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. 1999 Dec;45(6):904–910. doi: 10.1136/gut.45.6.904

A tungsten supplemented diet attenuates bacterial translocation in chronic portal hypertensive and cholestatic rats: role of xanthine dehydrogenase and xanthine oxidase

G Schimpl 1, M Pabst 1, G Feierl 1, A Kuesz 1, H Ozbey 1, S Takahashi 1, M Hollwarth 1
PMCID: PMC1727743  PMID: 10562591

Abstract

BACKGROUND—Bacterial translocation (BT) plays a major role in the pathophysiological process of spontaneous infections in portal hypertension (PH) and cholestatic jaundice. The major mechanisms promoting BT in experimental animal models are the disruption of the intestinal ecological equilibrium and disruption of the intestinal mucosal barrier. The enzymes xanthine dehydrogenase (XD) and xanthine oxidase (XO) are often implicated as a significant source of oxidants which have a major impact on the impairment of intestinal barrier function.
AIM—To investigate the incidence of BT in rats with PH and obstructive jaundice, and to evaluate the impact of XD and XO.
METHODS—Animals were subjected to sham laparotomy (SL), PH by calibrated stenosis of the portal vein, and common bile duct ligation (CBDL). They were fed either a standard pellet diet or a tungsten supplemented molybdenum-free diet. Four weeks after the operative procedure, intestinal colonisation and BT to portal vein, vena cava, mesenteric lymph nodes, liver, and spleen were determined. Intestinal XD and XO activity were measured enzymatically and histochemically.
RESULTS—Significant (p<0.01) intestinal bacterial overgrowth was present in all PH and CBDL groups compared with the SL group. In normally fed animals after SL, BT occurred in 12%. In PH and after CBDL, the rate of BT increased significantly (p<0.05) to 28% and 54% respectively. In the jejunum of normally fed animals subjected to PH or CBDL, a significant increase in XO was observed (p<0.01). Animals fed a tungsten supplemented diet showed a significant attenuation of BT to 14% in PH and 22% after CBDL (p<0.05). Tungsten treatment completely suppressed jejunal XD and XO activities.
CONCLUSIONS—Significant intestinal bacterial overgrowth, BT, and XD to XO conversion occurred in PH and after CBDL. XD and XO inactivation by a tungsten supplemented molybdenum-free diet significantly reduced the incidence of BT without affecting intestinal bacterial overgrowth. These data strongly support the hypothesis that increased XD to XO conversion may contribute to intestinal barrier failure in PH and after CBDL.


Keywords: bacterial translocation; portal hypertension; chronic cholestasis; xanthine oxidase; xanthine dehydrogenase

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Figure 1  .

Figure 1  

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Xanthine oxidase (XO) and xanthine dehydrogenase (XD) activities in the jejunum of untreated rats subjected to sham laparotomy, portal hypertension, and common bile duct ligation. In all tungsten supplemented groups, no XO or XD activity was detected, indicating their complete inactivation. **p<0.01 v sham laparotomy.

Figure 2  .

