Skip to main content
Log in

Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis

  • Original Contribution
  • Published:
European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Background

Intestinal homeostasis plays an important role in bacteria-derived complications in cirrhosis. Intestinal lymphocytes are responsible for immune effector functions and can be modulated by certain probiotics. We evaluate the interaction between Bifidobacterium pseudocatenulatum CECT7765 and intestinal lymphocytes in mice with cirrhosis.

Animals and methods

Cirrhosis was induced by intragastrical administration of carbon tetrachloride in Balb/C mice. One week prior to laparotomy, animals received B. pseudocatenulatum CECT7765 (107, 109 or 1010 cfu/daily) or placebo. Chemokine receptor and cytokine expression were evaluated in intestinal lymphocytes. Gut permeability was studied by FITC-LPS recovery in vivo. Luminal antigens, inflammation and functional markers were evaluated in liver samples.

Results

Bifidobacterium pseudocatenulatum CECT7765 decreased the expression of pro-inflammatory chemokine receptors CCR6, CCR9, CXCR3 and CXCR6 in intestinal lymphocytes from cirrhotic mice in a concentration-dependent manner. The bifidobacterial strain induced a shift towards an anti-inflammatory cytokine profile in this cell subset. B. pseudocatenulatum CECT7765-induced inflammatory modulation was TLR2-mediated, as in vitro TLR2 blockade inhibited the reduction of TNF-alpha and its receptors and the increase of IL-10 and IL-10 receptor secretion. The recovery rate of administered fluorescence-labelled endotoxin was significantly and dose-dependently lowered with the bifidobacterial strain. The reduced intestinal permeability was associated with a decreased burden of bacterial antigens in the liver of mice treated with B. pseudocatenulatum CECT7765. Liver function and inflammation were improved with the use of the bifidobacterial strain at the highest dose tested (1010 cfu).

Conclusion

Bifidobacterium pseudocatenulatum CECT7765 improves gut homeostasis and prevents gut-derived complications in experimental chronic liver disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Berg RD (1992) Bacterial translocation from the gastrointestinal tract. J Med 23:217–244

    CAS  Google Scholar 

  2. Wiest R, Garcia-Tsao G (2005) Bacterial translocation (BT) in cirrhosis. Hepatology 41:422–433

    Article  CAS  Google Scholar 

  3. Yan AW, Fouts DE, Brandl J, Starkel P, Torralba M, Schott E et al (2011) Enteric dysbiosis associated with a mouse model of alcoholic liver disease. Hepatology 53:96–105

    Article  CAS  Google Scholar 

  4. Gomez-Hurtado I, Santacruz A, Peiro G, Zapater P, Gutierrez A, Perez-Mateo M et al (2011) Gut microbiota dysbiosis is associated with inflammation and bacterial translocation in mice with CCl4-induced fibrosis. PLoSOne 6:e23037

    Article  CAS  Google Scholar 

  5. Kirpich IA, McClain CJ (2012) Probiotics in the treatment of the liver diseases. J Am Coll Nutr 31:14–23

    Article  CAS  Google Scholar 

  6. Stadlbauer V, Mookerjee RP, Hodges S, Wright GA, Davies NA, Jalan R (2008) Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis. J Hepatol 48:945–951

    Article  CAS  Google Scholar 

  7. Pereg D, Kotliroff A, Gadoth N, Hadary R, Lishner M, Kitay-Cohen Y (2011) Probiotics for patients with compensated liver cirrhosis: a double-blind placebo-controlled study. Nutrition 27:177–181

    Article  CAS  Google Scholar 

  8. Moratalla A, Gomez-Hurtado I, Santacruz A, Moya A, Peiro G, Zapater P, et al. (2014) Protective effect of Bifidobacterium pseudocatenulatum CECT7765 against induced bacterial antigen translocation in experimental cirrhosis. Liver Int 34:850–858

    Article  CAS  Google Scholar 

  9. Agace WW (2006) Tissue-tropic effector T cells: generation and targeting opportunities. Nat Rev Immunol 6:682–692

    Article  CAS  Google Scholar 

  10. de Kivit S, Tobin MC, Forsyth CB, Keshavarzian A, Landay AL (2014) Regulation of intestinal immune responses through TLR activation: implications for pro- and prebiotics. Front Immunol 5:60

    Article  Google Scholar 

  11. Jeon SG, Kayama H, Ueda Y, Takahashi T, Asahara T, Tsuji H et al (2012) Probiotic Bifidobacterium breve induces IL-10-producing Tr1 cells in the colon. PLoS Pathog 8:e1002714

