Search tips
Search criteria 


Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. 1997 March 15; 99(6): 1158–1164.
PMCID: PMC507928

Modulation of intestinal tight junctions by Zonula occludens toxin permits enteral administration of insulin and other macromolecules in an animal model.


The intestinal epithelium represents the major barrier to absorption of orally administered drugs and peptides into the systemic circulation. Entry of molecules through the paracellular pathway is restricted by tight junctions. We have previously reported that these structures can be modulated by Zonula occludens toxin (Zot). In the present report, we show that Zot reversibly increases rabbit intestinal permeability to insulin by 72% (P = 0.034) and immunoglobulins by 52% (P = 0.04) in vitro. When tested in vivo, Zot induced a 10-fold increase of insulin absorption in both the rabbit jejunum and ileum, whereas no substantial changes were detected in the colon. Similar results were obtained with immunoglobulins, whereby Zot induced twofold and sixfold increases of IgG absorption in the jejunum and ileum, respectively. In diabetic rats, bioavailability of oral insulin coadministered with Zot was sufficient to lower serum glucose concentrations to levels comparable to those obtained after parenteral injection of the hormone. The survival time of diabetic animals chronically treated with oral insulin + Zot was comparable to that observed in parenterally treated rats. These studies offer an innovative strategy for the oral delivery of drugs and proteins normally not absorbed through the intestine.

Full Text

The Full Text of this article is available as a PDF (200K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Lee VH, Yamamoto A, Kompella UB. Mucosal penetration enhancers for facilitation of peptide and protein drug absorption. Crit Rev Ther Drug Carrier Syst. 1991;8(2):91–192. [PubMed]
  • Muranishi S. Absorption enhancers. Crit Rev Ther Drug Carrier Syst. 1990;7(1):1–33. [PubMed]
  • Citi S. Protein kinase inhibitors prevent junction dissociation induced by low extracellular calcium in MDCK epithelial cells. J Cell Biol. 1992 Apr;117(1):169–178. [PMC free article] [PubMed]
  • Fasano A, Baudry B, Pumplin DW, Wasserman SS, Tall BD, Ketley JM, Kaper JB. Vibrio cholerae produces a second enterotoxin, which affects intestinal tight junctions. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5242–5246. [PubMed]
  • Baudry B, Fasano A, Ketley J, Kaper JB. Cloning of a gene (zot) encoding a new toxin produced by Vibrio cholerae. Infect Immun. 1992 Feb;60(2):428–434. [PMC free article] [PubMed]
  • Fasano A, Fiorentini C, Donelli G, Uzzau S, Kaper JB, Margaretten K, Ding X, Guandalini S, Comstock L, Goldblum SE. Zonula occludens toxin modulates tight junctions through protein kinase C-dependent actin reorganization, in vitro. J Clin Invest. 1995 Aug;96(2):710–720. [PMC free article] [PubMed]
  • Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. [PubMed]
  • Fasano A, Noriega FR, Maneval DR, Jr, Chanasongcram S, Russell R, Guandalini S, Levine MM. Shigella enterotoxin 1: an enterotoxin of Shigella flexneri 2a active in rabbit small intestine in vivo and in vitro. J Clin Invest. 1995 Jun;95(6):2853–2861. [PMC free article] [PubMed]
  • Guandalini S, Fasano A, Albini F, Marchesano G, Nocerino A, De Curtis M, Rubaltelli FF, Pettenazzo A, Rubino A. Unconjugated bilirubin and the bile from light exposed Gunn rats inhibit intestinal water and electrolyte absorption. Gut. 1988 Mar;29(3):366–371. [PMC free article] [PubMed]
  • Harms PG, Ojeda SR. A rapid and simple procedure for chronic cannulation of the rat jugular vein. J Appl Physiol. 1974 Mar;36(3):391–392. [PubMed]
  • Bellgrau D, Lagarde AC. Cytotoxic T-cell precursors with low-level CD8 in the diabetes-prone Biobreeding rat: implications for generation of an autoimmune T-cell repertoire. Proc Natl Acad Sci U S A. 1990 Jan;87(1):313–317. [PubMed]
  • Haber BA, Chin S, Chuang E, Buikhuisen W, Naji A, Taub R. High levels of glucose-6-phosphatase gene and protein expression reflect an adaptive response in proliferating liver and diabetes. J Clin Invest. 1995 Feb;95(2):832–841. [PMC free article] [PubMed]
  • Langer R. New methods of drug delivery. Science. 1990 Sep 28;249(4976):1527–1533. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation