Nollet F, de Leeuw WJ, van de Vijver M, Cornelisse C, van Roy F. E‐cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers. EMBO J 14: 6107‐6115, 1995.
 21.Binder HJ, Rajendran V, Sadasivan V, Geibel JP. Bicarbonate secretion: A neglected aspect of colonic ion transport. J Clin Gastroenterol 39: S53‐S58, 2005.
 22.Blasky AJ, Mangan A, Prekeris R. Polarized protein transport and lumen formation during epithelial tissue morphogenesis. Annu Rev Cell Dev Biol 31: 575‐591, 2015.
 23.Boletta A, Germino GG. Role of polycystins in renal tubulogenesis. Trends Cell Biol 13: 484‐492, 2003.
 24.Bonazzi M, Lecuit M, Cossart P. Listeria monocytogenes internalin and E‐cadherin: From structure to pathogenesis. Cell Microbiol 11: 693‐702, 2009.
 25.Bordin M, D'Atri F, Guillemot L, Citi S. Histone deacetylase inhibitors up‐regulate the expression of tight junction proteins. Mol Cancer Res 2: 692‐701, 2004.
 26.Breuza L, Garcia M, Delgrossi MH, Le Bivic A. Role of the membrane‐proximal O‐glycosylation site in sorting of the human receptor for neurotrophins to the apical membrane of MDCK cells. Exp Cell Res 273: 178‐186, 2002.
 27.Brooke MA, Nitoiu D, Kelsell DP. Cell‐cell connectivity: Desmosomes and disease. J Pathol 226: 158‐171, 2012.
 28.Bryant DM, Roignot J, Datta A, Overeem AW, Kim M, Yu W, Peng X, Eastburn DJ, Ewald AJ, Werb Z, Mostov KE. A molecular switch for the orientation of epithelial cell polarization. Dev Cell 31: 171‐187, 2014.
 29.Bryant DM, Stow JL. The ins and outs of E‐cadherin trafficking. Trends Cell Biol 14: 427‐434, 2004.
 30.Buhner S, Buning C, Genschel J, Kling K, Herrmann D, Dignass A, Kuechler I, Krueger S, Schmidt HH, Lochs H. Genetic basis for increased intestinal permeability in families with Crohn's disease: Role of CARD15 3020insC mutation? Gut 55: 342‐347, 2006.
 31.Buschmann MM, Shen L, Rajapakse H, Raleigh DR, Wang Y, Wang Y, Lingaraju A, Zha J, Abbott E, McAuley EM, Breskin LA, Wu L, Anderson K, Turner JR, Weber CR. Occludin OCEL‐domain interactions are required for maintenance and regulation of the tight junction barrier to macromolecular flux. Mol Biol Cell 24: 3056‐3068, 2013.
 32.Byers MS, Howard C, Wang X. Avian and mammalian facilitative glucose transporters. Microarrays (Basel) 6: 2017.
 33.Cadwell CM, Su W, Kowalczyk AP. Cadherin tales: Regulation of cadherin function by endocytic membrane trafficking. Traffic 17: 1262‐1271, 2016.
 34.Casaletto JB, Saotome I, Curto M, McClatchey AI. Ezrin‐mediated apical integrity is required for intestinal homeostasis. Proc Natl Acad Sci USA 108: 11924‐11929, 2011.
 35.Casanova JE, Breitfeld PP, Ross SA, Mostov KE. Phosphorylation of the polymeric immunoglobulin receptor required for its efficient transcytosis. Science 248: 742‐745, 1990.
 36.Castillo J, Crespo D, Capilla E, Diaz M, Chauvigne F, Cerda J, Planas JV. Evolutionary structural and functional conservation of an ortholog of the GLUT2 glucose transporter gene (SLC2A2) in zebrafish. Am J Physiol Regul Integr Comp Physiol 297: R1570‐R1581, 2009.
 37.Cereijido M, Ehrenfeld J, Meza I, Martinez‐Palomo A. Structural and functional membrane polarity in cultured monolayers of MDCK cells. J Membr Biol 52: 147‐159, 1980.
 38.Chalmers AD, Pambos M, Mason J, Lang S, Wylie C, Papalopulu N. aPKC, Crumbs3 and Lgl2 control apicobasal polarity in early vertebrate development. Development 132: 977‐986, 2005.
 39.Cheung ID, Bagnat M, Ma TP, Datta A, Evason K, Moore JC, Lawson ND, Mostov KE, Moens CB, Stainier DY. Regulation of intrahepatic biliary duct morphogenesis by Claudin 15‐like b. Dev Biol 361: 68‐78, 2012.
 40.Chu H, Pazgier M, Jung G, Nuccio SP, Castillo PA, de Jong MF, Winter MG, Winter SE, Wehkamp J, Shen B, Salzman NH, Underwood MA, Tsolis RM, Young GM, Lu W, Lehrer RI, Baumler AJ, Bevins CL. Human alpha‐defensin 6 promotes mucosal innate immunity through self‐assembled peptide nanonets. Science 337: 477‐481, 2012.
 41.Cil O, Phuan PW, Lee S, Tan J, Haggie PM, Levin MH, Sun L, Thiagarajah JR, Ma T, Verkman AS. CFTR activator increases intestinal fluid secretion and normalizes stool output in a mouse model of constipation. Cell Mol Gastroenterol Hepatol 2: 317‐327, 2016.
 42.Claude P. Morphological factors influencing transepithelial permeability: A model for the resistance of the zonula occludens. J Membr Biol 39: 219‐232, 1978.
 43.Clayburgh DR, Barrett TA, Tang Y, Meddings JB, Van Eldik LJ, Watterson DM, Clarke LL, Mrsny RJ, Turner JR. Epithelial myosin light chain kinase‐dependent barrier dysfunction mediates T cell activation‐induced diarrhea in vivo. J Clin Invest 115: 2702‐2715, 2005.
 44.Clayburgh DR, Musch MW, Leitges M, Fu YX, Turner JR. Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF‐mediated diarrhea in vivo. J Clin Invest 116: 2682‐2694, 2006.
 45.Cohen M, Kitsberg D, Tsytkin S, Shulman M, Aroeti B, Nahmias Y. Live imaging of GLUT2 glucose‐dependent trafficking and its inhibition in polarized epithelial cysts. Open biology 4: 140091, 2014.
 46.Crawley SW, Shifrin DA, Jr., Grega‐Larson NE, McConnell RE, Benesh AE, Mao S, Zheng Y, Zheng QY, Nam KT, Millis BA, Kachar B, Tyska MJ. Intestinal brush border assembly driven by protocadherin‐based intermicrovillar adhesion. Cell 157: 433‐446, 2014.
 47.Czuczman MA, Fattouh R, van Rijn JM, Canadien V, Osborne S, Muise AM, Kuchroo VK, Higgins DE, Brumell JH. Listeria monocytogenes exploits efferocytosis to promote cell‐to‐cell spread. Nature 509: 230‐234, 2014.
 48.D'Inca R, Di Leo V, Corrao G, Martines D, D'Odorico A, Mestriner C, Venturi C, Longo G, Sturniolo GC. Intestinal permeability test as a predictor of clinical course in Crohn's disease. Am J Gastroenterol 94: 2956‐2960, 1999.
 49.Drees F, Pokutta S, Yamada S, Nelson WJ, Weis WI. Alpha‐catenin is a molecular switch that binds E‐cadherin‐beta‐catenin and regulates actin‐filament assembly. Cell 123: 903‐915, 2005.
 50.Duc C, Farman N, Canessa CM, Bonvalet JP, Rossier BC. Cell‐specific expression of epithelial sodium channel alpha, beta, and gamma subunits in aldosterone‐responsive epithelia from the rat: Localization by in situ hybridization and immunocytochemistry. J Cell Biol 127: 1907‐1921, 1994.
 51.Edelblum KL, Shen L, Weber CR, Marchiando AM, Clay BS, Wang Y, Prinz I, Malissen B, Sperling AI, Turner JR. Dynamic migration of gammadelta intraepithelial lymphocytes requires occludin. Proc Natl Acad Sci U S A 109: 7097‐7102, 2012.
 52.Edelblum KL, Singh G, Odenwald MA, Lingaraju A, El Bissati K, McLeod R, Sperling AI, Turner JR. gammadelta intraepithelial lymphocyte migration limits transepithelial pathogen invasion and systemic disease in mice. Gastroenterol 148: 1417‐1426, 2015.
 53.Elmes ME, Stanton MR, Howells CH, Lowe GH. Relation between the mucosal flora and Paneth cell population of human jejunum and ileum. J Clin Pathol 37: 1268‐1271, 1984.
 54.Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A. Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways. Histochem Cell Biol 137: 339‐353, 2012.
