Diarrhea pp 281-298 | Cite as

Diarrhea from Enterotoxins

  • Gianluca Terrin
  • Roberto Berni Canani
Part of the Clinical Gastroenterology book series (CG)


Diarrhea determined by enterotoxins is an important public health problem worldwide. A number of microorganisms can cause diarrhea by producing and secreting enterotoxins that affect the absorptive and/or secretory processes of the enterocyte without causing considerable acute inflammation or mucosal destruction. Our knowledge of diarrheal diseases determined by enterotoxins has expanded enormously over the past decade. The chapter reviews various aspects of diarrhea induced by enterotoxins, including its management.

Key Words

Intestinal transport Vibrio cholerae CFTR CLCA DRA Congenital chloride diarrhea NHE SGLT1 Cholera toxin Aquaporin TDH ETEC Heat-stable enterotoxin NSP4 Rotavirus Tat HIV-1 Virotoxin EPEC Therapy Oral rehydration solution Zinc 





cystic fibrosis transmembrane regulator


Ca2+-activated Cl channel


cholera toxin


downregulated in adenoma (DRA)


endoplasmic reticulum


enteropathogenic E. coli


enterotoxigenic Escherichia coli




heat-labile enterotoxin


Na+/H+ exchangers


non-structural protein 4


oral rehydration solution


protein kinase A


sodium/glucose cotransporter 1


heat-stable enterotoxin


transactivator factor peptide


vasointestinal peptide


  1. 1.
    Giannella RA. Infectious enteritis and proctocolitis and food poisoning. In: Feldman M, ed. Sleisenger and Fordtran’s gastrointestinal and liver disease, 8th edn. Philadelphia: WB Saunders; 2006. pp. 2333–2391.Google Scholar
  2. 2.
    Kimura J, Abe H, Kamitani S, Toshima H, et al. Clostridium perfringens enterotoxin interacts with claudins via electrostatic attraction. J Biol Chem 2010; 285: 401–408.PubMedCrossRefGoogle Scholar
  3. 3.
    Thielman NM Guerrant RL. Clinical practice. Acute infectious diarrhea. N Engl J Med 2004; 350:38–47.PubMedCrossRefGoogle Scholar
  4. 4.
    Musher DM, Musher BL. Contagious acute gastrointestinal infections. N Eng J Med 2004; 351:2417–2428.CrossRefGoogle Scholar
  5. 5.
    Dhar U, Bennish ML, Khan WA, et al. Clinical features, antimicrobial susceptibility and toxin production in Vibrio cholerae O139 infection: comparison with V. cholerae O1 infection. Trans R Soc Trop Med Hyg 1996; 90:402–405.PubMedCrossRefGoogle Scholar
  6. 6.
    Basu A, Garg P, Datta S, et al. Vibrio cholerae 0139 in Calcutta, 1992–1998: incidence, antibiograms, and genotypes. Emerg Infect Dis 2000; 6:139–142.PubMedCrossRefGoogle Scholar
  7. 7.
    Shogomori H, Futerman AH. Cholera toxin is found in detergent insoluble rafts/domains at the cell surface of hippocampal neurons but is internalized via a raft-independent mechanism. J Biol Chem 2001; 276:9182–9188.PubMedCrossRefGoogle Scholar
  8. 8.
    Massol RH Massol RH, Larsen JE, Fujinaga Y, et al. Cholera toxin toxicity does not require functional Arf6- and dynamin-dependent endocytic pathways. Mol Biol Cell 2004; 15:3631–3641.PubMedCrossRefGoogle Scholar
  9. 9.
    Lu L, Khan S, Lencer W, Walker WA. Endocytosis of cholera toxin by human enterocytes is developmentally regulated. Am J Physiol Gastrointest Liver Physiol 2005; 289 :G332–G341.PubMedCrossRefGoogle Scholar
  10. 10.
