Functional Morphology of the Intestinal Mucosae: From Crypts to Tips

Jerrold R. Turner

doi:10.1128/9781555817848.ch1

Chapter 1 : Functional Morphology of the Intestinal Mucosae: From Crypts to Tips

Author: Jerrold R. Turner

Content Type: Monograph

Publication Year: 2003

Category: Clinical Microbiology

Book DOI: 10.1128/9781555817848

Chapter DOI: 10.1128/9781555817848.ch1

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Preview this chapter:

Functional Morphology of the Intestinal Mucosae: From Crypts to Tips, Page 1 of 2

< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817848/9781555812614_Chap01-1.gif /docserver/preview/fulltext/10.1128/9781555817848/9781555812614_Chap01-2.gif

Abstract:

This chapter focuses on structure and function of the intestinal mucosa and its relevance to absorption, secretion, and microbial pathogenesis. In the small intestine, the crypt is populated by stem cells, goblet cells, undifferentiated secretory cells, enteroendocrine cells, Paneth cells, and occasional rarer cell types, such as tuft cells. The carbohydrate binding sites present on mucins may serve as decoys that compete with epithelial binding sites for attachment of pathogenic bacteria. Enteroendocrine cells are found throughout the intestinal mucosa, interspersed among other epithelial cell types, and arise from the same stem cells as enterocytes, goblet cells, and Paneth cells. In severe cases, features of chronic colitis, including branched crypts, may occasionally be present and are evidence of cyclical mucosal injury and regeneration. When it was first discovered that some epithelia had permeabilities far greater than those explained by the serial conductances of the apical and basolateral membranes, epithelia were classified as leaky (e.g., proximal tubule, gallbladder, small intestine, and colon) or tight (e.g., skin, urinary bladder). To evaluate the potential of myosin oligopeptide as a therapeutic agent, it was applied to cultured cell monolayers after infection with enteropathogenic E. coli but before transepithelial electrical resistance fell. Further study of this oligopeptide may lead to the development of a novel class of therapeutic agents that restore intestinal barrier function following noncytolytic epithelial injury.

Citation: Turner J. 2003. Functional Morphology of the Intestinal Mucosae: From Crypts to Tips, p 1-22. In Hecht G (ed), Microbial Pathogenesis and the Intestinal Epithelial Cell. ASM Press, Washington, DC. doi: 10.1128/9781555817848.ch1

Key Concept Ranking

Human immunodeficiency virus 1: 0.46457934
Light Chain: 0.42831743

0.46457934

Highlighted Text: Show | Hide

Full text loading...

Figures

Functional Morphology of the Intestinal Mucosae: From Crypts to Tips

[com.pub2web.rdf.cci.facet.ContentItem[id=http://asm.metastore.ingenta.com/content/author/10.1128/9781555817848.chap1-1,webId=/content/author/10.1128/9781555817848.chap1-1,properties={foaf_givenname=Jerrold R., foaf_name=Jerrold R. Turner, foaf_surname=Turner}]]

/content/10.1128/9781555817848.chap1.fig1-1

FIGURE 1

Human duodenum. The mucosa (M) and submucosa (SM) are drawn into a prominent ridge, or plica circularis, at the right side of the photomicrograph. The mucosa, composed of epithelium, lamina propria, and muscularis mucosa, is organized into crypts and villi. The submucosa contains numerous Brunner's glands (B), found only in the duodenum. A prominent lymphoid aggregate (L) can also be seen. The epithelium overlying this area lacks villi and assumes a dome-shaped configuration. M cells are found at this site. The inner circular layer of the muscularis propria (MP) can be seen at the bottom of the field. Together with the outer longitudinal layer, these layers of smooth muscle effect peristalsis.

10.1128/9781555817848/fig1-1_thmb.gif

10.1128/9781555817848/fig1-1.gif

FIGURE 1

/content/10.1128/9781555817848.chap1.fig1-2

FIGURE 2

Human duodenal villus tip. The lamina propria of the villus core contains a prominent vascular supply (black arrows). Absorptive enterocytes cover the villus tip. At the apical (luminal) edge, the microvillus brush border (see Fig. 4 ) can be appreciated as a faint fuzzy area. Just beneath the brush border, the terminal bar (white arrow) can be seen as an area of increased density. This structure is composed of the terminal web and apical junctional complex. The epithelial cells rest on a thin layer of collagen, the basement membrane (black arrowhead).

10.1128/9781555817848/fig1-2_thmb.gif

10.1128/9781555817848/fig1-2.gif

FIGURE 2

/content/10.1128/9781555817848.chap1.fig1-3

FIGURE 3

Human duodenum. The small intestinal mucosa is organized into villi (V) and crypts (C). Epithelial cell proliferation occurs within the crypt. The crypt is also functionally specialized for water and ion secretion. As enterocytes migrate to the villus, they mature and become specialized for ion and nutrient absorption.

10.1128/9781555817848/fig1-3_thmb.gif

10.1128/9781555817848/fig1-3.gif

FIGURE 3

/content/10.1128/9781555817848.chap1.fig1-4

FIGURE 4

Human duodenal villus. Digestive enzyme expression increases during enterocyte migration to the villus. This micrograph shows brush border alkaline phosphatase expression (white band indicated by arrow). Expression increases progressively from crypt (C) to villus (V).