 55.Escaffit F, Boudreau F, Beaulieu JF. Differential expression of claudin‐2 along the human intestine: Implication of GATA‐4 in the maintenance of claudin‐2 in differentiating cells. J Cell Physiol 203: 15‐26, 2005.
 56.Etienne‐Manneville S, Manneville JB, Nicholls S, Ferenczi MA, Hall A. Cdc42 and Par6‐PKCzeta regulate the spatially localized association of Dlg1 and APC to control cell polarization. J Cell Biol 170: 895‐901, 2005.
 57.Fanning AS, Anderson JM. Zonula occludens‐1 and ‐2 are cytosolic scaffolds that regulate the assembly of cellular junctions. Ann N Y Acad Sci 1165: 113‐120, 2009.
 58.Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO‐1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273: 29745‐29753, 1998.
 59.Farquhar M, Palade G. Junctional complexes in various epithelia. J Cell Biol 17: 375‐412, 1963.
 60.Fedeles SV, Gallagher AR, Somlo S. Polycystin‐1: A master regulator of intersecting cystic pathways. Trends Mol Med 20: 251‐260, 2014.
 61.Fernandez‐Gonzalez R, Zallen JA. Wounded cells drive rapid epidermal repair in the early Drosophila embryo. Mol Biol Cell 24: 3227‐3237, 2013.
 62.Ferrannini E. Sodium‐glucose co‐transporters and their inhibition: Clinical physiology. Cell Metab 26: 27‐38, 2017.
 63.Fihn BM, Sjoqvist A, Jodal M. Permeability of the rat small intestinal epithelium along the villus‐crypt axis: Effects of glucose transport. Gastroenterol 119: 1029‐1036, 2000.
 64.Fogg VC, Liu CJ, Margolis B. Multiple regions of Crumbs3 are required for tight junction formation in MCF10A cells. J Cell Sci 118: 2859‐2869, 2005.
 65.Forte JG, Zhu L. Apical recycling of the gastric parietal cell H,K‐ATPase. Annu Rev Physiol 72: 273‐296, 2010.
 66.Freeman TC, Wood IS, Sirinathsinghji DJ, Beechey RB, Dyer J, Shirazi‐Beechey SP. The expression of the Na+/glucose cotransporter (SGLT1) gene in lamb small intestine during postnatal development. Biochim Biophys Acta 1146: 203‐212, 1993.
 67.Frey MR. Disease‐associated microbial communities in healthy relatives: A bacteria‐filled crystal ball? Cell Mol Gastroenterol Hepatol 2: 710‐711, 2016.
 68.Frindt G, Palmer LG. Regulation of epithelial Na+ channels by adrenal steroids: Mineralocorticoid and glucocorticoid effects. Am J Physiol Renal Physiol 302: F20‐F26, 2012.
 69.Frisch SM, Francis H. Disruption of epithelial cell‐matrix interactions induces apoptosis. J Cell Biol 124: 619‐626, 1994.
 70.Fujimoto K, Beauchamp RD, Whitehead RH. Identification and isolation of candidate human colonic clonogenic cells based on cell surface integrin expression. Gastroenterol 123: 1941‐1948, 2002.
 71.Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Occludin: A novel integral membrane protein localizing at tight junctions. J Cell Biol 123: 1777‐1788, 1993.
 72.Garrod D, Chidgey M. Desmosome structure, composition and function. Biochim Biophys Acta 1778: 572‐587, 2008.
 73.Gilbert T, Le Bivic A, Quaroni A, Rodriguez‐Boulan E. Microtubular organization and its involvement in the biogenetic pathways of plasma membrane proteins in Caco‐2 intestinal epithelial cells. J Cell Biol 113: 275‐288, 1991.
 74.Gimenez I, Forbush B. Regulatory phosphorylation sites in the NH2 terminus of the renal Na‐K‐Cl cotransporter (NKCC2). Am J Physiol Renal Physiol 289: F1341‐F1345, 2005.
 75.Gong Y, Yu M, Yang J, Gonzales E, Perez R, Hou M, Tripathi P, Hering‐Smith KS, Hamm LL, Hou J. The Cap1‐claudin‐4 regulatory pathway is important for renal chloride reabsorption and blood pressure regulation. Proc Natl Acad Sci U S A 111: E3766‐E3774, 2014.
 76.Gorbsky G, Borisy GG. Microtubule distribution in cultured cells and intact tissues: Improved immunolabeling resolution through the use of reversible embedment cytochemistry. Proc Natl Acad Sci U S A 82: 6889‐6893, 1985.
 77.Grencis RK, Worthington JJ. Tuft cells: A new flavor in innate epithelial immunity. Trends Parasitol 32: 583‐585, 2016.
 78.Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, Joslyn G, Stevens J, Spirio L, Robertson M, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell 66: 589‐600, 1991.
 79.Grosse AS, Pressprich MF, Curley LB, Hamilton KL, Margolis B, Hildebrand JD, Gumucio DL. Cell dynamics in fetal intestinal epithelium: Implications for intestinal growth and morphogenesis. Development 138: 4423‐4432, 2011.
 80.Guichard A, Cruz‐Moreno B, Aguilar B, van Sorge NM, Kuang J, Kurkciyan AA, Wang Z, Hang S, Pineton de Chambrun GP, McCole DF, Watnick P, Nizet V, Bier E. Cholera toxin disrupts barrier function by inhibiting exocyst‐mediated trafficking of host proteins to intestinal cell junctions. Cell Host Microbe 14: 294‐305, 2013.
 81.Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE. E‐cadherin germline mutations in familial gastric cancer. Nature 392: 402‐405, 1998.
 82.Gumbiner BM. Regulation of cadherin‐mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6: 622‐634, 2005.
 83.Gurney MA, Laubitz D, Ghishan FK, Kiela PR. Pathophysiology of intestinal Na+/H+ exchange. Cell Mol Gastroenterol Hepatol 3: 27‐40, 2016.
 84.Hanada S, Harada M, Koga H, Kawaguchi T, Taniguchi E, Kumashiro R, Ueno T, Ueno Y, Ishii M, Sakisaka S, Sata M. Tumor necrosis factor‐alpha and interferon‐gamma directly impair epithelial barrier function in cultured mouse cholangiocytes. Liver Int 23: 3‐11, 2003.
 85.Harada N, Inagaki N. Role of sodium‐glucose transporters in glucose uptake of the intestine and kidney. J Diabetes Investig 3: 352‐353, 2012.
 86.Hardin JA, Wallace LE, Wong JF, O'Loughlin EV, Urbanski SJ, Gall DG, MacNaughton WK, Beck PL. Aquaporin expression is downregulated in a murine model of colitis and in patients with ulcerative colitis, Crohn's disease and infectious colitis. Cell Tissue Res 318: 313‐323, 2004.
 87.Hase K, Nakatsu F, Ohmae M, Sugihara K, Shioda N, Takahashi D, Obata Y, Furusawa Y, Fujimura Y, Yamashita T, Fukuda S, Okamoto H, Asano M, Yonemura S, Ohno H. AP‐1B‐mediated protein sorting regulates polarity and proliferation of intestinal epithelial cells in mice. Gastroenterol 145: 625‐635, 2013.
 88.Haskins J, Gu L, Wittchen ES, Hibbard J, Stevenson BR. ZO‐3, a novel member of the MAGUK protein family found at the tight junction, interacts with ZO‐1 and occludin. J Cell Biol 141: 199‐208, 1998.
 89.Hattrup CL, Gendler SJ. Structure and function of the cell surface (tethered) mucins. Annu Rev Physiol 70: 431‐457, 2008.
 90.Hayes P, Dhillon S, O'Neill K, Thoeni C, Hui KY, Elkadri A, Guo CH, Kovacic L, Aviello G, Alvarez LA, Griffiths AM, Snapper SB, Brant SR, Doroshow JH, Silverberg MS, Peter I, McGovern DP, Cho J, Brumell JH, Uhlig HH, Bourke B, Muise AA, Knaus UG. Defects in NADPH oxidase genes NOX1 and DUOX2 in very early onset inflammatory bowel disease. Cell Mol Gastroenterol Hepatol 1: 489‐502, 2015.
 91.Helander HF, Fandriks L. Surface area of the digestive tract—revisited. Scand J Gastroenterol 49: 681‐689, 2014.
 92.Heller F, Florian P, Bojarski C, Richter J, Christ M, Hillenbrand B, Mankertz J, Gitter AH, Burgel N, Fromm M, Zeitz M, Fuss I, Strober W, Schulzke JD. Interleukin‐13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution. Gastroenterol 129: 550‐564, 2005.
 93.Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA. A serine/threonine kinase gene defective in Peutz‐Jeghers syndrome. Nature 391: 184‐187, 1998.
