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Bile modulates intestinal epithelial barrier function via an extracellular signal related kinase 1/2 dependent mechanism

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Abstract

Objective

Obstructive jaundice is frequently complicated by infections and has been associated with increased bacterial translocation and gut mucosal hyperpermeability in animal models. Proper expression of the tight junction (TJ) proteins ZO-1 and occludin is important for normal gut barrier function. We tested whether bile modulates intestinal epithelial ZO-1 and occludin expression.

Animals

(a) Male C57BL/6 mice; (b) male Sprague-Dawley rats.

Interventions

(a) Mice were subjected to common bile duct ligation (CBDL) or a sham procedure, and 96 h later all surviving animals were killed for measurement of ileal mucosal permeability to FITC-labeled dextran (everted gut sac technique), bacterial translocation to mesenteric lymph nodes, and ileal epithelial ZO-1 and occludin expression (western blots). (b) Rat IEC-6 enterocytic monolayers were incubated in the presence or absence of graded concentrations of rat bile and/or U0126, an inhibitor of extracellular signal related kinase (ERK) 1/2 activation.

Results

(a) Compared to sham-treated controls, CBDL significantly increased gut mucosal permeability and bacterial translocation and markedly decreased ileal epithelial expression of ZO-1 and occludin. In a follow-up in vivo experiment, gavaging mice with fresh rat bile twice daily significantly ameliorated the deleterious effects of CBDL on gut barrier function. (b) Addition of 1% (v/v) bile to media enhanced phosphorylation of ERK1/2, increased the expression of ZO-1 and occludin and decreased permeability to FITC-dextran. All of these bile-mediated effects were blocked by 10 µM U0126.

Conclusions

These data support the view that the presence of bile in the intestinal lumen is essential for normal gut barrier function, possibly because compounds present in bile initiate ERK1/2-dependent signaling that is essential for normal expression of key TJ proteins.

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References

  1. Pitt HA, Cameron JL, Postier RG, Gadacz TR (1981) Factors affecting mortality in biliary tract surgery. Am J Surg 141:66–72

    Google Scholar 

  2. Armstrong CP, Dixon JM, Taylor TV, Davies GC (1984) Surgical experience of deeply jaundiced patients with bile duct obstruction. Br J Surg 71:234–238

    Google Scholar 

  3. Povoski SP, Karpeh MS Jr, Conlon KC, Blumgart LH, Brennan MF (1999) Preoperative biliary drainage: impact on intraoperative bile cultures and infectious morbidity and mortality after pancreaticoduodenectomy. J Gastrointest Surg 3:496–505

    Article  CAS  PubMed  Google Scholar 

  4. Welsh FKS, Ramsden CW, MacLennan K, Sheridan MB, Barclay RG, Guillou PJ, Reynolds JV (1998) Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice. Ann Surg 227:205–212

    Google Scholar 

  5. Parks RW, Halliday MI, McCrory DC, Erwin P, Smye M, Diamond T, Rowlands BJ (2003) Host immune responses and intestinal permeability in patients with jaundice. Br J Surg 90:239–245

    Google Scholar 

  6. Parks RW, Clements WD, Smye MG, Pope C, Rowlands BJ, Diamond T (1996) Intestinal barrier dysfunction in clinical and experimental obstructive jaundice and its reversal by internal biliary drainage. Br J Surg 83:1345–1349

    Google Scholar 

  7. Deitch EA, Sittig K, Li M, Berg R, Specian RD (1990) Obstructive jaundice promotes bacterial translocation from the gut. Am J Surg 159:79–84

    Google Scholar 

  8. Sileri P, Morini S, Sica GS, Schena S, Rastellini C, Gaspari AL, Benedetti E, Cicalese L (2002) Bacterial translocation and intestinal morphological findings in jaundiced rats. Dig Dis Sci 47:929–934

    Google Scholar 

  9. Ding JW, Andersson R, Soltesz V, Willen R, Bengmark S (1993) The role of bile bile acids in bacterial translocation in obstructive jaundice in rats. Eur Surg Res 25:11–19

    Google Scholar 

  10. Erbil Y, Berber E, Ozarmagan S, Seven R, Eminoglu L, Calis A, Olgac V, Gurler N (1999) The effects of sodium deoxycholate, lactulose glutamine on bacterial translocation in common bile duct ligated rats. Hepatogastroenterology 46:2791–2795

    Google Scholar 

  11. Ogata Y, Nishi M, Nakayama H, Kuwahara T, Ohnishi Y, Tashiro S (2003) Role of bile in intestinal barrier function its inhibitory effect on bacterial translocation in obstructive jaundice in rats. J Surg Res 115:18–23

    Google Scholar 

  12. Aldemir M, Geyik MF, Kokoglu OF, Buyukbayram H, Hosoglu S, Yagmur Y (2003) Effects of ursodeoxycholic acid, glutamine polyclonal immunoglobulins on bacterial translocation in common bile duct ligated rats. ANZ J Surg 73:722–726