    Lu L, Bao Y, Khan A, et al. Hydrocortisone modulates cholera toxin endocytosis by regulating immature enterocyte plasma membrane phospholipids. Gastroenterology 2008; 135:185–193.PubMedCrossRefGoogle Scholar
  11. 11.
    Lencer WI, de Almeida JB, Moe S, et al. Entry of cholera toxin into polarized human intestinal epithelial cells. Identification of an early brefeldin A sensitive event required for A1-peptide generation. J Clin Invest 1993; 92:2941–2951.PubMedCrossRefGoogle Scholar
  12. 12.
    Orlandi PA, Curran PK, Fishman PH. Brefeldin A blocks the response of cultured cells to cholera toxin. Implications for intracellular trafficking in toxin action. J Biol Chem 1993; 268:12010–12016.PubMedGoogle Scholar
  13. 13.
    Pelham HR, Roberts LM, Lord JM. Toxin entry: how reversible is the secretory pathway? Trends Cell Biol 1992; 2:183–185.PubMedCrossRefGoogle Scholar
  14. 14.
    Lencer WI, Constable C, Moe S, et al. Targeting of cholera toxin and Escherichia coli heat labile toxin in polarized epithelia: role of COOH-terminal KDEL. J Cell Biol 1995; 131:951–962.PubMedCrossRefGoogle Scholar
  15. 15.
    Vanden Broeck D, Horvath C, De Wolf MJ. Vibrio cholerae: cholera toxin. Int J Biochem Cell Biol 2007; 39:1771–1775.PubMedCrossRefGoogle Scholar
  16. 16.
    Mourad FH, O’Donnell LJ, Dias JA, et al. Role of 5-hydroxytryptamine type 3 receptors in rat intestinal fluid and electrolyte secretion induced by cholera and Escherichia coli enterotoxins. Gut 1995; 37:340–345.PubMedCrossRefGoogle Scholar
  17. 17.
    Moss J, Richardson SH. Activation of adenylate cyclase by heat-labile E. coli enterotoxin. J Clin Invest 1978; 62:281–285.PubMedCrossRefGoogle Scholar
  18. 18.
    Evans DG, Silver RP, Evans DJ Jr, et al. Plasmid-controlled colonization factor associated with virulence in Escherichia coli enterotoxigenic for humans. Infect Immun 1975; 12:656–667.PubMedGoogle Scholar
  19. 19.
    Saha S, Chowdhury P, Mazumdar A, et al. Role of Yersinia enterocolitica heat-stable enterotoxin (Y-STa) on differential regulation of nuclear and cytosolic calcium signaling in rat intestinal epithelial cells. Cell Biol Toxicol 2009; 25:297–308.PubMedCrossRefGoogle Scholar
  20. 20.
    Guarino A, Giannella R, Thompson MR. Citrobacter freundii produces an 18-amino-acid heat-stable enterotoxin identical to the 18-amino-acid Escherichia coli heat-stable enterotoxin (ST Ia). Infect Immun 1989; 57:649–652.PubMedGoogle Scholar
  21. 21.
    Begum K, Ahsan CR, Ansaruzzaman M, Dutta DK, Ahmad QS, Talukder KA. Toxin(s), other than cholera toxin, produced by environmental non O1 non O139 Vibrio cholerae. Cell Mol Immunol 2006; 3:115–121.PubMedGoogle Scholar
  22. 22.
    Navaneethan U, Giannella RA. Mechanisms of infectious diarrhea. Nat Clin Pract Gastroenterol Hepatol 2008; 5:637–647.PubMedCrossRefGoogle Scholar
  23. 23.
    Herold S, Karch H, Schmidt H. Shiga toxin-encoding bacteriophages-genomes in motion. Int J Med Microbiol 2004; 294:115–121.PubMedCrossRefGoogle Scholar
  24. 24.
    Weintraub A. Enteroaggregative E. coli: epidemiology, virulence, and detection. J Med Microbiol 2007; 56:4–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Takahashi A, Sato Y, Shiomi Y, et al. Mechanisms of chloride secretion induced by thermostable direct haemolysin of Vibrio parahaemolyticus in human colonic tissue and a human intestinal epithelial cell line. J Med Microbiol 2000; 49: 801–810.PubMedGoogle Scholar