 94.Hollander D, Vadheim CM, Brettholz E, Petersen GM, Delahunty T, Rotter JI. Increased intestinal permeability in patients with Crohn's disease and their relatives. A possible etiologic factor. Ann Intern Med 105: 883‐885, 1986.
 95.Holman GD, Naftalin RJ. Fluid movements across rabbit ileum coupled to passive paracellular ion movements. J Physiol 290: 351‐366, 1979.
 96.Holmes JL, Van Itallie CM, Rasmussen JE, Anderson JM. Claudin profiling in the mouse during postnatal intestinal development and along the gastrointestinal tract reveals complex expression patterns. Gene Expr Patterns 6: 581‐588, 2006.
 97.Hoogerwerf WA, Tsao SC, Devuyst O, Levine SA, Yun CH, Yip JW, Cohen ME, Wilson PD, Lazenby AJ, Tse CM, Donowitz M. NHE2 and NHE3 are human and rabbit intestinal brush‐border proteins. Am J Physiol 270: G29‐G41, 1996.
 98.Hopwood D, Logan KR, Bouchier IA. The electron microscopy of normal human oesophageal epithelium. Virchows Arch B Cell Pathol 26: 345‐358, 1978.
 99.Hou J, Rajagopal M, Yu AS. Claudins and the kidney. Annu Rev Physiol 75: 479‐501, 2013.
 100.Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, Gallini CA, Redding K, Margolskee RF, Osborne LC, Artis D, Garrett WS. Tuft cells, taste‐chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351: 1329‐1333, 2016.
 101.Hu CH, Michel B, Schiltz JR. Epidermal acantholysis induced in vitro by pemphigus autoantibody. An ultrastructural study. Am J Pathol 90: 345‐362, 1978.
 102.Hu Z, Wang Y, Graham WV, Su L, Musch MW, Turner JR. MAPKAPK‐2 is a critical signaling intermediate in NHE3 activation following Na+‐glucose cotransport. J Biol Chem 281: 24247‐24253, 2006.
 103.Huang B, Wang H, Yang B. Water transport mediated by other membrane proteins. Adv Exp Med Biol 969: 251‐261, 2017.
 104.Hurd TW, Gao L, Roh MH, Macara IG, Margolis B. Direct interaction of two polarity complexes implicated in epithelial tight junction assembly. Nat Cell Biol 5: 137‐142, 2003.
 105.Hurley PT, Ferguson CJ, Kwon TH, Andersen ML, Norman AG, Steward MC, Nielsen S, Case RM. Expression and immunolocalization of aquaporin water channels in rat exocrine pancreas. Am J Physiol ‐ Gastrointest Liver Physiol 280: G701‐G709, 2001.
 106.Hwang ES, Hirayama BA, Wright EM. Distribution of the SGLT1 Na+/glucose cotransporter and mRNA along the crypt‐villus axis of rabbit small intestine. Biochem Biophys Res Commun 181: 1208‐1217, 1991.
 107.Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol 171: 939‐945, 2005.
 108.In J, Foulke‐Abel J, Zachos NC, Hansen AM, Kaper JB, Bernstein HD, Halushka M, Blutt S, Estes MK, Donowitz M, Kovbasnjuk O. Enterohemorrhagic Escherichia coli reduce mucus and intermicrovillar bridges in human stem cell‐derived colonoids. Cell Mol Gastroenterol Hepatol 2: 48‐62 e43, 2016.
 109.Irvine EJ, Marshall JK. Increased intestinal permeability precedes the onset of Crohn's disease in a subject with familial risk. Gastroenterol 119: 1740‐1744, 2000.
 110.Jacobs JP, Goudarzi M, Singh N, Tong M, McHardy IH, Ruegger P, Asadourian M, Moon BH, Ayson A, Borneman J, McGovern DP, Fornace AJ, Jr., Braun J, Dubinsky M. A disease‐associated microbial and metabolomics state in relatives of pediatric inflammatory bowel disease patients. Cell Mol Gastroenterol Hepatol 2: 750‐766, 2016.
 111.Jaks V, Barker N, Kasper M, van Es JH, Snippert HJ, Clevers H, Toftgard R. Lgr5 marks cycling, yet long‐lived, hair follicle stem cells. Nat Genet 40: 1291‐1299, 2008.
 112.Janecke AR, Heinz‐Erian P, Yin J, Petersen BS, Franke A, Lechner S, Fuchs I, Melancon S, Uhlig HH, Travis S, Marinier E, Perisic V, Ristic N, Gerner P, Booth IW, Wedenoja S, Baumgartner N, Vodopiutz J, Frechette‐Duval MC, De Lafollie J, Persad R, Warner N, Tse CM, Sud K, Zachos NC, Sarker R, Zhu X, Muise AM, Zimmer KP, Witt H, Zoller H, Donowitz M, Muller T. Reduced sodium/proton exchanger NHE3 activity causes congenital sodium diarrhea. Hum Mol Genet 24: 6614‐6623, 2015.
 113.Jenne DE, Reimann H, Nezu J, Friedel W, Loff S, Jeschke R, Muller O, Back W, Zimmer M. Peutz‐Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18: 38‐43, 1998.
 114.Jesaitis LA, Goodenough DA. Molecular characterization and tissue distribution of ZO‐2, a tight junction protein homologous to ZO‐1 and the Drosophila discs‐large tumor suppressor protein. J Cell Biol 124: 949‐961, 1994.
 115.Joberty G, Petersen C, Gao L, Macara IG. The cell‐polarity protein Par6 links Par3 and atypical protein kinase C to Cdc42. Nat Cell Biol 2: 531‐539, 2000.
 116.Johansson ME, Hansson GC. Mucus and the goblet cell. Dig Dis 31: 305‐309, 2013.
 117.Johansson ME, Phillipson M, Petersson J, Velcich A, Holm L, Hansson GC. The inner of the two Muc2 mucin‐dependent mucus layers in colon is devoid of bacteria. Proc Natl Acad Sci U S A 105: 15064‐15069, 2008.
 118.Johansson ME, Thomsson KA, Hansson GC. Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 mucin, is strongly bound to the Fcgbp protein. J Proteome Res 8: 3549‐3557, 2009.
 119.Kaetzel CS, Robinson JK, Chintalacharuvu KR, Vaerman JP, Lamm ME. The polymeric immunoglobulin receptor (secretory component) mediates transport of immune complexes across epithelial cells: A local defense function for IgA. Proc Natl Acad Sci U S A 88: 8796‐8800, 1991.
 120.Kanai Y, Lee WS, You G, Brown D, Hediger MA. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D‐glucose. J Clin Invest 93: 397‐404, 1994.
 121.Keller P, Toomre D, Diaz E, White J, Simons K. Multicolour imaging of post‐Golgi sorting and trafficking in live cells. Nat Cell Biol 3: 140‐149, 2001.
 122.Keller TC, III, Conzelman KA, Chasan R, Mooseker MS. Role of myosin in terminal web contraction in isolated intestinal epithelial brush borders. J Cell Biol 100: 1647‐1655, 1985.
 123.Kellett GL, Brot‐Laroche E, Mace OJ, Leturque A. Sugar absorption in the intestine: The role of GLUT2. Annu Rev Nutr 28: 35‐54, 2008.
 124.Kellett GL, Helliwell PA. The diffusive component of intestinal glucose absorption is mediated by the glucose‐induced recruitment of GLUT2 to the brush‐border membrane. Biochem J 350(Pt 1): 155‐162., 2000.
 125.Kevans D, Turpin W, Madsen K, Meddings J, Shestopaloff K, Xu W, Moreno‐Hagelsieb G, Griffiths A, Silverberg MS, Paterson A, Croitoru K. Determinants of intestinal permeability in healthy first‐degree relatives of individuals with Crohn's disease. Inflamm Bowel Dis 21: 879‐887, 2015.
 126.Kiesler P, Fuss IJ, Strober W. Experimental models of inflammatory bowel diseases. Cell Mol Gastroenterol Hepatol 1: 154‐170, 2015.
 127.Kim NG, Koh E, Chen X, Gumbiner BM. E‐cadherin mediates contact inhibition of proliferation through Hippo signaling‐pathway components. Proc Natl Acad Sci U S A 108: 11930‐11935, 2011.
 128.King LS, Agre P. Pathophysiology of the aquaporin water channels. Annu Rev Physiol 58: 619‐648, 1996.
 129.Knowles MR, Zariwala M, Leigh M. Primary ciliary dyskinesia. Clin Chest Med 37: 449‐461, 2016.
 130.Knudsen KA, Soler AP, Johnson KR, Wheelock MJ. Interaction of alpha‐actinin with the cadherin/catenin cell‐cell adhesion complex via alpha‐catenin. J Cell Biol 130: 67‐77, 1995.