    Google Scholar 

  13. Kamiya S, Nagino M, Kanazawa H, Komatsu S, Mayumi T, Takagi K, Asahara T, Nomoto K, Tanaka R, Nimura Y (2004) The value of bile replacement during external biliary drainage: an analysis of intestinal permeability, integrity, microflora. Ann Surg 239:510–517

    Google Scholar 

  14. Stevenson BR (1999) Understanding tight junction clinical physiology at the molecular level. J Clin Invest 104:3–4

    Google Scholar 

  15. Gonzalez-Mariscal L, Betanzos A, Nava P, Jaramillo BE (2003) Tight junction proteins. Prog Biophys Mol Biol 81:1–44

    Article  PubMed  Google Scholar 

  16. Anderson JM Van Itallie CM (1995) Tight junctions the molecular basis for regulation of paracellular permeability. Am J Physiol 269:G467–G475

    Google Scholar 

  17. Gumbiner BM (1993) Breaking through the tight junction barrier. J Cell Biol 123:1631–1633

    Article  CAS  PubMed  Google Scholar 

  18. Balda MS Matter K (2000) Transmembrane proteins of tight junctions. Semin Cell Dev Biol 11:281–289

    Google Scholar 

  19. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM (1998) The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin the actin cytoskeleton. J Biol Chem 273:29745–29753

    Google Scholar 

  20. Mitic LL Anderson JM (1998) Molecular architecture of tight junctions. Annu Rev Physiol 60:121–142

    Article  CAS  PubMed  Google Scholar 

  21. Gonzalez-Mariscal L, Betanzos A, Avila-Flores A (2000) MAGUK proteins: structure role in the tight junction. Semin Cell Dev Biol 11:315–324

    Article  PubMed  Google Scholar 

  22. Yang R, Gallo DJ, Baust JJ, Uchiyama T, Watkins SK, Delude RL, Fink MP (2002) Ethyl pyruvate modulates inflammatory gene expression in mice subjected to hemorrhagic shock. Am J Physiol Gastrointest Liver Physiol 283:G212-G22

    Google Scholar 

  23. Han X, Fink MP, Yang R, Delude RL (2004) Increased iNOS activity is essential for intestinal epithelial tight junction dysfunction in endotoxemic mice. Shock 21:261–270

    Google Scholar 

  24. Han X, Fink MP, Delude RL (2003) Proinflammatory cytokines cause NO·-dependent independent changes in expression localization of tight junction proteins in intestinal epithelial cells. Shock 19:229–237

    Google Scholar 

  25. Bemelmans MH, Gouma DJ, Greve JW, Buurman WA (1992) Cytokines tumor necrosis factor interleukin-6 in experimental biliary obstruction in mice. Hepatology 15:1132–1136

    Google Scholar 

  26. Tu B, Gong JP, Feng HY, Wu CX, Shi YY, Li XH, Peng Y, Liu CA, Li SW (2003) Role of NF-kB in multiple organ dysfunction during acute obstructive cholangitis. World J Gastroenterol 9:179–183

    Google Scholar 

  27. Guo X, Rao JN, Liu L, Zou TT, Turner DJ, Bass BL, Wang JY (2004) Regulation of adherens junctions epithelial paracellular permeability: a novel function for polyamines. Am J Physiol Cell Physiol 285:C1174–C1187

    Google Scholar 

  28. Clemente MG, De Virgiliis S, Kang JS, Macatagney R, Musu MP, Di Pierro MR, Drago S, Congia M, Fasano A (2003) Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 52:218–223

    Article  CAS  PubMed  Google Scholar 

  29. Xu DZ, Lu Q, Deitch EA (2002) Nitric oxide directly impairs intestinal barrier function. Shock 17:139–145

    Google Scholar 

  30. Sappington PL, Yang R, Yang H, Tracey KJ, Delude RL, Fink MP (2002) HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers impairs intestinal barrier function in mice. Gastroenterology 123:790–802

    Google Scholar 

  31. Le Bacquer O, Laboisse C, Darmaun D (2003) Glutamine preserves protein synthesis paracellular permeability in Caco-2 cells submitted to “luminal fasting.” Am J Physiol Gastrointest Liver Physiol 285:G128–G136

    Google Scholar 

  32. Banan A, Fields JZ, Talmage DA, Zhang L, Keshavarzian A (2002) PKC-zeta is required in EGF protection of microtubules intestinal barrier integrity against oxidant injury. Am J Physiol Gastrointest Liver Physiol 282:G794–G808

    Google Scholar 

  33. Qiao L, Han SI, Fang Y, Park JS, Gupta S, Gilfor D, Amorino G, Valerie K, Sealy L, Engelhardt JF, Grant S, Hylemon PB, Dent P (2003) Bile acid regulation of C/EBPbeta, CREB, c-Jun function, via the extracellular signal-regulated kinase c-Jun NH2-terminal kinase pathways, modulates the apoptotic response of hepatocytes. Mol Cell Biol 23:3052–3066