  26. 26.
    Fuller CM, Benos DJ. Electrophysiological characteristics of the Ca2+-activated Cl channel family of anion transport proteins. Clin Exp Pharmacol Physiol 2000; 27:906–910.PubMedCrossRefGoogle Scholar
  27. 27.
    Lundgren O, Svensson L. Pathogenesis of Rotavirus diarrhea. Microbes Infect 2001; 3:1145–1156.PubMedCrossRefGoogle Scholar
  28. 28.
    Berni Canani R, Secondo A, Passariello A, et al. Zinc inhibits calcium-mediated and nitric oxide-mediated ion secretion in human enterocytes. Eur J Pharmacol 2010; 25:266–270.CrossRefGoogle Scholar
  29. 29.
    Morris, AP, Estes, MK. Microbes and microbial toxins: paradigms for microbial-mucosal interactions. VIII. Pathological consequences of rotavirus infection and its enterotoxin. Am J Physiol Gastrointest Liver Physiol 2001; 281:G303.PubMedGoogle Scholar
  30. 30.
    Lundgren, O, Peregrin, AT, Persson, K, et al. Role of the enteric nervous system in the fluid and electrolyte secretion of rotavirus diarrhea. Science 2000; 287:491.PubMedCrossRefGoogle Scholar
  31. 31.
    Berni Canani R, Ruotolo S, Buccigrossi V, et al. Zinc fights diarrhoea in HIV-1-infected children: in-vitro evidence to link clinical data and pathophysiological mechanism. AIDS 2007; 21:108–110.CrossRefGoogle Scholar
  32. 32.
    Gill RK, Borthakur A, Hodges K, et al. Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli. J Clin Invest 2007; 117; 428–437.PubMedCrossRefGoogle Scholar
  33. 33.
    Berni Canani R, Terrin G, Cirillo P, et al. Butyrate as an effective treatment of congenital chloride diarrhea. Gastroenterology 2004; 127:630–634.CrossRefGoogle Scholar
  34. 34.
    Subramanya SB, Rajendran VM, Srinivasan P, et al. Differential regulation of cholera toxin-inhibited Na-H exchange isoforms by butyrate in rat ileum. Am J Physiol Gastrointest Liver Physiol 2007; 293:G857–G863.PubMedCrossRefGoogle Scholar
  35. 35.
    Hecht G, Hodges K, Gill RK, et al. Differential regulation of Na+/H+ exchange isoform activities by enteropathogenic E. coli in human intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 2004; 287:G370–G378.PubMedCrossRefGoogle Scholar
  36. 36.
    Dean P, Maresca M, Schuller S, et al. Potent diarrheagenic mechanism mediated by the cooperative action of three enteropathogenic Escherichia coli-injected effector proteins. Proc Natl Acad Sci 2006; 103:1876–1881.PubMedCrossRefGoogle Scholar
  37. 37.
    Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clin. Microbiol Rev 1998; 11:142–201.Google Scholar
  38. 38.
    Berni Canani R, De Marco G, Passariello A, et al. Inhibitory effect of HIV-1 Tat protein on the sodium-D-glucose symporter of human intestinal epithelial cells. AIDS 2006; 20:5–10.CrossRefGoogle Scholar
  39. 39.
    Halaihel N, Liévin V, Alvarado F, et al. Rotavirus infection impairs intestinal brush-border membrane Na (+) solute cotransport activities in young rabbits. Am J Physiol Gastrointest Liver Physiol 2000; 279:G587–G596.PubMedGoogle Scholar
  40. 40.
    Preston GM, Agre P. Isolation of the cDNA for erythrocyte integral membrane protein of 28 kilodaltons: member of an ancient channel family. Proc Natl Acad Sci 1991; 88:1110–1114.CrossRefGoogle Scholar