 131.Kohlnhofer BM, Thompson CA, Walker EM, Battle MA. GATA4 regulates epithelial cell proliferation to control intestinal growth and development in mice. Cell Mol Gastroenterol Hepatol 2: 189‐209, 2016.
 132.Kongkanuntn R, Bubb VJ, Sansom OJ, Wyllie AH, Harrison DJ, Clarke AR. Dysregulated expression of beta‐catenin marks early neoplastic change in Apc mutant mice, but not all lesions arising in Msh2 deficient mice. Oncogene 18: 7219‐7225, 1999.
 133.Konrad M, Schaller A, Seelow D, Pandey AV, Waldegger S, Lesslauer A, Vitzthum H, Suzuki Y, Luk JM, Becker C, Schlingmann KP, Schmid M, Rodriguez‐Soriano J, Ariceta G, Cano F, Enriquez R, Juppner H, Bakkaloglu SA, Hediger MA, Gallati S, Neuhauss SC, Nurnberg P, Weber S. Mutations in the tight‐junction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet 79: 949‐957, 2006.
 134.Koulouridis E, Koulouridis I. Molecular pathophysiology of Bartter's and Gitelman's syndromes. World J Pediatr 11: 113‐125, 2015.
 135.Krause G, Winkler L, Piehl C, Blasig I, Piontek J, Muller SL. Structure and function of extracellular claudin domains. Ann N Y Acad Sci 1165: 34‐43, 2009.
 136.Kreda SM, Davis CW, Rose MC. CFTR, mucins, and mucus obstruction in cystic fibrosis. Cold Spring Harb Perspect Med 2: a009589, 2012.
 137.Krug SM, Gunzel D, Conrad MP, Lee IF, Amasheh S, Fromm M, Yu AS. Charge‐selective claudin channels. Ann N Y Acad Sci 1257: 20‐28, 2012.
 138.Krug SM, Gunzel D, Conrad MP, Rosenthal R, Fromm A, Amasheh S, Schulzke JD, Fromm M. Claudin‐17 forms tight junction channels with distinct anion selectivity. Cell Mol Life Sci 69: 2765‐2778, 2012.
 139.Kuisma J, Nuutinen H, Luukkonen P, Jarvinen H, Kahri A, Farkkila M. Long term metabolic consequences of ileal pouch‐anal anastomosis for ulcerative colitis. Am J Gastroenterol 96: 3110‐3116, 2001.
 140.Lai C, Robinson J, Clark S, Stamp G, Poulsom R, Silver A. Elevation of WNT5A expression in polyp formation in Lkb1+/‐ mice and Peutz‐Jeghers syndrome. J Pathol 223: 584‐592, 2011.
 141.Lamprecht G, Seidler U. The emerging role of PDZ adapter proteins for regulation of intestinal ion transport. Am J Physiol Gastrointest Liver Physiol 291: G766‐G777, 2006.
 142.Lapierre LA, Kumar R, Hales CM, Navarre J, Bhartur SG, Burnette JO, Provance DW, Jr., Mercer JA, Bahler M, Goldenring JR. Myosin vb is associated with plasma membrane recycling systems. Mol Biol Cell 12: 1843‐1857, 2001.
 143.Larmonier CB, Laubitz D, Hill FM, Shehab KW, Lipinski L, Midura‐Kiela MT, McFadden RM, Ramalingam R, Hassan KA, Golebiewski M, Besselsen DG, Ghishan FK, Kiela PR. Reduced colonic microbial diversity is associated with colitis in NHE3‐deficient mice. Am J Physiol ‐ Gastrointest Liver Physiol 305: G667‐G677, 2013.
 144.Larmonier CB, Laubitz D, Thurston RD, Bucknam AL, Hill FM, Midura‐Kiela M, Ramalingam R, Kiela PR, Ghishan FK. NHE3 modulates the severity of colitis in IL‐10‐deficient mice. Am J Physiol Gastrointest Liver Physiol 300: G998‐G1009, 2011.
 145.Laubitz D, Harrison CA, Midura‐Kiela MT, Ramalingam R, Larmonier CB, Chase JH, Caporaso JG, Besselsen DG, Ghishan FK, Kiela PR. Reduced epithelial Na+/H+ exchange drives gut microbial dysbiosis and promotes inflammatory response in T cell‐mediated murine colitis. PLoS One 11: e0152044, 2016.
 146.Le TL, Yap AS, Stow JL. Recycling of E‐cadherin: A potential mechanism for regulating cadherin dynamics. J Cell Biol 146: 219‐232, 1999.
 147.Lee JL, Streuli CH. Integrins and epithelial cell polarity. J Cell Sci 127: 3217‐3225, 2014.
 148.Lee WS, Kanai Y, Wells RG, Hediger MA. The high affinity Na+/glucose cotransporter. Re‐evaluation of function and distribution of expression. J Biol Chem 269: 12032‐12039, 1994.
 149.Lescale‐Matys L, Dyer J, Scott D, Freeman TC, Wright EM, Shirazi‐Beechey SP. Regulation of the ovine intestinal Na+/glucose co‐transporter (SGLT1) is dissociated from mRNA abundance. Biochem J 291(Pt 2): 435‐440, 1993.
 150.Lewis SA. Everything you wanted to know about the bladder epithelium but were afraid to ask. Am J Physiol ‐ Renal Physiol 278: F867‐F874, 2000.
 151.Lewis SA, Eaton DC, Diamond JM. The mechanism of Na+ transport by rabbit urinary bladder. J Membr Biol 28: 41‐70, 1976.
 152.Li J, Newhall J, Ishiyama N, Gottardi C, Ikura M, Leckband DE, Tajkhorshid E. Structural determinants of the mechanical stability of alpha‐catenin. J Biol Chem 290: 18890‐18903, 2015.
 153.Lim X, Tan SH, Koh WL, Chau RM, Yan KS, Kuo CJ, van Amerongen R, Klein AM, Nusse R. Interfollicular epidermal stem cells self‐renew via autocrine Wnt signaling. Science 342: 1226‐1230, 2013.
 154.Lin R, Murtazina R, Cha B, Chakraborty M, Sarker R, Chen TE, Lin Z, Hogema BM, de Jonge HR, Seidler U, Turner JR, Li X, Kovbasnjuk O, Donowitz M. D‐glucose acts via sodium/glucose cotransporter 1 to increase NHE3 in mouse jejunal brush border by a Na+/H+ exchange regulatory factor 2‐dependent process. Gastroenterol 140: 560‐571, 2011.
 155.Lindstedt G, Lindstedt S, Gustafsson BE. Mucus in intestinal contents of germfree rats. J Exp Med 121: 201‐213, 1965.
 156.Lingaraju A, Long TM, Wang Y, Austin JR, II, Turner JR. Conceptual barriers to understanding physical barriers. Semin Cell Dev Biol 42: 13‐21, 2015.
 157.Liu J, Walker NM, Ootani A, Strubberg AM, Clarke LL. Defective goblet cell exocytosis contributes to murine cystic fibrosis‐associated intestinal disease. J Clin Invest 125: 1056‐1068, 2015.
 158.Llorente C, Schnabl B. The gut microbiota and liver disease. Cell Mol Gastroenterol Hepatol 1: 275‐284, 2015.
 159.Lo Y‐H, Chung E, Li Z, Wan Y‐W, Mahe MM, Chen M‐S, Noah TK, Bell KN, Yalamanchili HK, Klisch TJ, Liu Z, Park J‐S, Shroyer NF. Transcriptional regulation by ATOH1 and its target SPDEF in the intestine. Cell Mol Gastroenterol Hepatol 3: 51‐71, 2016.
 160.Lubarsky B, Krasnow MA. Tube morphogenesis: Making and shaping biological tubes. Cell 112: 19‐28, 2003.
 161.Luna RA, Oezguen N, Balderas M, Venkatachalam A, Runge JK, Versalovic J, Veenstra‐VanderWeele J, Anderson GM, Savidge T, Williams KC. Distinct microbiome‐neuroimmune signatures correlate with functional abdominal pain in children with autism spectrum disorder. Cell Molec Gastroenterol Hepatol 3: 218‐230, 2016.
 162.Mace OJ, Morgan EL, Affleck JA, Lister N, Kellett GL. Calcium absorption by Cav1.3 induces terminal web myosin II phosphorylation and apical GLUT2 insertion in rat intestine. J Physiol 580: 605‐616, 2007.
 163.Macpherson AJ, Geuking MB, Slack E, Hapfelmeier S, McCoy KD. The habitat, double life, citizenship, and forgetfulness of IgA. Immunol Rev 245: 132‐146, 2012.