    Google Scholar 

  34. Haussinger D, Kurz AK, Wettstein M, Graf D, Vom Dahl S, Schliess F (2003) Involvement of integrins Src in tauroursodeoxycholate-induced swelling-induced choleresis. Gastroenterology 124:1476–1487

    Google Scholar 

  35. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632

    Google Scholar 

  36. Assimakopoulos SF, Scopa CD, Charonis A, Spiliopoulou I, Georgiou C, Nikolopoulou V, Vagianos CE (2004) Experimental obstructive jaundice disrupts intestinal mucosal barrier by altering occludin expression: beneficial effect of bombesin neurotensin. J Am Coll Surg 198:748–757

    Google Scholar 

  37. Yang R, Gallo DJ, Baust JJ, Watkins SK, Delude RL, Fink MP (2002) Effect of hemorrhagic shock on gut barrier function expression of stress-related genes in normal gnotobiotic mice. Am J Physiol Regul Integr Comp Physiol 283:R1263–R1274

    Google Scholar 

  38. Yang R, Han X, Uchiyama T, Watkins SK, Yaguchi A, Delude RL, Fink MP (2003) IL-6 is essential for development of gut barrier dysfunction after hemorrhagic shock resuscitation in mice. Am J Physiol Gastrointest Liver Physiol 285:G621–G629

    Google Scholar 

  39. Wang Q, Fang CH, Hasselgren PO (2001) Intestinal permeability is reduced IL-10 levels are increased in septic IL-6 knockout mice. Am J Physiol 281:R1013–R1023

    Google Scholar 

  40. Li Z, Tanaka M, Kataoka H, Nakamura R, Sanjar R, Shinmura K, Sugimura H (2003) EphA2 up-regulation induced by deoxycholic acid in human colon carcinoma cells, an involvement of extracellular signal-regulated kinase p53-independence. J Cancer Res Clin Oncol 129:703–708

    Google Scholar 

  41. Qiao D, Stratagouleas ED, Martinez JD (2001) Activation role of mitogen-activated protein kinases in deoxycholic acid-induced apoptosis. Carcinogenesis 22:35–41

    Article  CAS  PubMed  Google Scholar 

  42. Dieckgraefe BK, Weems DM, Santoro SA, Alpers DH (1997) ERK p38 MAP kinase pathways are mediators of intestinal epithelial wound-induced signal transduction. Biochem Biophys Res Commun 233:389–394

    Google Scholar 

  43. Goke M, Kanai M, Lynch-Devaney K, Podolsky DK (1998) Rapid mitogen-activated protein kinase activation by transforming growth factor alpha in wounded rat intestinal epithelial cells. Gastroenterology 114:697–705

    Google Scholar 

  44. Bhattacharya S, Ray RM, Johnson LR (2004) Prevention of TNF-alpha-induced apoptosis in polyamine-depleted IEC-6 cells is mediated through the activation of ERK1/2. Am J Physiol Gastrointest Liver Physiol 286:G479–G490

    Google Scholar 

  45. Kevil CG, Oshima T, Alexander B, Coe LL, Alexander JS (2000) H2O2-mediated permeability: role of MAPK occludin. Am J Physiol Cell Physiol 279:C21–C30

    Google Scholar 

  46. Pedram A, Razandi M, Levin ER (2002) Deciphering vascular endothelial cell growth factor/vascular permeability factor signaling to vascular permeability. Inhibition by atrial natriuretic peptide. J Biol Chem 277:44385–44398

    Google Scholar 

  47. Wachtel M, Frei K, Ehler E, Bauer C, Gassmann M, Gloor SM (2002) Extracellular signal-regulated protein kinase activation during reoxygenation is required to restore ischaemia-induced endothelial barrier failure. Biochem J 367:873–879

    Google Scholar 

  48. Kinugasa T, Salaguchi T, Gu X, Reinecker HC (2000) Claudins regulate the intestinal barrier in response to immune mediators. Gastroenterology 118:1001–1011

    Google Scholar 

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Authors and Affiliations

  1. Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Runkuan Yang, Tomoyuki Harada, Jinyou Li, Takashi Uchiyama, Yusheng Han, Joshua A. Englert & Mitchell P. Fink

  2. Department of Surgery, School of Medicine, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA, 15261, USA

    Mitchell P. Fink

Authors
  1. Runkuan Yang
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  2. Tomoyuki Harada
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  3. Jinyou Li
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  4. Takashi Uchiyama
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  5. Yusheng Han
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  6. Joshua A. Englert
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  7. Mitchell P. Fink
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Corresponding author

Correspondence to Mitchell P. Fink.

Additional information

Grant support: 5R01 GM 37631-18 from the National Institutes of Health

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Yang, R., Harada, T., Li, J. et al. Bile modulates intestinal epithelial barrier function via an extracellular signal related kinase 1/2 dependent mechanism. Intensive Care Med 31, 709–717 (2005). https://doi.org/10.1007/s00134-005-2601-9

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  • DOI: https://doi.org/10.1007/s00134-005-2601-9

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