10.1128/9781555817848/fig1-4_thmb.gif

10.1128/9781555817848/fig1-4.gif

FIGURE 4

/content/10.1128/9781555817848.chap1.fig1-5

FIGURE 5

Human small intestinal epithelium. This intermediate-magnification electron micrograph of the apical region of absorptive enterocytes emphasizes the dense, well-developed microvillus brush border and overlying mucous gel. Microfilament rootlets can be seen protruding into the apical cytoplasm (arrow), where they become embedded within the terminal web (bracket).

10.1128/9781555817848/fig1-5_thmb.gif

10.1128/9781555817848/fig1-5.gif

FIGURE 5

/content/10.1128/9781555817848.chap1.fig1-6

FIGURE 6

Goblet cell. This low-magnification electron micrograph shows abundant mucin granules (G) within the apical cytoplasm of the goblet cell. These granules are ready for discharge into the lumen (L). The nucleus (N) is located basally.

10.1128/9781555817848/fig1-6_thmb.gif

10.1128/9781555817848/fig1-6.gif

FIGURE 6

/content/10.1128/9781555817848.chap1.fig1-7

FIGURE 7

Human small intestinal crypt. The most basal portions of the small intestinal crypt are populated by Paneth cells (P). These cells contain an abundance of large apically located granules. In contrast, enteroendocrine cell (E) granules are small and basally oriented. The stem cell zone (S) is located several cell diameters above the crypt base. Goblet cells (G) are also abundant in the crypt.

10.1128/9781555817848/fig1-7_thmb.gif

10.1128/9781555817848/fig1-7.gif

FIGURE 7

/content/10.1128/9781555817848.chap1.fig1-8

FIGURE 8

Crypt abscess in human colon. The crypt epithelium (E) is damaged and, at the lower right, penetrated (arrow) by a migrating mass of neutrophils (PMN) that fill the crypt lumen.

10.1128/9781555817848/fig1-8_thmb.gif

10.1128/9781555817848/fig1-8.gif

FIGURE 8

Crypt abscess in human colon. The crypt epithelium (E) is damaged and, at the lower right, penetrated (arrow) by a migrating mass of neutrophils (PMN) that fill the crypt lumen.

/content/10.1128/9781555817848.chap1.fig1-9

FIGURE 9

C. difficile-associated pseudomembranous colitis. The colonic crypt (arrow) is lined by flattened, severely damaged epithelium. The crypt lumen contains purulent debris primarily composed of neutrophils and mucus. This seems to explode from the crypt, forming a volcano-shaped eruption that, at the surface, becomes confluent with exudate from other damaged crypts. Dense sheets of purulent debris, pseudomembranes (PM), cover the mucosal surface.

10.1128/9781555817848/fig1-9_thmb.gif

10.1128/9781555817848/fig1-9.gif

FIGURE 9

/content/10.1128/9781555817848.chap1.fig1-10

FIGURE 10

(A) Immunofluorescence microscopy of human small intestinal mucosa demonstrates tight junctions to be dot-like areas at the apical portion of each cell-cell junction site (arrows), as shown by immunostaining for occludin. (B) Electron microscopy of the apical junctional complex of a small intestinal enterocyte shows an area of tight membrane apposition, the tight junction (solid arrow) at the most apical region of the lateral membrane. The adherens junction (dashed arrow) is located subapical to the tight junction.

10.1128/9781555817848/fig1-10_thmb.gif

10.1128/9781555817848/fig1-10.gif

FIGURE 10

/content/10.1128/9781555817848.chap1.fig1-11

FIGURE 11

Human jejunal mucosae were double-labeled with antiphosphorylated myosin regulatory light chain antisera (A) and antitotal myosin regulatory light chain antisera (B). Focal enrichment of phosphorylated myosin regulatory light chain is obvious at cell-cell junctions (arrows), although total myosin regulatory light chain content is not increased in these areas (B).

10.1128/9781555817848/fig1-11_thmb.gif

10.1128/9781555817848/fig1-11.gif

FIGURE 11

/content/10.1128/9781555817848.chap1.fig1-12

FIGURE 12

In monolayer culture, the Caco-2 human intestinal epithelial cell line has many of the morphological characteristics common to villus enterocytes, including a well-developed microvillus brush border, terminal web (arrow), and mature apical junction complexes (bracket).

10.1128/9781555817848/fig1-12_thmb.gif

10.1128/9781555817848/fig1-12.gif

FIGURE 12

References

/content/book/10.1128/9781555817848.chap1

1. Atisook, K.,, S. Carlson,, and J. L. Madara. 1990. Effects of phlorizin and sodium on glucose-elicited alterations of cell junctions in intestinal epithelia. Am. J. Physiol. 258: C77– C85.

2. Atisook, K.,, and J. L. Madara. 1991. An oligopeptide permeates intestinal tight junctions at glucose-elicited dilatations. Implications for oligopeptide absorption. Gastroenterology 100: 719– 724.

3. Barrett, K. E.,, and S. J. Keely. 2000. Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu. Rev. Physiol. 62: 535– 572.