 164.Madara JL, Carlson S. Supraphysiologic L‐tryptophan elicits cytoskeletal and macromolecular permeability alterations in hamster small intestinal epithelium in vitro. J Clin Invest 87: 454‐462, 1991.
 165.Madara JL, Pappenheimer JR. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J Membr Biol 100: 149‐164, 1987.
 166.Mahraoui L, Rousset M, Dussaulx E, Darmoul D, Zweibaum A, Brot‐Laroche E. Expression and localization of GLUT‐5 in Caco‐2 cells, human small intestine, and colon. Am J Physiol 263: G312‐G318, 1992.
 167.Manary M. The paneth cell: A guardian of gut health. Cell Mol Gastroenterol Hepatol 2: 259, 2016.
 168.Mandel LJ, Bacallao R, Zampighi G. Uncoupling of the molecular ‘fence’ and paracellular ‘gate’ functions in epithelial tight junctions. Nature 361: 552‐555, 1993.
 169.Marchiando AM, Shen L, Graham WV, Weber CR, Schwarz BT, Austin JR, 2nd, Raleigh DR, Guan Y, Watson AJ, Montrose MH, Turner JR. Caveolin‐1‐dependent occludin endocytosis is required for TNF‐induced tight junction regulation in vivo. J Cell Biol 189: 111‐126, 2010.
 170.Marciano DK. A holey pursuit: Lumen formation in the developing kidney. Pediatr Nephrol 32: 7‐20, 2017.
 171.Mather A, Pollock C. Glucose handling by the kidney. Kidney Int Suppl 120: S1‐S6, 2011.
 172.Mathewson ND, Jenq R, Mathew AV, Koenigsknecht M, Hanash A, Toubai T, Oravecz‐Wilson K, Wu SR, Sun Y, Rossi C, Fujiwara H, Byun J, Shono Y, Lindemans C, Calafiore M, Schmidt TC, Honda K, Young VB, Pennathur S, van den Brink M, Reddy P. Gut microbiome‐derived metabolites modulate intestinal epithelial cell damage and mitigate graft‐versus‐host disease. Nat Immunol 17: 505‐513, 2016.
 173.Matsumine A, Ogai A, Senda T, Okumura N, Satoh K, Baeg GH, Kawahara T, Kobayashi S, Okada M, Toyoshima K, Akiyama T. Binding of APC to the human homolog of the Drosophila discs large tumor suppressor protein. Science 272: 1020‐1023, 1996.
 174.May GR, Sutherland LR, Meddings JB. Is small intestinal permeability really increased in relatives of patients with Crohn's disease? Gastroenterol 104: 1627‐1632, 1993.
 175.McConnell RE, Higginbotham JN, Shifrin DA, Jr., Tabb DL, Coffey RJ, Tyska MJ. The enterocyte microvillus is a vesicle‐generating organelle. J Cell Biol 185: 1285‐1298, 2009.
 176.McConnell RE, Tyska MJ. Myosin‐1a powers the sliding of apical membrane along microvillar actin bundles. J Cell Biol 177: 671‐681, 2007.
 177.Meddings JB, Westergaard H. Intestinal glucose transport using perfused rat jejunum in vivo: Model analysis and derivation of corrected kinetic constants. Clin Sci (Lond) 76: 403‐413, 1989.
 178.Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Tada Y, Saito K, Tamura A, Igarashi M, Endo T, Takeuchi K, Tsukita S. Predicted expansion of the claudin multigene family. FEBS Lett 585: 606‐612, 2011.
 179.Mollajew R, Zocher F, Horner A, Wiesner B, Klussmann E, Pohl P. Routes of epithelial water flow: Aquaporins versus cotransporters. Biophys J 99: 3647‐3656, 2010.
 180.Morales MM, Falkenstein D, Lopes AG. The cystic fibrosis transmembrane regulator (CFTR) in the kidney. An Acad Bras Cienc 72: 399‐406, 2000.
 181.Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW. Activation of beta‐catenin‐Tcf signaling in colon cancer by mutations in beta‐catenin or APC. Science 275: 1787‐1790, 1997.
 182.Mortensen PB, Clausen MR. Short‐chain fatty acids in the human colon: Relation to gastrointestinal health and disease. Scand J Gastroenterol Suppl 216: 132‐148, 1996.
 183.Mukherjee TM, Williams AW. A comparative study of the ultrastructure of microvilli in the epithelium of small and large intestine of mice. J Cell Biol 34: 447‐461, 1967.
 184.Musch MW, Clarke LL, Mamah D, Gawenis LR, Zhang Z, Ellsworth W, Shalowitz D, Mittal N, Efthimiou P, Alnadjim Z, Hurst SD, Chang EB, Barrett TA. T cell activation causes diarrhea by increasing intestinal permeability and inhibiting epithelial Na+/K+‐ATPase. J Clin Invest 110: 1739‐1747, 2002.
 185.Muto S. Physiological roles of claudins in kidney tubule paracellular transport. Am J Physiol Renal Physiol 312: F9‐F24, 2016.
 186.Muto S, Furuse M, Kusano E. Claudins and renal salt transport. Clin Exp Nephrol 16: 61‐67, 2012.
 187.Nagao‐Kitamoto H, Shreiner AB, Gillilland MG, 3rd, Kitamoto S, Ishii C, Hirayama A, Kuffa P, El‐Zaatari M, Grasberger H, Seekatz AM, Higgins PD, Young VB, Fukuda S, Kao JY, Kamada N. Functional characterization of inflammatory bowel disease‐associated gut dysbiosis in gnotobiotic mice. Cell Mol Gastroenterol Hepatol 2: 468‐481, 2016.
 188.Nalle SC, Turner JR. Intestinal barrier loss as a critical pathogenic link between inflammatory bowel disease and graft‐versus‐host disease. Mucosal Immunol 8: 720‐730, 2015.
 189.Naren AP, Cobb B, Li C, Roy K, Nelson D, Heda GD, Liao J, Kirk KL, Sorscher EJ, Hanrahan J, Clancy JP. A macromolecular complex of beta 2 adrenergic receptor, CFTR, and ezrin/radixin/moesin‐binding phosphoprotein 50 is regulated by PKA. Proc Natl Acad Sci U S A 100: 342‐346, 2003.
 190.Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM, Sinha GP, Rafeeq M, Jones SM, Belyantseva IA, Anderson JM, Forge A, Frolenkov GI, Riazuddin S. Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 123: 4036‐4049, 2013.
 191.Neisch AL, Fehon RG. Ezrin, Radixin and Moesin: Key regulators of membrane‐cortex interactions and signaling. Curr Opin Cell Biol 23: 377‐382, 2011.
 192.Nelson WJ, Veshnock PJ. Ankyrin binding to (Na+ + K+)ATPase and implications for the organization of membrane domains in polarized cells. Nature 328: 533‐536, 1987.
 193.Noda Y, Sohara E, Ohta E, Sasaki S. Aquaporins in kidney pathophysiology. Nat Rev Nephrol 6: 168‐178, 2010.
 194.Odenwald MA, Choi W, Buckley A, Shashikanth N, Joseph NE, Wang Y, Warren MH, Buschmann MM, Pavlyuk R, Hildebrand J, Margolis B, Fanning AS, Turner JR. ZO‐1 interactions with F‐actin and occludin direct epithelial polarization and single lumen specification in 3D culture. J Cell Sci 130: 243‐259, 2017.
 195.Oriolo AS, Wald FA, Ramsauer VP, Salas PJ. Intermediate filaments: A role in epithelial polarity. Exp Cell Res 313: 2255‐2264, 2007.
 196.Palmer LG, Patel A, Frindt G. Regulation and dysregulation of epithelial Na+ channels. Clin Exp Nephrol 16: 35‐43, 2012.
 197.Pappenheimer JR. Role of pre‐epithelial “unstirred” layers in absorption of nutrients from the human jejunum. J Membr Biol 179: 185‐204, 2001.
 198.Patz J, Jacobsohn WZ, Gottschalk‐Sabag S, Zeides S, Braverman DZ. Treatment of refractory distal ulcerative colitis with short chain fatty acid enemas. Am J Gastroenterol 91: 731‐734, 1996.
 199.Pearson AD, Eastham EJ, Laker MF, Craft AW, Nelson R. Intestinal permeability in children with Crohn's disease and coeliac disease. Br Med J (Clin Res Ed) 285: 20‐21, 1982.
 200.Pei L, Solis G, Nguyen MT, Kamat N, Magenheimer L, Zhuo M, Li J, Curry J, McDonough AA, Fields TA, Welch WJ, Yu AS. Paracellular epithelial sodium transport maximizes energy efficiency in the kidney. J Clin Invest 126: 2509‐2518, 2016.
