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Digestive Diseases and Sciences

, Volume 49, Issue 11–12, pp 1845–1852 | Cite as

A Role for CagA/VacA in Helicobacter pylori Inhibition of Murine Duodenal Mucosal Bicarbonate Secretion

  • Bi-Guang Tuo
  • Zachary M. Sellers
  • Anders J. Smith
  • Kim E. Barrett
  • Jon I. Isenberg
  • Hui DongEmail author
Article

Abstract

Duodenal mucosal bicarbonate secretion is diminished in patients with Helicobacter pylori (HP)-associated duodenal ulcer disease. We examined whether HP water extracts inhibit murine duodenal mucosal bicarbonate secretion {in vitro}, and the mechanisms involved. Murine duodenal mucosae were mounted in Ussing chambers. Short-circuit current and bicarbonate secretion was measured. CagA/VacA-positive HP water extract (HPWE+/plus;) markedly inhibited PGE2-, carbachol-, or the calcium ionophore A23187-stimulated bicarbonate secretion in a dose-dependent manner. While 3-isobutyl-1-methylxanthine-stimulated bicarbonate secretion was not affected by HPWE+/plus;, HPWE+/plus; did diminish forskolin-stimulated bicarbonate secretion. HPWE+/plus; markedly diminished PGE2-induced increases in duodenal mucosal cAMP. CagA/VacA of HP decreases Ca2+-mediated bicarbonate secretiondownstream of increases in intracellular Ca2+. Dimunition of PGE2-stimulated bicarbonate secretion occurs, in part, by inhibition of adenylate cyclase, which leads to decreased cAMP levels. The ability of virulent HP strains to inhibit duodenal bicarbonate secretion through multiple intracellular pathways likely contributes to the pathogenesis of HP-associated duodenal ulcer disease.