    Article  CAS  Google Scholar 

  12. Isono A, Katsuno T, Sato T, Nakagawa T, Kato Y, Sato N et al (2007) Clostridium butyricum TO-A culture supernatant downregulates TLR4 in human colonic epithelial cells. Dig Dis Sci 52:2963–2971

    Article  Google Scholar 

  13. Hayashi A, Sato T, Kamada N, Mikami Y, Matsuoka K, Hisamatsu T et al (2013) A single strain of Clostridium butyricum induces intestinal IL-10-producing macrophages to suppress acute experimental colitis in mice. Cell Host Microbe 13:711–722

    Article  CAS  Google Scholar 

  14. Mazmanian SK, Round JL, Kasper DL (2008) A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453:620–625

    Article  CAS  Google Scholar 

  15. Vizoso Pinto MG, Rodriguez Gomez M, Seifert S, Watzl B, Holzapfel WH, Franz CM (2009) Lactobacilli stimulate the innate immune response and modulate the TLR expression of HT29 intestinal epithelial cells in vitro. Int J Food Microbiol 133:86–93

    Article  CAS  Google Scholar 

  16. Furrie E, Macfarlane S, Thomson G, Macfarlane GT, Microbiology and Gut Biology Group et al (2005) Toll-like receptors-2, -3 and -4 expression patterns on human colon and their regulation by mucosal-associated bacteria. Immunology 115:565–574

    Article  CAS  Google Scholar 

  17. Kingma SD, Li N, Sun F, Valladares RB, Neu J, Lorca GL (2011) Lactobacillus johnsonii N6.2 stimulates the innate immune response through Toll-like receptor 9 in Caco-2 cells and increases intestinal crypt Paneth cell number in biobreeding diabetes-prone rats. J Nutr 141:1023–1028

    Article  CAS  Google Scholar 

  18. Such J, Frances R, Munoz C, Zapater P, Casellas JA, Cifuentes A et al (2002) Detection and identification of bacterial DNA in patients with cirrhosis and culture-negative, nonneutrocytic ascites. Hepatology 36:135–141

    Article  CAS  Google Scholar 

  19. Guarner C, Gonzalez-Navajas JM, Sanchez E, Soriano G, Frances R, Chiva M et al (2006) The detection of bacterial DNA in blood of rats with CCl(4)-induced cirrhosis with ascites represents episodes of bacterial translocation. Hepatology 44:633–639

    Article  CAS  Google Scholar 

  20. Gautreaux MD, Gelder FB, Deitch EA, Berg RD (1995) Adoptive transfer of T lymphocytes to T-cell-depleted mice inhibits Escherichia coli translocation from the gastrointestinal tract. Infect Immun 63:3827–3834

    CAS  Google Scholar 

  21. Choudhry MA, Fazal N, Goto M, Gamelli RL, Sayeed MM (2002) Gut-associated lymphoid T cell suppression enhances bacterial translocation in alcohol and burn injury. Am J Physiol Gastrointest Liver Physiol 282:G937–G947

    Article  CAS  Google Scholar 

  22. Stenstad H, Ericsson A, Johansson-Lindbom B, Svensson M, Marsal J, Mack M et al (2006) Gut-associated lymphoid tissue-primed CD4 + T cells display CCR9-dependent and -independent homing to the small intestine. Blood 107:3447–3454

    Article  CAS  Google Scholar 

  23. Chu PS, Nakamoto N, Ebinuma H, Usui S, Saeki K, Matsumoto A et al (2013) C-C motif chemokine receptor 9 positive macrophages activate hepatic stellate cells and promote liver fibrosis in mice. Hepatology 58:337–350

    Article  CAS  Google Scholar 

  24. Hammerich L, Bangen JM, Govaere O, Zimmermann HW, Gassler N, Huss S et al (2014) Chemokine receptor CCR6-dependent accumulation of gammadelta T cells in injured liver restricts hepatic inflammation and fibrosis. Hepatology 59:630–642

    Article  CAS  Google Scholar 

  25. Helwig U, Lammers KM, Rizzello F, Brigidi P, Rohleder V, Caramelli E et al (2006) Lactobacilli, Bifidobacteria and E. coli nissle induce pro- and anti-inflammatory cytokines in peripheral blood mononuclear cells. World J Gastroenterol 12:5978–5986

    CAS  Google Scholar 

  26. Medina M, Izquierdo E, Ennahar S, Sanz Y (2007) Differential immunomodulatory properties of Bifidobacterium logum strains: relevance to probiotic selection and clinical applications. Clin Exp Immunol 150:531–538