4. Berglund, J. J.,, M. Riegler,, Y. Zolotarevsky,, E. Wenzl,, and J. R. Turner. 2001. Regulation of human jejunal transmucosal resistance and MLC phosphorylation by Na +-glucose cotransport. Am. J. Physiol. Gastrointest. Liver Physiol. 281: G1487– G1493.

5. Bjerknes, M.,, and H. Cheng. 2001. Modulation of specific intestinal epithelial progenitors by enteric neurons. Proc. Natl. Acad. Sci. USA 98: 12497– 12502.

6. Booth, C.,, and C. S. Potten. 2000. Gut instincts: thoughts on intestinal epithelial stem cells. J. Clin. Invest. 105: 1493– 1499.

7. Brandtzaeg, P. 1978. Polymeric IgA is complexed with secretory component (SC) on the surface of human intestinal epithelial cells. Scand. J. Immunol. 8: 39– 52.

8. Buchan, A. M.,, J. M. Polak,, E. Solcia,, and A. G. Pearse. 1979. Localisation of intestinal gastrin in a distinct endocrine cell type. Nature 277: 138– 140.

9. Burgess, D. R. 1982. Reactivation of intestinal epithelial cell brush border motility: ATP-dependent contraction via a terminal web contractile ring. J. Cell Biol. 95: 853– 863.

10. Casanova, J. E.,, P. P. Breitfeld,, S. A. Ross,, and K. E. Mostov. 1990. Phosphorylation of the polymeric immunoglobulin receptor required for its efficient transcytosis. Science 248: 742– 745.

11. Chen, Y.,, C. Merzdorf,, D. L. Paul,, and D. A. Goodenough. 1997. COOH terminus of occludin is required for tight junction barrier function in early Xenopus embryos. J. Cell Biol. 138: 891– 899.

12. Cheng, H.,, J. Merzel,, and C. P. Leblond. 1969. Renewal of Paneth cells in the small intestine of the mouse. Am. J. Anat. 126: 507– 525.

13. Chung, B. M.,, J. K. Wong,, J. A. Hardin,, and D. G. Gall. 1999. Role of actin in EGF-induced alterations in enterocyte SGLT1 expression. Am. J. Physiol. 276: G463– G469.

14. Dickman, K. G.,, S. J. Hempson,, J. Anderson,, S. Lippe,, L. Zhao,, R. Burakoff,, and R. D. Shaw. 2000 . Rotavirus alters paracellular permeability and energy metabolism in Caco-2 cells. Am. J. Physiol. Gastrointest. Liver Physiol. 279: G757– 766.

15. Drumm, B.,, A. M. Roberton,, and P. M. Sherman. 1988. Inhibition of attachment of Escherichia coli RDEC-1 to intestinal microvillus membranes by rabbit ileal mucus and mucin in vitro. Infect. Immun. 56: 2437– 2442.

16. Dura, W. T.,, and E. Bernatowska. 1984. Secretory component, alpha 1-antitrypsin and lysozyme in IgA deficient children. An immunohistochemical evaluation of intestinal mucosa. Histopathology 8: 747– 757.

17. Elmes, M. E.,, M. R. Stanton,, C. H. Howells,, and G. H. Lowe. 1984. Relation between the mucosal flora and Paneth cell population of human jejunum and ileum. J. Clin. Pathol. 37: 1268– 1271.

18. Farquhar, M.,, and G. Palade. 1963. Junctional complexes in various epithelia. J. Cell Biol. 17: 375– 412.

19. Fasano, A.,, C. Fiorentini,, G. Donelli,, S. Uzzau,, J. B. Kaper,, K. Margaretten,, X. Ding,, S. Guandalini,, L. Comstock,, and S. E. Goldblum. 1995. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J. Clin. Invest. 96: 710– 720.

20. Fihn, B. M.,, A. Sjoqvist,, and M. Jodal. 2000. Permeability of the rat small intestinal epithelium along the villus-crypt axis: effects of glucose transport. Gastroenterology 119: 1029– 1036.

21. Fine, K. D.,, C. A. Santa Ana,, J. L. Porter,, and J. S. Fordtran. 1994. Mechanism by which glucose stimulates the passive absorption of small solutes by the human jejunum in vivo. Gastroenterology 107: 389– 395.

22. Fujita, K.,, J. Katahira,, Y. Horiguchi,, N. Sonoda,, M. Furuse,, and S. Tsukita. 2000. Clostridium perfringens enterotoxin binds to the second extracellular loop of claudin-3, a tight junction integral membrane protein. FEBS Lett. 476: 258– 261.

23. Furuse, M.,, K. Fujimoto,, N. Sato,, T. Hirase,, and S. Tsukita. 1996. Overexpression of occludin, a tight junction-associated integral membrane protein, induces the formation of intracellular multilamellar bodies bearing tight junction-like structures. J. Cell Sci. 109: 429– 435.

24. Furuse, M.,, K. Furuse,, H. Sasaki,, and S. Tsukita. 2001. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J. Cell Biol. 153: 263– 272.

25. Furuse, M.,, T. Hirase,, M. Itoh,, A. Nagafuchi,, S. Yonemura,, S. Tsukita,, and S. Tsukita. 1993. Occludin: a novel integral membrane protein localizing at tight junctions. J. Cell Biol. 123: 1777– 1788.