Helicobacter pylori CagA VacA duodenal bicarbonate secretion 

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References

  1. 1.
    Flemström G: Gastric and duodenal mucosal secretion of bicarbonate. In Physiology of the Gastrointestinal Tract. Johnson L (ed). New York, Raven Press, 1994, pp 1285–1309Google Scholar
  2. 2.
    Flemström G, Isenberg J: Gastroduodenal mucosal alkaline secretion and mucosal protection. News Physiol Sci 16:23–28, 2001PubMedGoogle Scholar
  3. 3.
    Hogan D, Ainsworth M, Isenberg J: Gastroduodenal bicarbonate secretion. Aliment Pharmacol Ther 8:475–488, 1994CrossRefGoogle Scholar
  4. 4.
    Hojgaard L, Mertz-Nielson A, Rune S: Peptic ulcer pathophysiology: Acid, bicarbonate, and mucosal function. Scand J Gastroenterol 216:10–15, 1996CrossRefGoogle Scholar
  5. 5.
    Guba M, Kuhn M, Forssmann W, et al.: Guanylin strongly stimulates rat duodenal HCO3− secretion: Proposed mechanism and comparison with other secretagogues. Gastroenterology 111:1558–1568, 1996CrossRefGoogle Scholar
  6. 6.
    Heylings J, Garner H, Flemstrom G: Regulation of gastroduodenal HCO3− transport by luminal acid in the frog in vitro. Am J Physiol 246:G235–G240, 1984CrossRefGoogle Scholar
  7. 7.
    Hogan D, Yao B, Isenberg J: Modulation of bicarbonate secretion in rabbit duodenum: the role of calcium. Dig Dis Sci 43:120–125, 1998CrossRefGoogle Scholar
  8. 8.
    Isenberg J, Hogan D, Koss M, et al.: Human duodenal mucosal bicarbonate secretion. Evidence for basal secretion and stimulation by hydrochloric acid and a synthetic E1 analogue. Gastroenterology 91:370–378, 1986CrossRefGoogle Scholar
  9. 9.
    Odes H, Muallem R, Reimer R, et al.: Cholinergic regulation of guinea pig duodenal bicarbonate secretion. Am J Physiol 265:G270–G276, 1993PubMedGoogle Scholar
  10. 10.
    Yao B, Hogan D, Bukhave K, et al.: Bicarbonate transport by rabbit duodenum in vitro: effect of casoactive intestinal polypeptide, prostaglandin E2, and cyclic adenosine monophosphate. Gastroenterology 104:732–740, 1993CrossRefGoogle Scholar
  11. 11.
    Hogan D, Yao B, Barrett K, et al.: Histamine inhibits prostaglandin E2-stimulated rabbit duodenal bicarbonate secretion via H2 receptors and enteric nerves. Gastroenterology 108:1676–1682, 1995CrossRefGoogle Scholar
  12. 12.
    Mertz-Nielson A, Hillingso J, Bukhave K, et al.: Indomethacin decreases gastroduodenal mucosal bicarbonate secretion in humans. Scand J Gastroenterol 30:1160–1165, 1995CrossRefGoogle Scholar
  13. 13.
    Myers C, Hogan D, Yao B, et al.: Inhibition of rabbit duodenal bicarbonate by ulcerogenic agents: Histamine-dependent and -independent effects. Gastroenterology 114:527–535, 1998CrossRefGoogle Scholar
  14. 14.
    Bukhave K, Rask-Madsen J, Hogan D, et al.: Proximal duodenal prostaglandin E2 release and mucosal bicarbonate secretion are altered in patients with duodenal ulcer. Gastroenterology 99:951–955, 1990CrossRefGoogle Scholar
  15. 15.
    Isenberg J, Selling J, Hogan D, et al.: Impaired proximal duodenal mucosal bicarbonate secretion in patients with duodenal ulcer. N Engl J Med 316:374–379, 1987CrossRefGoogle Scholar
  16. 16.
    Taylor D, Parsonnet J: Epidemiology and natural history of H. pylori infections. In Infections of the Gastrointestinal Tract. Blaser M, Smith P, Ravdin J, et al. (eds). New York, Raven, 1995, pp 551–564Google Scholar
  17. 17.
    Marshall B: Helicobacter pylori: The etiologic agent for peptic ulcer. JAMA 1064–1066, 1995Google Scholar
  18. 18.
    Hogan D, Rapier R, Dreilinger A, et al.: Duodenal bicarbonate secretion: Eradication of Helicobacter pylori and duodenal structure and function in humans. Gastroenterology 110:705–716, 1996CrossRefGoogle Scholar
  19. 19.
    Pratha V, Hogan D, Zhou R, et al.: Helicobacter pylori water extract alters PGE2-stimulated HCO3− secretion in the human duodenum. Gastroenterology 116:A285, 1999Google Scholar
  20. 20.
    Fandriks L, Bothmer C, Johannon B, et al.: Water extract of Helicobacter pylori inhibits duodenal mucosal alkaline secretion in anesthetized rats. Gastroenterology 113:1570–1575, 1997CrossRefGoogle Scholar
  21. 21.
    Beales I, Blaser M, Srinivasan S, et al.: Effect of Helicobacter pylori products and recombinant cytokines on gastrin release from cultured canine G-cells. Gastroenterology 113:465–471, 1997CrossRefGoogle Scholar
  22. 22.