 201.Pentecost M, Otto G, Theriot JA, Amieva MR. Listeria monocytogenes invades the epithelial junctions at sites of cell extrusion. PLoS Pathog 2: e3, 2006.
 202.Pierschbacher MD, Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature 309: 30‐33, 1984.
 203.Podany AB, Wright J, Lamendella R, Soybel DI, Kelleher SL. ZnT2‐mediated zinc import into paneth cell granules is necessary for coordinated secretion and paneth cell function in mice. Cell Mol Gastroenterol Hepatol 2: 369‐383, 2016.
 204.Polishchuk R, Di Pentima A, Lippincott‐Schwartz J. Delivery of raft‐associated, GPI‐anchored proteins to the apical surface of polarized MDCK cells by a transcytotic pathway. Nat Cell Biol 6: 297‐307, 2004.
 205.Pollack AL, Barth AI, Altschuler Y, Nelson WJ, Mostov KE. Dynamics of beta‐catenin interactions with APC protein regulate epithelial tubulogenesis. J Cell Biol 137: 1651‐1662, 1997.
 206.Powell AE, Wang Y, Li Y, Poulin EJ, Means AL, Washington MK, Higginbotham JN, Juchheim A, Prasad N, Levy SE, Guo Y, Shyr Y, Aronow BJ, Haigis KM, Franklin JL, Coffey RJ. The pan‐ErbB negative regulator Lrig1 is an intestinal stem cell marker that functions as a tumor suppressor. Cell 149: 146‐158, 2012.
 207.Raghavan M, Bjorkman PJ. Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol 12: 181‐220, 1996.
 208.Ragkousi K, Gibson MC. Cell division and the maintenance of epithelial order. J Cell Biol 207: 181‐188, 2014.
 209.Rahner C, Mitic LL, Anderson JM. Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut. Gastroenterol 120: 411‐422, 2001.
 210.Raleigh DR, Boe DM, Yu D, Weber CR, Marchiando AM, Bradford EM, Wang Y, Wu L, Schneeberger EE, Shen L, Turner JR. Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function. J Cell Biol 193: 565‐582, 2011.
 211.Raleigh DR, Marchiando AM, Zhang Y, Shen L, Sasaki H, Wang Y, Long M, Turner JR. Tight junction‐associated MARVEL proteins marveld3, tricellulin, and occludin have distinct but overlapping functions. Mol Biol Cell 21: 1200‐1213, 2010.
 212.Ramos‐e‐Silva M, Jacques C. Epidermal barrier function and systemic diseases. Clin Dermatol 30: 277‐279, 2012.
 213.Raymond C, Anne V, Millane G. Development of esophageal epithelium in the fetal and neonatal mouse. Anat Rec 230: 225‐234, 1991.
 214.Reddy MM, Light MJ, Quinton PM. Activation of the epithelial Na+ channel (ENaC) requires CFTR Cl‐channel function. Nature 402: 301‐304, 1999.
 215.Reynolds A, Parris A, Evans LA, Lindqvist S, Sharp P, Lewis M, Tighe R, Williams MR. Dynamic and differential regulation of NKCC1 by calcium and cAMP in the native human colonic epithelium. J Physiol 582: 507‐524, 2007.
 216.Riazuddin S, Ahmed ZM, Fanning AS, Lagziel A, Kitajiri S, Ramzan K, Khan SN, Chattaraj P, Friedman PL, Anderson JM, Belyantseva IA, Forge A, Friedman TB. Tricellulin is a tight‐junction protein necessary for hearing. Am J Hum Genet 79: 1040‐1051, 2006.
 217.Ricanek P, Lunde LK, Frye SA, Stoen M, Nygard S, Morth JP, Rydning A, Vatn MH, Amiry‐Moghaddam M, Tonjum T. Reduced expression of aquaporins in human intestinal mucosa in early stage inflammatory bowel disease. Clin Exp Gastroenterol 8: 49‐67, 2015.
 218.Ritsma L, Ellenbroek SI, Zomer A, Snippert HJ, de Sauvage FJ, Simons BD, Clevers H, van Rheenen J. Intestinal crypt homeostasis revealed at single‐stem‐cell level by in vivo live imaging. Nature 507: 362‐365, 2014.
 219.Rock B, Martins CR, Theofilopoulos AN, Balderas RS, Anhalt GJ, Labib RS, Futamura S, Rivitti EA, Diaz LA. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem). N Engl J Med 320: 1463‐1469, 1989.
 220.Roh MH, Margolis B. Composition and function of PDZ protein complexes during cell polarization. Am J Physiol ‐ Renal Physiol 285: F377‐F387, 2003.
 221.Rosenthal R, Gunzel D, Krug SM, Schulzke JD, Fromm M, Yu AS. Claudin‐2‐mediated cation and water transport share a common pore. Acta Physiol (Oxf) 219: 521‐536, 2016.
 222.Rosenthal R, Milatz S, Krug SM, Oelrich B, Schulzke JD, Amasheh S, Gunzel D, Fromm M. Claudin‐2, a component of the tight junction, forms a paracellular water channel. J Cell Sci 123: 1913‐1921, 2010.
 223.Salas PJ, Misek DE, Vega‐Salas DE, Gundersen D, Cereijido M, Rodriguez‐Boulan E. Microtubules and actin filaments are not critically involved in the biogenesis of epithelial cell surface polarity. J Cell Biol 102: 1853‐1867, 1986.
 224.Sanchez de Medina F, Romero‐Calvo I, Mascaraque C, Martinez‐Augustin O. Intestinal inflammation and mucosal barrier function. Inflamm Bowel Dis 20: 2394‐2404, 2014.
 225.Saotome I, Curto M, McClatchey AI. Ezrin is essential for epithelial organization and villus morphogenesis in the developing intestine. Dev Cell 6: 855‐864, 2004.
 226.Sasaki H, Matsui C, Furuse K, Mimori‐Kiyosue Y, Furuse M, Tsukita S. Dynamic behavior of paired claudin strands within apposing plasma membranes. Proc Natl Acad Sci U S A 100: 3971‐3976, 2003.
 227.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. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469: 415‐418, 2011.
 228.Sauvanet C, Wayt J, Pelaseyed T, Bretscher A. Structure, regulation, and functional diversity of microvilli on the apical domain of epithelial cells. Annu Rev Cell Dev Biol 31: 593‐621, 2015.
 229.Schlingmann B, Molina SA, Koval M. Claudins: Gatekeepers of lung epithelial function. Semin Cell Dev Biol 42: 47‐57, 2015.
 230.Schubert ML. Gastric exocrine and endocrine secretion. Curr Opin Gastroenterol 25: 529‐536, 2009.
 231.Schuck S, Simons K. Polarized sorting in epithelial cells: Raft clustering and the biogenesis of the apical membrane. J Cell Sci 117: 5955‐5964, 2004.
 232.Schultheis PJ, Clarke LL, Meneton P, Miller ML, Soleimani M, Gawenis LR, Riddle TM, Duffy JJ, Doetschman T, Wang T, Giebisch G, Aronson PS, Lorenz JN, Shull GE. Renal and intestinal absorptive defects in mice lacking the NHE3 Na+/H+ exchanger. Nat Genet 19: 282‐285, 1998.
 233.Shen L, Weber CR, Raleigh DR, Yu D, Turner JR. Tight junction pore and leak pathways: A dynamic duo. Annu Rev Physiol 73: 283‐309, 2011.
 234.Shimokawa M, Ohta Y, Nishikori S, Matano M, Takano A, Fujii M, Date S, Sugimoto S, Kanai T, Sato T. Visualization and targeting of LGR5+ human colon cancer stem cells. Nature 545: 187‐192, 2017.
 235.Simon DB, Lu Y, Choate KA, Velazquez H, Al‐Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez‐Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP. Paracellin‐1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 285: 103‐106, 1999.
 236.Simpson JE, Gawenis LR, Walker NM, Boyle KT, Clarke LL. Chloride conductance of CFTR facilitates basal Cl‐/HCO3‐ exchange in the villous epithelium of intact murine duodenum. Am J Physiol Gastrointest Liver Physiol 288: G1241‐G1251, 2005.
 237.Singh V, Yeoh BS, Chassaing B, Zhang B, Saha P, Xiao X, Awasthi D, Shashidharamurthy R, Dikshit M, Gewirtz A, Vijay‐Kumar M. Microbiota‐inducible innate immune, siderophore binding protein lipocalin 2 is critical for intestinal homeostasis. Cell Mol Gastroenterol Hepatol 2: 482‐498 e486, 2016.
 238.Sourisseau T, Georgiadis A, Tsapara A, Ali RR, Pestell R, Matter K, Balda MS. Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO‐1‐regulated transcription factor ZONAB/DbpA. Mol Cell Biol 26: 2387‐2398, 2006.