  41. 41.
    Guttman, J. A. et al. Aquaporins contribute to diarrhoea caused by attaching and effacing bacterial pathogens. Cell Microbiol 2007; 9:131–141.PubMedCrossRefGoogle Scholar
  42. 42.
    Lee YS, Lin HJ, Chen KT. McKittrick-Wheelock syndrome: a rare cause of life-threatening electrolyte disturbances and volume depletion. J Emerg Med 2010; Epub ahead of print Jan 21.Google Scholar
  43. 43.
    Borenshtein D, Fry RC, Groff EB. Diarrhea as a cause of mortality in a mouse model of infectious colitis. Genome Biol 2008; 9:R122.PubMedCrossRefGoogle Scholar
  44. 44.
    WHO Library Cataloging-in-Publication Data Diarrhoea: Why children are still dying and what can be done. The United Nations Children’s Fund (UNICEF)/World Health Organization (WHO) 2009. Accessed February 1, 2010.
  45. 45.
    Guarino A, Albano F, Ashkenazi S, et al, for the ESPGHAN/ESPID. Evidence-Based Guidelines for the Management of Acute Gastroenteritis in Children in Europe Expert Working Group. European Society for Paediatric Gastroenterology, Hepatology, and Nutrition/European Society for Paediatric Infectious Diseases evidence-based guidelines for the management of acute gastroenteritis in children in Europe: executive summary. J Pediatr Gastroenterol Nutr 2008; 46:619–621.PubMedCrossRefGoogle Scholar
  46. 46.
    Atia AN, Buchman AL. Oral rehydration solutions in non-cholera diarrhea: a review. Am J Gastroenterol 2009; 104:2596–2604.PubMedCrossRefGoogle Scholar
  47. 47.
    Berni Canani R, Ruotolo S. The dawning of the “zinc era” in the treatment of pediatric acute gastroenteritis worldwide? J Pediatr Gastroenterol Nutr 2006; 42:253–255.CrossRefGoogle Scholar
  48. 48.
    Hoque KM, Sarker R, Guggino SE, et al. A new insight into pathophysiological mechanisms of zinc in diarrhea. Ann N Y Acad Sci 2009; 1165:279–284.PubMedCrossRefGoogle Scholar
  49. 49.
    Passariello A, Terrin G, Ruotolo S, et al. New hypotonic oral rehydration solution containing zinc and prebiotics for the management of children with acute gastroenteritis. Dig Liv Dis 2008; 40:A 66.CrossRefGoogle Scholar
  50. 50.
    Baldi F, Bianco MA, Nardone G, et al. Focus on acute diarrhoeal disease. World J Gastroenterol 2009; 15:3341–3348.PubMedCrossRefGoogle Scholar
  51. 51.
    Pawlowski SW, Warren CA, Guerrant R. Diagnosis and treatment of acute or persistent diarrhea. Gastroenterology 2009; 136:1874–1886.PubMedCrossRefGoogle Scholar
  52. 52.
    Guarino A, Lo Vecchio A, Berni Canani R. Probiotics as prevention and treatment for diarrhea. Curr Opin Gastroenterol 2009; 25:18–23.PubMedCrossRefGoogle Scholar
  53. 53.
    De Marco G, Bracale I, Buccigrossi V, et al. Rotavirus induces a biphasic enterotoxic and cytotoxic response in human-derived intestinal enterocytes, which is inhibited by human immunoglobulins. J Infect Dis 2009; 200:813–819.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Gianluca Terrin
    • 1
  • Roberto Berni Canani
    • 2
  1. 1.Department of Pediatrics and European Laboratory for the Investigation on Food Induced DiseasesUniversity of Naples “Federico II”NaplesItaly
  2. 2.Department of Pediatrics and European Laboratory for the Investigation on Food Induced DiseasesUniversity of Naples “Federico II”NaplesItaly

Personalised recommendations