    Hogan DL, Crombie DL, Isenberg JI, et al.: Acid -stimulated duodenal bicarbonate secretion involves a CFTR-mediated transport pathway in mice. Gastroenterology 113:533–541, 1997CrossRefGoogle Scholar
  23. 23.
    Seidler U, Blumenstein I, Kretz A, et al.: A functional CFTR protein is required for mouse intestinal cAMP-, cGMP-, and Ca2 +-dependent HCO3− secretion. J Physiol 505:411–423, 1997CrossRefGoogle Scholar
  24. 24.
    Chew C, Safsten B, Flemström G: Calcium signaling in cultured human rat duodenal enterocytes. Am J Physiol 275:G296–G304, 1998CrossRefGoogle Scholar
  25. 25.
    Takeuchi K, Yagi K, Kato S, et al.: Roles of prostaglandin E-receptor subtypes in gastric and duodenal bicarbonate secretion in rats. Gastroenterology 113:1553–1559, 1997CrossRefGoogle Scholar
  26. 26.
    Takeuchi K, Ukawa H, Kato S, et al.: Impaired duodenal bicarbonate secretion and mucosal integrity in mice lacking prostaglandin E-receptor subtype EP3. Gastroenterology 117:1128–1135, 1999CrossRefGoogle Scholar
  27. 27.
    Reimer R, Odes H, Muallem R, et al.: Cyclic adenosine monophosphate is the second messenger of prostaglandin E2- and vasoactive intestinal polypeptide-stimulated active bicarbonate secretion by guinea-pig duodenum. Scand J Gastroenterol 29:153–159, 1994CrossRefGoogle Scholar
  28. 28.
    Taha A, Fraser W, Kelly R, et al.: Inhibition of human gastric cyclic AMP production by Helicobacter pylori protein-possible involvement of mucosal prostaglandin E2. Aliment Pharmacol Ther 5:379–389, 1991CrossRefGoogle Scholar
  29. 29.
    Konturek S, Bilski J, Tasler J, et al.: Role of endogenous prostaglandins in duodenal alkaline response to luminal hydrochloric acid or arachidonic acid in conscious dogs. Digestion 34(268):274, 1986Google Scholar
  30. 30.
    Sugamoto S, Kawauchi S, Furukawa O, et al.: Role of endogenous nitric oxide and prostaglandin in duodenal bicarbonate response induced by mucosal acidification in rats. Dig Dis Sci 46:1208–1216, 2001CrossRefGoogle Scholar
  31. 31.
    Olbe L, Hamlet A, Dalenback J, et al.: A mechanism by which Helicobacter pylori infection of the antrum contributes to the development of duodenal ulcer. Gastroenterology 110:1386–1394, 1996CrossRefGoogle Scholar
  32. 32.
    Olbe L, Fandriks L, Hamlet A, et al.: Conceivable mechanisms by which Helicobacter pylori provokes duodenal ulcer disease. Bailliere’s Clin Gastroenterol 140:1–12, 2000Google Scholar
  33. 33.
    Van-der-Hulst R, Tytgat C: Helicobacter pylori and peptic ulcer disease. Scand J Gastroenterol 220:10–18, 1996CrossRefGoogle Scholar
  34. 34.
    Walker M, Crabtree J: Helicobacter pylori infection and the pathogenesis of duodenal ulceration. Ann NY Acad Sci 859:96–111, 1998CrossRefGoogle Scholar
  35. 35.
    Cover T, Blaser M: Helicobacter pylori factors associated with disease. Gastroenterology 117:257–261, 1999CrossRefGoogle Scholar
  36. 36.
    Dundon W, de-Berbard M, Montecucco C: Virulence factors of Helicobacter pylori. Int J Med Microbiol 290:647–658, 2001CrossRefGoogle Scholar
  37. 37.
    Tee W, Lambert J, Dwyer B: Cytotoxin production by Helicobacter pylori from patients with upper gastrointestinal tract disease. J Clin Microbiol 33:1203–1205, 1995PubMedPubMedCentralGoogle Scholar
  38. 38.
    Hamlet A, Thoreson A, Nilsson O, et al.: Duodenal Helicobacter pylori infection differs in CagA genotype between asymptomatic subjects and patients with duodenal ulcers. Gastroenterology 116:259–268, 1999CrossRefGoogle Scholar
  39. 39.
    Hogan D, Yao B, Steinbach J, et al.: The enteric nervous system modulates mammalian duodenal mucosal bicarbonate secretion. Gastroenterology 105:410–417, 1993CrossRefGoogle Scholar
  40. 40.
    Pratha V, Hogan D, Martenssön B, et al.: Identification of transport abnormalities in duodenal mucosa and duodenal enterocytes from patients with cystic fibrosis. Gastroenterology 118:1051–1060, 2000CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2004

Authors and Affiliations

  • Bi-Guang Tuo
    • 1
    • 2
  • Zachary M. Sellers
    • 1
  • Anders J. Smith
    • 1
  • Kim E. Barrett
    • 1
  • Jon I. Isenberg
    • 1
  • Hui Dong
    • 1
    Email author
  1. 1.Division of Gastroenterology, Department of MedicineUniversity of California, San Diego, School of MedicineSan DiegoUSA
  2. 2.Department of Gastroenterology and Hepatology Hannover Medical SchoolHannoverGermany

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