26. Furuse, M.,, H. Sasaki,, K. Fujimoto,, and S. Tsukita. 1998. A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J. Cell Biol. 143: 391– 401.

27. Gallardo, P.,, L. P. Cid,, C. P. Vio,, and F. V. Sepulveda. 2001. Aquaporin-2, a regulated water channel, is expressed in apical membranes of rat distal colon epithelium. Am. J. Physiol. Gastrointest. Liver Physiol. 281: G856– G863.

28. Gerhard, R.,, G. Schmidt,, F. Hofmann,, and K. Aktories. 1998. Activation of Rho GTPases by Escherichia coli cytotoxic necrotizing factor 1 increases intestinal permeability in Caco-2 cells. Infect. Immun. 66: 5125– 5131.

29. Gledhill, A.,, P. A. Hall,, J. P. Cruse,, and D. J. Pollock. 1986. Enteroendocrine cell hyperplasia, carcinoid tumours and adenocarcinoma in long-standing ulcerative colitis. Histopathology 10: 501– 508.

30. Gorbach, S. L.,, A. G. Plaut,, L. Nahas,, L. Weinstein,, G. Spanknebel,, and R. Levitan. 1967. Studies of intestinal microflora. II. Microorganisms of the small intestine and their relations to oral and fecal flora. Gastroenterology 53: 856– 867.

31. Hallback, D. A.,, M. Jodal,, M. Mannischeff,, and O. Lundgren. 1991. Tissue osmolality in intestinal villi of four mammals in vivo and in vitro. Acta Physiol. Scand. 143: 271– 277.

32. Hardin, J. A.,, A. Buret,, J. B. Meddings,, and D. G. Gall. 1993. Effect of epidermal growth factor on enterocyte brush-border surface area. Am. J. Physiol. 264: G312– G318.

33. Hatakeyama, S.,, Y. Yoshida,, T. Tani,, Y. Koyama,, K. Nihei,, K. Ohshiro,, J. I. Kamiie,, E. Yaoita,, T. Suda,, K. Hatakeyama,, and T. Yamamoto. 2001. Cloning of a new aquaporin (AQP10) abundantly expressed in duodenum and jejunum. Biochem. Biophys. Res. Commun. 287: 814– 819.

34. Hecht, G.,, A. Koutsouris,, C. Pothoulakis,, J. T. LaMont,, and J. L. Madara. 1992. Clostridium difficile toxin B disrupts the barrier function of T84 monolayers. Gastroenterology 102: 416– 423.

35. Hecht, G.,, L. Pestic,, G. Nikcevic,, A. Koutsouris,, J. Tripuraneni,, D. D. Lorimer,, G. Nowak, , V. Guerriero, Jr.,, E. L. Elson, , and P. D. Lanerolle. 1996. Expression of the catalytic domain of myosin light chain kinase increases paracellular permeability. Am. J. Physiol. 271: C1678– C1684.

36. Hecht, G.,, C. Pothoulakis,, J. T. LaMont,, and J. L. Madara. 1988. Clostridium difficile toxin A perturbs cytoskeletal structure and tight junction permeability of cultured human intestinal epithelial monolayers. J. Clin. Invest. 82: 1516– 1524.

37. Hermiston, M. L.,, and J. I. Gordon. 1995. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science 270: 1203– 1207.

38. Hermiston, M. L.,, R. P. Green,, and J. I. Gordon. 1993. Chimeric-transgenic mice represent a powerful tool for studying how the proliferation and differentiation programs of intestinal epithelial cell lineages are regulated. Proc. Natl. Acad. Sci. USA 90: 8866– 8870.

39. Hermiston, M. L.,, M. H. Wong,, and J. I. Gordon. 1996. Forced expression of E-cadherin in the mouse intestinal epithelium slows cell migration and provides evidence for nonautonomous regulation of cell fate in a self-renewing system. Genes Dev. 10: 985– 996.

40. Hirokawa, N.,, T. C. Keller 3rd,, R. Chasan,, and M. S. Mooseker. 1983. Mechanism of brush border contractility studied by the quick-freeze, deep-etch method. J. Cell Biol. 96: 1325– 1336.

41. Hwang, E. S.,, B. A. Hirayama,, and E. M. Wright. 1991. 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.

42. Ikebe, M.,, M. Stepinska,, B. E. Kemp,, A. R. Means,, and D. J. Hartshorne. 1987. Proteolysis of smooth muscle myosin light chain kinase. Formation of inactive and calmodulin-independent fragments. J. Biol. Chem. 262: 13828– 13834.

43. Ikeda, T. S.,, E.-S. Hwang,, M. J. Coady,, B. A. Hirayama,, M. A. Hediger,, and E. M. Wright. 1989. Characterization of a Na +/glucose cotransporter cloned from rabbit small intestine. J. Membr. Biol. 110: 87– 95.

44. Ito, M., , V. Guerriero, Jr.,, X. M. Chen, , and D. J. Hartshorne. 1991. Definition of the inhibitory domain of smooth muscle myosin light chain kinase by site-directed mutagenesis. Biochemistry 30: 3498– 3503.