 239.Stairs DB, Bayne LJ, Rhoades B, Vega ME, Waldron TJ, Kalabis J, Klein‐Szanto A, Lee JS, Katz JP, Diehl JA, Reynolds AB, Vonderheide RH, Rustgi AK. Deletion of p120‐catenin results in a tumor microenvironment with inflammation and cancer that establishes it as a tumor suppressor gene. Cancer Cell 19: 470‐483, 2011.
 240.Stappenbeck TS, Green KJ. The desmoplakin carboxyl terminus coaligns with and specifically disrupts intermediate filament networks when expressed in cultured cells. J Cell Biol 116: 1197‐1209, 1992.
 241.Steed E, Rodrigues NT, Balda MS, Matter K. Identification of MarvelD3 as a tight junction‐associated transmembrane protein of the occludin family. BMC Cell Biol 10: 95, 2009.
 242.Steinfeld S, Cogan E, King LS, Agre P, Kiss R, Delporte C. Abnormal distribution of aquaporin‐5 water channel protein in salivary glands from Sjogren's syndrome patients. Lab Invest 81: 143‐148, 2001.
 243.Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. Identification of ZO‐1: A high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103: 755‐766, 1986.
 244.Strong TV, Boehm K, Collins FS. Localization of cystic fibrosis transmembrane conductance regulator mRNA in the human gastrointestinal tract by in situ hybridization. J Clin Invest 93: 347‐354, 1994.
 245.Su L, Nalle SC, Shen L, Turner ES, Singh G, Breskin LA, Khramtsova EA, Khramtsova G, Tsai PY, Fu YX, Abraham C, Turner JR. TNFR2 activates MLCK‐dependent tight junction dysregulation to cause apoptosis‐mediated barrier loss and experimental colitis. Gastroenterol 145: 407‐415, 2013.
 246.Su L, Shen L, Clayburgh DR, Nalle SC, Sullivan EA, Meddings JB, Abraham C, Turner JR. Targeted epithelial tight junction dysfunction causes immune activation and contributes to development of experimental colitis. Gastroenterol 136: 551‐563, 2009.
 247.Su T, Bryant DM, Luton F, Verges M, Ulrich SM, Hansen KC, Datta A, Eastburn DJ, Burlingame AL, Shokat KM, Mostov KE. A kinase cascade leading to Rab11‐FIP5 controls transcytosis of the polymeric immunoglobulin receptor. Nat Cell Biol 12: 1143‐1153, 2010.
 248.Sullivan S, Alex P, Dassopoulos T, Zachos NC, Iacobuzio‐Donahue C, Donowitz M, Brant SR, Cuffari C, Harris ML, Datta LW, Conklin L, Chen Y, Li X. Downregulation of sodium transporters and NHERF proteins in IBD patients and mouse colitis models: potential contributors to IBD‐associated diarrhea. Inflamm Bowel Dis 15: 261‐274, 2009.
 249.Sumigray KD, Lechler T. Cell adhesion in epidermal development and barrier formation. Curr Top Dev Biol 112: 383‐414, 2015.
 250.Suzuki H, Nishizawa T, Tani K, Yamazaki Y, Tamura A, Ishitani R, Dohmae N, Tsukita S, Nureki O, Fujiyoshi Y. Crystal structure of a claudin provides insight into the architecture of tight junctions. Science 344: 304‐307, 2014.
 251.Suzuki H, Tani K, Tamura A, Tsukita S, Fujiyoshi Y. Model for the architecture of claudin‐based paracellular ion channels through tight junctions. J Mol Biol 427: 291‐297, 2015.
 252.Takahashi D, Hase K, Kimura S, Nakatsu F, Ohmae M, Mandai Y, Sato T, Date Y, Ebisawa M, Kato T, Obata Y, Fukuda S, Kawamura YI, Dohi T, Katsuno T, Yokosuka O, Waguri S, Ohno H. The epithelia‐specific membrane trafficking factor AP‐1B controls gut immune homeostasis in mice. Gastroenterol 141: 621‐632, 2011.
 253.Tamura A, Hayashi H, Imasato M, Yamazaki Y, Hagiwara A, Wada M, Noda T, Watanabe M, Suzuki Y, Tsukita S. Loss of claudin‐15, but not claudin‐2, causes Na+ deficiency and glucose malabsorption in mouse small intestine. Gastroenterol 140: 913‐923, 2011.
 254.Tanentzapf G, Tepass U. Interactions between the crumbs, lethal giant larvae and bazooka pathways in epithelial polarization. Nat Cell Biol 5: 46‐52, 2003.
 255.Thiagarajah JR, Chang J, Goettel JA, Verkman AS, Lencer WI. Aquaporin‐3 mediates hydrogen peroxide‐dependent responses to environmental stress in colonic epithelia. Proc Natl Acad Sci U S A 114: 568‐573, 2017.
 256.Thiagarajah JR, Zhao D, Verkman AS. Impaired enterocyte proliferation in aquaporin‐3 deficiency in mouse models of colitis. Gut 56: 1529‐1535, 2007.
 257.Thinwa J, Segovia JA, Bose S, Dube PH. Integrin‐mediated first signal for inflammasome activation in intestinal epithelial cells. J Immunol 193: 1373‐1382, 2014.
 258.Tsai PY, Zhang B, He WQ, Zha JM, Odenwald MA, Singh G, Tamura A, Shen L, Sailer A, Yeruva S, Kuo WT, Fu YX, Tsukita S, Turner JR. IL‐22 upregulates epithelial claudin‐2 to drive diarrhea and enteric pathogen clearance. Cell Host & Microbe 21: 671‐681, 2017.
 259.Tsai Y‐H, Hill DR, Kumar N, Huang S, Chin AM, Dye BR, Nagy MS, Verzi MP, Spence JR. LGR4 and LGR5 function redundantly during human endoderm differentiation. Cell Mol Gastroenterol Hepatol 2: 648‐662.e648, 2016.
 260.Turk E, Zabel B, Mundlos S, Dyer J, Wright EM. Glucose/galactose malabsorption caused by a defect in the Na+/glucose cotransporter. Nature 350: 354‐356, 1991.
 261.Turner JR. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9: 799‐809, 2009.
 262.Turner JR, Cohen DE, Mrsny RJ, Madara JL. Noninvasive in vivo analysis of human small intestinal paracellular absorption: Regulation by Na+‐glucose cotransport. Dig Dis Sci 45: 2122‐2126, 2000.
 263.Turner JR, Rill BK, Carlson SL, Carnes D, Kerner R, Mrsny RJ, Madara JL. Physiological regulation of epithelial tight junctions is associated with myosin light‐chain phosphorylation. Am J Physiol 273: C1378‐C1385, 1997.
 264.Tyska MJ. Brush border destruction by enterohemorrhagic Escherichia coli (EHEC): New insights from organoid culture. Cell Mol Gastroenterol Hepatol 2: 7‐8, 2016.
 265.Tyska MJ, Mackey AT, Huang JD, Copeland NG, Jenkins NA, Mooseker MS. Myosin‐1a is critical for normal brush border structure and composition. Mol Biol Cell 16: 2443‐2457, 2005.
 266.Tzaban S, Massol RH, Yen E, Hamman W, Frank SR, Lapierre LA, Hansen SH, Goldenring JR, Blumberg RS, Lencer WI. The recycling and transcytotic pathways for IgG transport by FcRn are distinct and display an inherent polarity. J Cell Biol 185: 673‐684, 2009.
 267.Ukena SN, Singh A, Dringenberg U, Engelhardt R, Seidler U, Hansen W, Bleich A, Bruder D, Franzke A, Rogler G, Suerbaum S, Buer J, Gunzer F, Westendorf AM. Probiotic Escherichia coli Nissle 1917 inhibits leaky gut by enhancing mucosal integrity. PLoS ONE 2: e1308, 2007.
 268.Umeda K, Ikenouchi J, Katahira‐Tayama S, Furuse K, Sasaki H, Nakayama M, Matsui T, Tsukita S, Furuse M. ZO‐1 and ZO‐2 independently determine where claudins are polymerized in tight‐junction strand formation. Cell 126: 741‐754, 2006.
 269.van der Flier LG, Clevers H. Stem cells, self‐renewal, and differentiation in the intestinal epithelium. Annu Rev Physiol 71: 241‐260, 2009.
 270.Van der Sluis M, De Koning BA, De Bruijn AC, Velcich A, Meijerink JP, Van Goudoever JB, Buller HA, Dekker J, Van Seuningen I, Renes IB, Einerhand AW. Muc2‐deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterol 131: 117‐129, 2006.