Figure 2  

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Histochemical distribution of xanthine oxidase in the jejunum of untreated animals. (A) sham laparotomy; (B) portal hypertension.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aranow J. S., Fink M. P. Determinants of intestinal barrier failure in critical illness. Br J Anaesth. 1996 Jul;77(1):71–81. doi: 10.1093/bja/77.1.71. [DOI] [PubMed] [Google Scholar]
  2. Basista M. H., Stauber R. E., Van Thiel D. H., Tauxe W. N., Dindzans V. J. Effect of isolated portal hypertension on Kupffer cell function. Dig Dis Sci. 1994 Jan;39(1):46–50. doi: 10.1007/BF02090059. [DOI] [PubMed] [Google Scholar]
  3. Benoit J. N., Womack W. A., Hernandez L., Granger D. N. "Forward" and "backward" flow mechanisms of portal hypertension. Relative contributions in the rat model of portal vein stenosis. Gastroenterology. 1985 Nov;89(5):1092–1096. [PubMed] [Google Scholar]
  4. Berg R. D., Garlington A. W. Translocation of certain indigenous bacteria from the gastrointestinal tract to the mesenteric lymph nodes and other organs in a gnotobiotic mouse model. Infect Immun. 1979 Feb;23(2):403–411. doi: 10.1128/iai.23.2.403-411.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blanchet L., Lebrec D. Changes in splanchnic blood flow in portal hypertensive rats. Eur J Clin Invest. 1982 Aug;12(4):327–330. doi: 10.1111/j.1365-2362.1982.tb02240.x. [DOI] [PubMed] [Google Scholar]
  6. Chojkier M., Groszmann R. J. Measurement of portal-systemic shunting in the rat by using gamma-labeled microspheres. Am J Physiol. 1981 May;240(5):G371–G375. doi: 10.1152/ajpgi.1981.240.5.G371. [DOI] [PubMed] [Google Scholar]
  7. Deitch E. A., Sittig K., Li M., Berg R., Specian R. D. Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg. 1990 Jan;159(1):79–84. doi: 10.1016/s0002-9610(05)80610-5. [DOI] [PubMed] [Google Scholar]
  8. Dickman M. D., Chappelka A. R., Schaedler R. W. The Microbial ecology of the upper small bowel. Am J Gastroenterol. 1976 Jan;65(1):57–62. [PubMed] [Google Scholar]
  9. Ding J. W., Andersson R., Soltesz V., Willén R., Bengmark S. The role of bile and bile acids in bacterial translocation in obstructive jaundice in rats. Eur Surg Res. 1993 Jan-Feb;25(1):11–19. doi: 10.1159/000129252. [DOI] [PubMed] [Google Scholar]
  10. Frederiks W. M., Bosch K. S. The proportion of xanthine oxidase activity of total xanthine oxidoreductase activity in situ remains constant in rat liver under various (patho)physiological conditions. Hepatology. 1996 Nov;24(5):1179–1184. doi: 10.1002/hep.510240533. [DOI] [PubMed] [Google Scholar]
  11. Fukushima R., Gianotti L., Alexander J. W. The primary site of bacterial translocation. Arch Surg. 1994 Jan;129(1):53–58. doi: 10.1001/archsurg.1994.01420250065008. [DOI] [PubMed] [Google Scholar]
  12. Garcia-Tsao G., Albillos A., Barden G. E., West A. B. Bacterial translocation in acute and chronic portal hypertension. Hepatology. 1993 Jun;17(6):1081–1085. [PubMed] [Google Scholar]
  13. Garcia-Tsao G. Spontaneous bacterial peritonitis. Gastroenterol Clin North Am. 1992 Mar;21(1):257–275. [PubMed] [Google Scholar]
  14. Gilbert J. A., Kamath P. S. Spontaneous bacterial peritonitis: an update. Mayo Clin Proc. 1995 Apr;70(4):365–370. doi: 10.4065/70.4.365. [DOI] [PubMed] [Google Scholar]
  15. Granger D. N., Höllwarth M. E., Parks D. A. Ischemia-reperfusion injury: role of oxygen-derived free radicals. Acta Physiol Scand Suppl. 1986;548:47–63. [PubMed] [Google Scholar]