45. Itoh, H.,, P. L. Beck,, N. Inoue,, R. Xavier,, and D. K. Podolsky. 1999. A paradoxical reduction in susceptibility to colonic injury upon targeted transgenic ablation of goblet cells. J. Clin. Invest. 104: 1539– 1547.

46. Johansen, K.,, G. Stintzing,, K. E. Magnusson,, T. Sundqvist,, F. Jalil,, A. Murtaza,, S. R. Khan,, B. S. Lindblad,, R. Mollby,, E. Orusild, et al. 1989. Intestinal permeability assessed with polyethylene glycols in children with diarrhea due to rotavirus and common bacterial pathogens in a developing community. J. Pediatr. Gastroenterol. Nutr. 9: 307– 313.

47. Just, I.,, J. Selzer,, M. Wilm,, C. von Eichel-Streiber,, M. Mann,, and K. Aktories. 1995. Glucosylation of Rho proteins by Clostridium difficile toxin B. Nature 375: 500– 503.

48. Karlsson, J.,, A. Ungell,, J. Grasjo,, and P. Artursson. 1999. Paracellular drug transport across intestinal epithelia: influence of charge and induced water flux. Eur. J. Pharm. Sci. 9: 47– 56.

49. Kerneis, S.,, A. Bogdanova,, J. P. Kraehenbuhl,, and E. Pringault. 1997. Conversion by Peyer’s patch lymphocytes of human enterocytes into M cells that transport bacteria. Science 277: 949– 952.

50. Kindon, H.,, C. Pothoulakis,, L. Thim,, K Lynch-Devaney, , and D. K. Podolsky. 1995. Trefoil peptide protection of intestinal epithelial barrier function: cooperative interaction with mucin glycoprotein. Gastroenterology 109: 516– 523.

51. Koyama, Y.,, T. Yamamoto,, T. Tani,, K. Nihei,, D. Kondo,, H. Funaki,, E. Yaoita,, K. Kawasaki,, N. Sato,, K. Hatakeyama,, and I. Kihara. 1999. Expression and localization of aquaporins in rat gastrointestinal tract. Am. J. Physiol. 276: C621– C627.

52. Lane, J. S.,, E. E. Whang,, D. A. Rigberg,, O. J. Hines,, D. Kwan,, M. J. Zinner,, D. W. McFadden,, J. Diamond,, and S. W. Ashley. 1999. Paracellular glucose transport plays a minor role in the unanesthetized dog. Am. J. Physiol. 276: G789– G794.

53. Leitch, G. J. 1988. Cholera enterotoxin-induced mucus secretion and increase in the mucus blanket of the rabbit ileum in vivo. Infect. Immun. 56: 2871– 2875.

54. Lelouard, H.,, A. Sahuquet,, H. Reggio,, and P. Montcourrier. 2001. Rabbit M cells and dome enterocytes are distinct cell lineages. J. Cell Sci. 114: 2077– 2083.

55. Li, D.,, and R. J. Mrsny. 2000. Oncogenic Raf-1 disrupts epithelial tight junctions via down-regulation of occludin. J. Cell Biol. 148: 791– 800.

56. Lu, H. H.,, J. D. Thomas,, J. J. Tukker,, and D. Fleisher. 1992. Intestinal water and solute absorption studies: comparison of in situ perfusion with chronic isolated loops in rats. Pharm. Res. 9: 894– 900.

57. Lukas, T. J.,, S. Mirzoeva,, U. Slomczynska,, and D. M. Watterson. 1999. Identification of novel classes of protein kinase inhibitors using combinatorial peptide chemistry based on functional genomics knowledge. J. Med. Chem. 42: 910– 919.

58. Madara, J. L. 1987. Intestinal absorptive cell tight junctions are linked to cytoskeleton. Am. J. Physiol. 253: C171– C175.

59. Madara, J. L. 1990. Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J. Membr. Biol. 116: 177– 184.

60. Madara, J. L. 1994. Sodium-glucose cotransport and epithelial permeability. Gastroenterology 107: 319– 320.

61. Madara, J. L.,, and J. R. Pappenheimer. 1987. Structural basis for physiological regulation of paracellular pathways in intestinal epithelia. J. Membr. Biol. 100: 149– 164.

62. Madara, J. L.,, J. Stafford,, D. Barenberg,, and S. Carlson. 1988. F unctional coupling of tight junctions and microfilaments in T84 monolayers. Am. J. Physiol. 254: G416– G423.

63. Marcial, M. A.,, S. L. Carlson,, and J. L. Madara. 1984. Partitioning of paracellular conductance along the ileal crypt-villus axis: a hypothesis based on structural analysis with detailed consideration of tight junction structure-function relationships. J. Membr. Biol. 80: 59– 70.

64. McCormick, D. A.,, L. W. Horton,, and A. S. Mee. 1990. Mucin depletion in inflammatory bowel disease. J. Clin. Pathol. 43: 143– 146.

65. Meddings, J. B.,, and H. Westergaard. 1989. Intestinal glucose transport using perfused rat jejunum in vivo: model analysis and derivation of corrected kinetic constants. Clin. Sci. (London) 76: 403– 413.