    Article  CAS  Google Scholar 

  27. Agrawal S, Agrawal A, Doughty B, Gerwitz A, Blenis J, Van Dyke T et al (2003) Cutting edge: different Toll-like receptor agonists instruct dendritic cells to induce distinct Th responses via differential modulation of extracellular signal-regulated kinase-mitogen-activated protein kinase and c-Fos. J Immunol 171:4984–4989

    Article  CAS  Google Scholar 

  28. Dillon S, Agrawal A, Van Dyke T, Landreth G, McCauley L, Koh A et al (2004) A Toll-like receptor 2 ligand stimulates Th2 responses in vivo, via induction of extracellular signal-regulated kinase mitogen-activated protein kinase and c-Fos in dendritic cells. J Immunol 172:4733–4743

    Article  CAS  Google Scholar 

  29. Redecke V, Hacker H, Datta SK, Fermin A, Pitha PM, Broide DH et al (2004) Cutting edge: activation of Toll-like receptor 2 induces a Th2 immune response and promotes experimental asthma. J Immunol 172:2739–2743

    Article  CAS  Google Scholar 

  30. Plantinga TS, van Maren WW, van Bergenhenegouwen J, Hameetman M, Nierkens S, Jacobs C et al (2011) Differential Toll-like receptor recognition and induction of cytokine profile by Bifidobacterium breve and Lactobacillus strains of probiotics. Clin Vaccine Immunol 18:621–628

    Article  CAS  Google Scholar 

  31. Hartmann P, Haimerl M, Mazagova M, Brenner DA, Schnabl B (2012) Toll-like receptor 2-mediated intestinal injury and enteric tumor necrosis factor receptor I contribute to liver fibrosis in mice. Gastroenterology 143(1330–1340):e1331

    Google Scholar 

  32. Frances R, Zapater P, Gonzalez-Navajas JM, Munoz C, Cano R, Moreu R et al (2008) Bacterial DNA in patients with cirrhosis and noninfected ascites mimics the soluble immune response established in patients with spontaneous bacterial peritonitis. Hepatology 47:978–985

    Article  CAS  Google Scholar 

  33. Moorthy G, Murali MR, Devaraj SN (2009) Lactobacilli facilitate maintenance of intestinal membrane integrity during Shigella dysenteriae 1 infection in rats. Nutrition 25:350–358

    Article  CAS  Google Scholar 

  34. Khailova L, Dvorak K, Arganbright KM, Halpern MD, Kinouchi T, Yajima M et al (2009) Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 297:G940–G949

    Article  CAS  Google Scholar 

  35. Mennigen R, Nolte K, Rijcken E, Utech M, Loeffler B, Senninger N et al (2009) Probiotic mixture VSL#3 protects the epithelial barrier by maintaining tight junction protein expression and preventing apoptosis in a murine model of colitis. Am J Physiol Gastrointest Liver Physiol 296:G1140–G1149

    Article  CAS  Google Scholar 

  36. Zhou YK, Qin HL, Zhang M, Shen TY, Chen HQ, Ma YL et al (2012) Effects of Lactobacillus plantarum on gut barrier function in experimental obstructive jaundice. World J Gastroenterol 18:3977–3991

    Article  Google Scholar 

  37. Sanchez E, Nieto JC, Boullosa A, Vidal S, Sancho FJ, Rossi G, et al. (2014) VSL#3 probiotic treatment decreases bacterial translocation in rats with carbon tetrachloride-induced cirrhosis. Liver Int 34:1504–1512

    Article  Google Scholar 

  38. Velayudham A, Dolganiuc A, Ellis M, Petrasek J, Kodys K, Mandrekar P et al (2009) VSL#3 probiotic treatment attenuates fibrosis without changes in steatohepatitis in a diet-induced nonalcoholic steatohepatitis model in mice. Hepatology 49:989–997

    Article  CAS  Google Scholar 

  39. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB et al (2003) Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology 37:343–350

    Article  CAS  Google Scholar 

Download references

Acknowledegments

This work has been supported by grants PI13/1443 from the Instituto de Salud Carlos III, Madrid, Spain, and AGL2011-25169 from MINECO, Spain; Moratalla A. is recipient of a grant ACIF-2012/015, Consellería d’Educació, Generalitat Valenciana, Spain. A. Moya is recipient of a FPU scholarship from MINECO, Spain.

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Rubén Francés.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moratalla, A., Gómez-Hurtado, I., Moya-Pérez, Á. et al. Bifidobacterium pseudocatenulatum CECT7765 promotes a TLR2-dependent anti-inflammatory response in intestinal lymphocytes from mice with cirrhosis. Eur J Nutr 55, 197–206 (2016). https://doi.org/10.1007/s00394-015-0837-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00394-015-0837-x

Keywords

Navigation