  16. Grisham M. B., Hernandez L. A., Granger D. N. Xanthine oxidase and neutrophil infiltration in intestinal ischemia. Am J Physiol. 1986 Oct;251(4 Pt 1):G567–G574. doi: 10.1152/ajpgi.1986.251.4.G567. [DOI] [PubMed] [Google Scholar]
  17. Hille R. The reaction mechanism of oxomolybdenum enzymes. Biochim Biophys Acta. 1994 Mar 8;1184(2-3):143–169. doi: 10.1016/0005-2728(94)90220-8. [DOI] [PubMed] [Google Scholar]
  18. Johnson J. L., Waud W. R., Cohen H. J., Rajagopalan K. V. Molecular basis of the biological function of molybdenum. Molybdenum-free xanthine oxidase from livers of tungsten-treated rats. J Biol Chem. 1974 Aug 25;249(16):5056–5061. [PubMed] [Google Scholar]
  19. Kato S., Kawase T., Alderman J., Inatomi N., Lieber C. S. Role of xanthine oxidase in ethanol-induced lipid peroxidation in rats. Gastroenterology. 1990 Jan;98(1):203–210. doi: 10.1016/0016-5085(90)91311-s. [DOI] [PubMed] [Google Scholar]
  20. Kooij A. A re-evaluation of the tissue distribution and physiology of xanthine oxidoreductase. Histochem J. 1994 Dec;26(12):889–915. [PubMed] [Google Scholar]
  21. Lemasters J. J., Nieminen A. L. Mitochondrial oxygen radical formation during reductive and oxidative stress to intact hepatocytes. Biosci Rep. 1997 Jun;17(3):281–291. doi: 10.1023/a:1027332611839. [DOI] [PubMed] [Google Scholar]
  22. Llovet J. M., Bartolí R., Planas R., Cabré E., Jimenez M., Urban A., Ojanguren I., Arnal J., Gassull M. A. Bacterial translocation in cirrhotic rats. Its role in the development of spontaneous bacterial peritonitis. Gut. 1994 Nov;35(11):1648–1652. doi: 10.1136/gut.35.11.1648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Mihas A. A., Toussaint J., Hsu H. S., Dotherow P., Achord J. L. Spontaneous bacterial peritonitis in cirrhosis: clinical and laboratory features, survival and prognostic indicators. Hepatogastroenterology. 1992 Dec;39(6):520–522. [PubMed] [Google Scholar]
  24. Miller D. M., Grover T. A., Nayini N., Aust S. D. Xanthine oxidase- and iron-dependent lipid peroxidation. Arch Biochem Biophys. 1993 Feb 15;301(1):1–7. doi: 10.1006/abbi.1993.1107. [DOI] [PubMed] [Google Scholar]
  25. Moreau R., Lee S. S., Soupison T., Roche-Sicot J., Sicot C. Abnormal tissue oxygenation in patients with cirrhosis and liver failure. J Hepatol. 1988 Aug;7(1):98–105. doi: 10.1016/s0168-8278(88)80512-9. [DOI] [PubMed] [Google Scholar]
  26. Moriwaki Y., Yamamoto T., Yamakita J., Takahashi S., Higashino K. Comparative localization of aldehyde oxidase and xanthine oxidoreductase activity in rat tissues. Histochem J. 1998 Feb;30(2):69–74. doi: 10.1023/a:1003222831002. [DOI] [PubMed] [Google Scholar]
  27. Muriel P., Suarez O. R. Role of lipid peroxidation in biliary obstruction in the rat. J Appl Toxicol. 1994 Nov-Dec;14(6):423–426. doi: 10.1002/jat.2550140607. [DOI] [PubMed] [Google Scholar]
  28. O'Boyle C. J., MacFie J., Mitchell C. J., Johnstone D., Sagar P. M., Sedman P. C. Microbiology of bacterial translocation in humans. Gut. 1998 Jan;42(1):29–35. doi: 10.1136/gut.42.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Parks D. A., Bulkley G. B., Granger D. N. Role of oxygen-derived free radicals in digestive tract diseases. Surgery. 1983 Sep;94(3):415–422. [PubMed] [Google Scholar]
  30. Parks D. A., Granger D. N. Xanthine oxidase: biochemistry, distribution and physiology. Acta Physiol Scand Suppl. 1986;548:87–99. [PubMed] [Google Scholar]