66. Meinild, A.,, D. A. Klaerke,, D. D. Loo,, E. M. Wright,, and T. Zeuthen. 1998. The human Na +-glucose cotransporter is a molecular water pump. J. Physiol. (London) 508: 15– 21.

67. Merzel, J.,, and C. P. Leblond. 1969. Origin and renewal of goblet cells in the epithelium of the mouse small intestine. Am. J. Anat. 124: 281– 305.

68. Moon, H. W.,, S. C. Whipp,, and A. L. Baetz. 1971. Comparative effects of enterotoxins from Escherichia coli and Vibrio cholerae on rabbit and swine small intestine. Lab. Invest. 25: 133– 140.

69. Morson, B. C.,, L. H. Sobin,, E. Grundmann,, A. Johansen,, T. Nagayo,, and A. Serck-Hanssen. 1980. Precancerous conditions and epithelial dysplasia in the stomach. J. Clin. Pathol. 33: 711– 721.

70. Mostov, K. E. 1994. Transepithelial transport of immunoglobulins. Annu. Rev. Immunol. 12: 63– 84.

71. Mouricout, M. A.,, and R. A. Julien. 1987. Pilus-mediated binding of bovine enterotoxigenic Escherichia coli to calf small intestinal mucins. Infect. Immun. 55: 1216– 1223.

72. Muresan, Z.,, D. L. Paul,, and D. A. Goodenough. 2000. Occludin 1B, a variant of the tight junction protein occludin. Mol. Biol. Cell 11: 627– 634.

73. Neutra, M. R.,, N. J. Mantis,, and J. P. Kraehenbuhl. 2001. Collaboration of epithelial cells with organized mucosal lymphoid tissues. Nat. Immunol. 2: 1004– 1009.

74. Nieminen, U.,, A. Kahri,, E. Savilahti,, and M. A. Farkkila. 2001. Duodenal disaccharidase activities in the follow-up of villous atrophy in coeliac disease. Scand. J. Gastroenterol. 36: 507– 510.

75. Nusrat, A.,, J. A. Chen,, C. S. Foley,, T. W. Liang,, J. Tom,, M. Cromwell,, C. Quan,, and R. J. Mrsny. 2000. The coiled-coil domain of occludin can act to organize structural and functional elements of the epithelial tight junction. J. Biol. Chem. 275: 29816– 29822.

76. Nusrat, A.,, M. Giry,, J. R. Turner,, S. P. Colgan,, C. A. Parkos,, D. Carnes,, E. Lemichez,, P. Boquet,, and J. L. Madara. 1995. Rho protein regulates tight junctions and perijunctional actin organization in polarized epithelia. Proc. Natl. Acad. Sci. USA 92: 10629– 10633.

77. Obert, G.,, I. Peiffer,, and A. L. Servin. 2000. Rotavirus-induced structural and functional alterations in tight junctions of polarized intestinal Caco-2 cell monolayers. J. Virol. 74: 4645– 4651.

78. Paerregaard, A.,, F. Espersen,, O. M. Jensen,, and M. Skurnik. 1991. Interactions between Yersinia enterocolitica and rabbit ileal mucus: growth, adhesion, penetration, and subsequent changes in surface hydrophobicity and ability to adhere to ileal brush border membrane vesicles. Infect. Immun. 59: 253– 260.

79. Pappenheimer, J. R. 1987. Physiological regulation of transepithelial impedance in the intestinal mucosa of rats and hamsters. J. Membr. Biol. 100: 137– 148.

80. Pappenheimer, J. R. 1993. On the coupling of membrane digestion with intestinal absorption of sugars and amino acids. Am. J. Physiol. 265: G409– G417.

81. Pearse, A. G.,, and J. M. Polak. 1975. Immunocytochemical localization of substance P in mammalian intestine. Histochemistry 41: 373– 375.

82. Philpott, D. J.,, D. M. McKay,, W. Mak,, M. H. Perdue,, and P. M. Sherman. 1998. Signal transduction pathways involved in enterohemorrhagic Escherichia coli-induced alterations in T84 epithelial permeability. Infect. Immun. 66: 1680– 1687.

83. Potten, C. S.,, and M. Loeffler. 1990. Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110: 1001– 1020.

84. Powell, D. W. 1981. Barrier function of epithelia. Am. J. Physiol. 241: G275– G288.

85. Rahner, C.,, L. L. Mitic,, and J. M. Anderson. 2001. Heterogeneity in expression and subcellular localization of claudins 2, 3, 4, and 5 in the rat liver, pancreas, and gut. Gastroenterology 120: 411– 422.

86. Rosenblatt, J.,, M. C. Raff,, and L. P. Cramer. 2001. An epithelial cell destined for apoptosis signals its neighbors to extrude it by an actin-and myosin-dependent mechanism. Curr. Biol. 11: 1847– 1857.

87. Roth, K. A.,, S. Kim,, and J. I. Gordon. 1992. Immunocytochemical studies suggest two pathways for enteroendocrine cell differentiation in the colon. Am. J. Physiol. 263: G174– 180.

88. Rubin, D. C.,, E. Swietlicki,, K. A. Roth,, and J. I. Gordon. 1992. Use of fetal intestinal isografts from normal and transgenic mice to study the programming of positional information along the duodenal-to-colonic axis. J. Biol. Chem. 267: 15122– 15133.