 271.van Es JH, Jay P, Gregorieff A, van Gijn ME, Jonkheer S, Hatzis P, Thiele A, van den Born M, Begthel H, Brabletz T, Taketo MM, Clevers H. Wnt signalling induces maturation of Paneth cells in intestinal crypts. Nat Cell Biol 7: 381‐386, 2005.
 272.Van Itallie C, Rahner C, Anderson JM. Regulated expression of claudin‐4 decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest 107: 1319‐1327, 2001.
 273.Van Itallie CM, Fanning AS, Holmes J, Anderson JM. Occludin is required for cytokine‐induced regulation of tight junction barriers. J Cell Sci 123: 2844‐2852, 2010.
 274.Van Itallie CM, Holmes J, Bridges A, Gookin JL, Coccaro MR, Proctor W, Colegio OR, Anderson JM. The density of small tight junction pores varies among cell types and is increased by expression of claudin‐2. J Cell Sci 121: 298‐305, 2008.
 275.Van Itallie CM, Rogan S, Yu A, Vidal LS, Holmes J, Anderson JM. Two splice variants of claudin‐10 in the kidney create paracellular pores with different ion selectivities. Am J Physiol Renal Physiol 291: F1288‐F1299, 2006.
 276.Van Itallie CM, Tietgens AJ, Anderson JM. Visualizing the dynamic coupling of claudin strands to the actin cytoskeleton through ZO‐1. Mol Biol Cell 28: 524‐534, 2016.
 277.Vayro S, Wood IS, Dyer J, Shirazi‐Beechey SP. Transcriptional regulation of the ovine intestinal Na+/glucose cotransporter SGLT1 gene. Role of HNF‐1 in glucose activation of promoter function. Eur J Biochem 268: 5460‐5470, 2001.
 278.Veigel C, Coluccio LM, Jontes JD, Sparrow JC, Milligan RA, Molloy JE. The motor protein myosin‐I produces its working stroke in two steps. Nature 398: 530‐533, 1999.
 279.Verkman AS. Physiological importance of aquaporin water channels. Ann Med 34: 192‐200, 2002.
 280.Wada M, Tamura A, Takahashi N, Tsukita S. Loss of claudins 2 and 15 from mice causes defects in paracellular Na+ flow and nutrient transport in gut and leads to death from malnutrition. Gastroenterol 144: 369‐380, 2013.
 281.Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR. Interferon‐gamma and tumor necrosis factor‐alpha synergize to induce intestinal epithelial barrier dysfunction by up‐regulating myosin light chain kinase expression. Am J Pathol 166: 409‐419, 2005.
 282.Wang Q, Chen XW, Margolis B. PALS1 regulates E‐cadherin trafficking in mammalian epithelial cells. Mol Biol Cell 18: 874‐885, 2007.
 283.Watts JL, Morton DG, Bestman J, Kemphues KJ. The C. elegans par‐4 gene encodes a putative serine‐threonine kinase required for establishing embryonic asymmetry. Development 127: 1467‐1475, 2000.
 284.Weber CR, Liang GH, Wang Y, Das S, Shen L, Yu AS, Nelson DJ, Turner JR. Claudin‐2‐dependent paracellular channels are dynamically gated. eLife 4: e09906, 2015.
 285.Weber CR, Raleigh DR, Su L, Shen L, Sullivan EA, Wang Y, Turner JR. Epithelial myosin light chain kinase activation induces mucosal interleukin‐13 expression to alter tight junction ion selectivity. J Biol Chem 285: 12037‐12046, 2010.
 286.Wehkamp J, Salzman NH, Porter E, Nuding S, Weichenthal M, Petras RE, Shen B, Schaeffeler E, Schwab M, Linzmeier R, Feathers RW, Chu H, Lima H, Jr., Fellermann K, Ganz T, Stange EF, Bevins CL. Reduced Paneth cell alpha‐defensins in ileal Crohn's disease. Proc Natl Acad Sci U S A 102: 18129‐18134, 2005.
 287.Weis GV, Knowles BC, Choi E, Goldstein AE, Williams JA, Manning EH, Roland JT, Lapierre LA, Goldenring JR. Loss of MYO5B in mice recapitulates Microvillus Inclusion Disease and reveals an apical trafficking pathway distinct to neonatal duodenum. Cell Mol Gastroenterol Hepatol 2: 131‐157, 2016.
 288.Whiteman EL, Fan S, Harder JL, Walton KD, Liu CJ, Soofi A, Fogg VC, Hershenson MB, Dressler GR, Deutsch GH, Gumucio DL, Margolis B. Crumbs3 is essential for proper epithelial development and viability. Mol Cell Biol 34: 43‐56, 2014.
 289.Whitsett JA, Weaver TE. Alveolar development and disease. Am J Respir Cell Mol Biol 53: 1‐7, 2015.
 290.Wilson‐O'Brien AL, Patron N, Rogers S. Evolutionary ancestry and novel functions of the mammalian glucose transporter (GLUT) family. BMC Evol Biol 10: 152, 2010.
 291.Witcher LL, Collins R, Puttagunta S, Mechanic SE, Munson M, Gumbiner B, Cowin P. Desmosomal cadherin binding domains of plakoglobin. J Biol Chem 271: 10904‐10909, 1996.
 292.Wong VW, Stange DE, Page ME, Buczacki S, Wabik A, Itami S, van de Wetering M, Poulsom R, Wright NA, Trotter MW, Watt FM, Winton DJ, Clevers H, Jensen KB. Lrig1 controls intestinal stem‐cell homeostasis by negative regulation of ErbB signalling. Nat Cell Biol 14: 401‐408, 2012.
 293.Wyatt J, Vogelsang H, Hubl W, Waldhoer T, Lochs H. Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet 341: 1437‐1439, 1993.
 294.Yamada S, Pokutta S, Drees F, Weis WI, Nelson WJ. Deconstructing the cadherin‐catenin‐actin complex. Cell 123: 889‐901, 2005.
 295.Yamanaka T, Ohno S. Role of Lgl/Dlg/Scribble in the regulation of epithelial junction, polarity and growth. Front Biosci 13: 6693‐6707, 2008.
 296.Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ. The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 109: 466‐471, 2012.
 297.Yonemura S, Wada Y, Watanabe T, Nagafuchi A, Shibata M. alpha‐Catenin as a tension transducer that induces adherens junction development. Nat Cell Biol 12: 533‐542, 2010.
 298.Yu AS, Cheng MH, Angelow S, Gunzel D, Kanzawa SA, Schneeberger EE, Fromm M, Coalson RD. Molecular basis for cation selectivity in claudin‐2‐based paracellular pores: Identification of an electrostatic interaction site. J Gen Physiol 133: 111‐127, 2009.
 299.Yu D, Marchiando AM, Weber CR, Raleigh DR, Wang Y, Shen L, Turner JR. MLCK‐dependent exchange and actin binding region‐dependent anchoring of ZO‐1 regulate tight junction barrier function. Proc Natl Acad Sci U S A 107: 8237‐8241, 2010.
 300.Yu W, Shewan AM, Brakeman P, Eastburn DJ, Datta A, Bryant DM, Fan QW, Weiss WA, Zegers MM, Mostov KE. Involvement of RhoA, ROCK I and myosin II in inverted orientation of epithelial polarity. EMBO Rep 9: 923‐929, 2008.
 301.Zhang X, Gao N. Intestinal GPCRs control paneth cell maturation and susceptibility to experimental colitis. Cell Mol Gastroenterol Hepatol 2: 712‐713, 2016.
 302.Zhao H, Shiue H, Palkon S, Wang Y, Cullinan P, Burkhardt JK, Musch MW, Chang EB, Turner JR. Ezrin regulates NHE3 translocation and activation after Na+‐glucose cotransport. Proc Natl Acad Sci U S A 101: 9485‐9490, 2004.
 303.Zhu C, Chen Z, Jiang Z. Expression, distribution and role of aquaporin water channels in human and animal stomach and intestines. Int J Mol Sci 17: 1399, 2016.
 304.Zhu JX, Xue H, Ji T, Xing Y. Cellular localization of NKCC2 and its possible role in the Cl‐ absorption in the rat and human distal colonic epithelia. Transl Res 158: 146‐154, 2011.
 305.Zolotarevsky Y, Hecht G, Koutsouris A, Gonzalez DE, Quan C, Tom J, Mrsny RJ, Turner JR. A membrane‐permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterol 123: 163‐172, 2002.

Related Articles:

Enterocyte Cytoskeleton: Its Structure and Function
Claudins and Other Tight Junction Proteins

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Nitesh Shashikanth, Sunil Yeruva, Ma. Lora Drizella M. Ong, Matthew A. Odenwald, Roman Pavlyuk, Jerrold R. Turner. Epithelial Organization: The Gut and Beyond. Compr Physiol 2017, 7: 1497-1518. doi: 10.1002/cphy.c170003