  31. Parks D. A., Williams T. K., Beckman J. S. Conversion of xanthine dehydrogenase to oxidase in ischemic rat intestine: a reevaluation. Am J Physiol. 1988 May;254(5 Pt 1):G768–G774. doi: 10.1152/ajpgi.1988.254.5.G768. [DOI] [PubMed] [Google Scholar]
  32. Parola M., Leonarduzzi G., Robino G., Albano E., Poli G., Dianzani M. U. On the role of lipid peroxidation in the pathogenesis of liver damage induced by long-standing cholestasis. Free Radic Biol Med. 1996;20(3):351–359. doi: 10.1016/0891-5849(96)02055-2. [DOI] [PubMed] [Google Scholar]
  33. Reilly J. A., Jr, Quigley E. M., Forst C. F., Rikkers L. F. Small intestinal transit in the portal hypertensive rat. Gastroenterology. 1991 Mar;100(3):670–674. doi: 10.1016/0016-5085(91)80010-7. [DOI] [PubMed] [Google Scholar]
  34. Rimola A., Soto R., Bory F., Arroyo V., Piera C., Rodes J. Reticuloendothelial system phagocytic activity in cirrhosis and its relation to bacterial infections and prognosis. Hepatology. 1984 Jan-Feb;4(1):53–58. doi: 10.1002/hep.1840040109. [DOI] [PubMed] [Google Scholar]
  35. Saugstad O. D. Role of xanthine oxidase and its inhibitor in hypoxia: reoxygenation injury. Pediatrics. 1996 Jul;98(1):103–107. [PubMed] [Google Scholar]
  36. Schimpl G., Pesendorfer P., Steinwender G., Feierl G., Ratschek M., Höllwarth M. E. Allopurinol reduces bacterial translocation, intestinal mucosal lipid peroxidation, and neutrophil-derived myeloperoxidase activity in chronic portal hypertensive and common bile duct-ligated growing rats. Pediatr Res. 1996 Sep;40(3):422–428. doi: 10.1203/00006450-199609000-00010. [DOI] [PubMed] [Google Scholar]
  37. Spitzer J. A., Mayer A. M. Hepatic neutrophil influx: eicosanoid and superoxide formation in endotoxemia. J Surg Res. 1993 Jul;55(1):60–67. doi: 10.1006/jsre.1993.1109. [DOI] [PubMed] [Google Scholar]
  38. Topham R. W., Jackson M. R., Joslin S. A., Walker M. C. Studies of the ferroxidase activity of native and chemically modified xanthine oxidoreductase. Biochem J. 1986 Apr 1;235(1):39–44. doi: 10.1042/bj2350039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tribble D. L., Aw T. Y., Jones D. P. The pathophysiological significance of lipid peroxidation in oxidative cell injury. Hepatology. 1987 Mar-Apr;7(2):377–386. doi: 10.1002/hep.1840070227. [DOI] [PubMed] [Google Scholar]
  40. Van Den Munckhof R. J., Vreeling-Sindelarova H., Schellens J. P., Van Noorden C. J., Frederiks W. M. Ultrastructural localization of xanthine oxidase activity in the digestive tract of the rat. Histochem J. 1995 Nov;27(11):897–905. [PubMed] [Google Scholar]
  41. Vettenranta K., Raivio K. O. Xanthine oxidase during human fetal development. Pediatr Res. 1990 Mar;27(3):286–288. doi: 10.1203/00006450-199003000-00017. [DOI] [PubMed] [Google Scholar]
  42. Wajner M., Harkness R. A. Distribution of xanthine dehydrogenase and oxidase activities in human and rabbit tissues. Biochim Biophys Acta. 1989 Apr 25;991(1):79–84. doi: 10.1016/0304-4165(89)90031-7. [DOI] [PubMed] [Google Scholar]
  43. Weiss S. J. Tissue destruction by neutrophils. N Engl J Med. 1989 Feb 9;320(6):365–376. doi: 10.1056/NEJM198902093200606. [DOI] [PubMed] [Google Scholar]
  44. Xu P., Huecksteadt T. P., Harrison R., Hoidal J. R. Molecular cloning, tissue expression of human xanthine dehydrogenase. Biochem Biophys Res Commun. 1994 Mar 15;199(2):998–1004. doi: 10.1006/bbrc.1994.1328. [DOI] [PubMed] [Google Scholar]

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