89. Sachdev, H. P.,, V. Chadha,, V. Malhotra,, A. Verghese,, and R. K. Puri. 1993. Rectal histopathology in endemic Shigella and Salmonella diarrhea. J. Pediatr. Gastroenterol. Nutr. 16: 33– 38.

90. Sadowski, D. C.,, and J. B. Meddings. 1993. Luminal nutrients alter tight-junction permeability in the rat jejunum: an in vivo perfusion model. Can. J. Physiol. Pharmacol. 71: 835– 839.

91. Saitou, M.,, M. Furuse,, H. Sasaki,, J. D. Schulzke,, M. Fromm,, H. Takano,, T. Noda,, and S. Tsukita. 2000. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol. Biol. Cell 11: 4131– 4142.

92. Sajjan, S. U.,, and J. F. Forstner. 1990. Characteristics of binding of Escherichia coli serotype O157:H7 strain CL-49 to purified intestinal mucin. Infect. Immun. 58: 860– 867.

93. Schaerer, E.,, M. R. Neutra,, and J. P. Kraehenbuhl. 1991. Molecular and cellular mechanisms involved in transepithelial transport. J. Membr. Biol. 123: 93– 103.

94. Schneider, D. R.,, and C. D. Parker. 1982. Purification and characterization of the mucinase of Vibrio cholerae. J. Infect. Dis. 145: 474– 482.

95. Schreiber, R.,, H. Pavenstadt,, R. Greger,, and K. Kunzelmann. 2000. Aquaporin 3 cloned from Xenopus laevis is regulated by the cystic fibrosis transmembrane conductance regulator. FEBS Lett. 475: 291– 295.

96. Schwarze, S. R.,, A. Ho,, A. Vocero-Akbani,, and S. F. Dowdy. 1999. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285: 1569– 1572.

97. Simon, D. B.,, Y. Lu,, K. A. Choate,, H. Velazquez,, E. Al-Sabban,, M. Praga,, G. Casari,, A. Bettinelli,, G. Colussi,, J. Rodriguez-Soriano,, D. McCredie,, D. Milford,, S. Sanjad,, and R. P. Lifton. 1999. Paracellin-1, a renal tight junction protein required for paracellular Mg2 + resorption. Science 285: 103– 106.

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

99. Smith, M. W.,, M. A. Peacock,, and P. S. James. 1991. Galactose increases microvillus development in mouse jejunal enterocytes. Comp. Biochem. Physiol. A 100: 489– 493.

100. Sonoda, N.,, M. Furuse,, H. Sasaki,, S. Yonemura,, J. Katahira,, Y. Horiguchi,, and S. Tsukita. 1999. Clostridium perfringens enterotoxin fragment removes specific claudins from tight junction strands. Evidence for direct involvement of claudins in tight junction barrier. J. Cell Biol. 147: 195– 204.

101. Specian, R. D.,, and M. R. Neutra. 1980. Mechanism of rapid mucus secretion in goblet cells stimulated by acetylcholine. J. Cell Biol. 85: 626– 640.

102. Spitz, J.,, R. Yuhan,, A. Koutsouris,, C. Blatt,, J. Alverdy,, and G. Hecht. 1995. Enteropathogenic Escherichia coli adherence to intestinal epithelial monolayers diminishes barrier function. Am. J. Physiol. 268: G374– G379.

103. Staehelin, L. A.,, T. M. Mukherjee,, and A. W. Williams. 1969. Freeze-etch appearance of the tight junctions in the epithelium of small and large intestine of mice. Protoplasma 67: 165– 184.

104. Stintzing, G.,, K. Johansen,, K. E. Magnusson,, L. Svensson,, and T. Sundqvist. 1986. Intestinal permeability in small children during and after rotavirus diarrhoea assessed with different-size polyethyleneglycols (PEG 400 and PEG 1000). Acta Paediatr. Scand. 75: 1005– 1009.

105. Thomson, A. B. 1984. Effect of region of intestine and unstirred layers on uptake of sugars into rabbit intestine. Q. J. Exp. Physiol. 69: 497– 505.

106. Trier, J. S. 1966. The Paneth cells: an enigma. Gastroenterology 51: 560– 562.

107. Turner, J. R. 2000. "Putting the squeeze" on the tight junction: understanding cytoskeletal regulation. Semin. Cell Dev. Biol. 11: 301– 308.

108. Turner, J. R.,, D. E. Cohen,, R. J. Mrsny,, and J. L. Madara. 2000. Noninvasive in vivo analysis of human small intestinal paracellular absorption: regulation by Na +-glucose cotransport. Dig. Dis. Sci. 45: 2122– 2126.

109. Turner, J. R., , V. Guerriero, Jr.,, E. D. Black, , and K. Haelewyn. 2000. Regulated expression of the myosin light chain kinase catalytic domain increases paracellular permeability and alters tight junction structure. Gastroenterology 118: A432.

110. Turner, J. R.,, and J. L. Madara. 1995. Physiological regulation of intestinal epithelial tight junctions as a consequence of Na +-coupled nutrient transport. Gastroenterology 109: 1391– 1396.

111. Turner, J. R.,, and R. D. Odze. 1996. Proliferative characteristics of differentiated cells in familial adenomatous polyposis-associated duodenal adenomas. Hum. Pathol. 27: 63– 69.

112. Turner, J. R.,, B. K. Rill,, S. L. Carlson,, D. Carnes,, R. Kerner,, R. J. Mrsny,, and J. L. Madara. 1997. Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation. Am. J. Physiol. 273: C1378– C1385.

113. Uhing, M. R.,, and R. E. Kimura. 1995. The effect of surgical bowel manipulation and anesthesia on intestinal glucose absorption in rats. J. Clin. Invest. 95: 2790– 2798.

114. Van Itallie, C.,, C. Rahner,, and J. M. Anderson. 2001. Regulated expression of claudin-4 decreases paracellular conductance through a selective decrease in sodium permeability. J. Clin. Invest. 107: 1319– 1327.

115. Van Itallie, C. M.,, and J. M. Anderson. 1997. Occludin confers adhesiveness when expressed in fibroblasts. J. Cell Sci. 110: 1113– 1121.

116. Vega-Salas, D. E.,, P. J. Salas,, and E. Rodriguez-Boulan. 1988. Exocytosis of vacuolar apical compartment (VAC): a cell-cell contact controlled mechanism for the establishment of the apical plasma membrane domain in epithelial cells. J. Cell Biol. 107: 1717– 1728.

117. Vimal, D. B.,, M. Khullar,, S. Gupta,, and N. K. Ganguly. 2000. Intestinal mucins: the binding sites for Salmonella typhimurium. Mol. Cell. Biochem. 204: 107– 117.

118. Wadolkowski, E. A.,, D. C. Laux,, and P. S. Cohen. 1988. Colonization of the streptomycin-treated mouse large intestine by a human fecal Escherichia coli strain: role of adhesion to mucosal receptors. Infect. Immun. 56: 1036– 1043.

119. Wadolkowski, E. A.,, D. C. Laux,, and P. S. Cohen. 1988. Colonization of the streptomycin-treated mouse large intestine by a human fecal Escherichia coli strain: role of growth in mucus. Infect. Immun. 56: 1030– 1035.

120. Wang, A. Z.,, J. C. Wang,, G. K. Ojakian,, and W. J. Nelson. 1994. Determinants of apical membrane formation and distribution in multicellular epithelial MDCK cysts. Am. J. Physiol. 267: C473– C481.

121. Wang, K. S.,, T. Ma,, F. Filiz,, A. S. Verkman,, and J. A. Bastidas. 2000. Colon water transport in transgenic mice lacking aquaporin-4 water channels. Am. J. Physiol. Gastrointest. Liver Physiol. 279: G463– G470.

122. Welsh, J. D.,, O. M. Zschiesche,, J. Anderson,, and A. Walker. 1969. Intestinal disaccharidase activity in celiac sprue (gluten-sensitive enteropathy). Arch. Intern. Med. 123: 33– 38.

123. Wong, V. 1997. Phosphorylation of occludin correlates with occludin localization and function at the tight junction. Am. J. Physiol. 273: C1859– C1867.

124. Wong, V.,, and B. M. Gumbiner. 1997. A synthetic peptide corresponding to the extracellular domain of occludin perturbs the tight junction permeability barrier. J. Cell Biol. 136: 399– 409.

125. Wu, M. S.,, C. T. Shun,, W. C. Lee,, C. J. Chen,, H. P. Wang,, W. J. Lee,, and J. T. Lin. 1998. Gastric cancer risk in relation to Helicobacter pylori infection and subtypes of intestinal metaplasia. Br. J. Cancer 78: 125– 128.

126. Wu, S.,, K. C. Lim,, J. Huang,, R. F. Saidi,, and C. L. Sears. 1998. Bacteroides fragilis enterotoxin cleaves the zonula adherens protein, E-cadherin. Proc. Natl. Acad. Sci. USA 95: 14979– 14984.

127. Xiao, Q.,, R. P. Boushey,, M. Cino,, D. J. Drucker,, and P. L. Brubaker. 2000. Circulating levels of glucagon-like peptide-2 in human subjects with inflammatory bowel disease. Am. J. Physiol. Regul. Integr. Comp. Physiol. 278: R1057– R1063.

128. Yang, Q.,, N. A. Bermingham,, M. J. Finegold,, and H. Y. Zoghbi. 2001. Requirement of Math1 for secretory cell lineage commitment in the mouse intestine. Science 294: 2155– 2158.

129. Yuhan, R.,, A. Koutsouris,, S. D. Savkovic,, and G. Hecht. 1997. Enteropathogenic Escherichia coli-induced myosin light chain phosphorylation alters intestinal epithelial permeability. Gastroenterology 113: 1873– 1882.

130. Zolotarevsky, Y.,, G. Hecht,, A. Koutsouris,, D. E. Gonzales,, C. Quan,, J. Tom,, R. J. Mrsny,, and J. R. Turner. 2002. A membrane-permeant peptide that inhibits MLC kinase restores barrier function in in vitro models of intestinal disease. Gastroenterology 123: 163– 172.