Skip to main content

Advertisement

SpringerLink
Log in

Intravenous Injection of Endogenous Microbial Components Abrogates DSS-Induced Colitis

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

The etiology of inflammatory bowel diseases (IBD) is largely unknown, but appears to be perpetuated by uncontrolled responses to antigenic components of the endogenous flora. Tolerance to antigenic stimulation can be achieved by exposure to a given antigen in high amounts (high dose tolerance). Colitis induced by feeding of Dextran Sodium Sulfate (DSS) is an often-used animal model mimicking clinical and histological features of human IBD.

Aims

We investigated whether treatment with high doses of endogenous bacterial components can affect the response to these antigenic components and thus impact the course of the inflammatory response induced by DSS.

Methods

129/SvEv mice were injected intravenously in the tail vein with lysates prepared from fecal material of conventionally-raised mice. Control mice received a solution of bacterial antigen-free lysates prepared from fecal material of germ-free mice. Seven days later, colitis was induced in these mice by introducing DSS (3.5%) in the drinking water for 5 days. Onset and course of the inflammatory response was monitored by assessment of weight loss. Mice were sacrificed at day 7 post colitis induction and tested for histopathologic injury, intestinal cytokine release, and systemic response to bacterial antigens.

Results

Intravenous injection with fecal lysates reduced intestinal and antigen-stimulated systemic pro-inflammatory cytokine release and prevented DSS-induced weight loss and intestinal injury.

Conclusion

Pretreatment with high amount of endogenous bacterial components has a profound tolerogenic effect on the systemic and mucosal immune responses resulting in reduced intestinal inflammation and abrogates colitis-induced weight loss.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Shroff KE, Meslin K, Cebra JJ. Commensal enteric bacteria engender a self-limiting humoral mucosal immune response while permanently colonizing the gut. Infect Immun. 1995;63:3904–3913.

    PubMed  CAS  Google Scholar 

  2. Sydora BC, MacFarlane SM, Lupicki M, et al. An imbalance in mucosal cytokine profile causes transient intestinal inflammation following an animal’s first exposure to faecal bacteria and antigens. Clin Exp Immunol. 2010;161:187–196.

    Article  PubMed  CAS  Google Scholar 

  3. Jump RL, Levine AD. Mechanisms of natural tolerance in the intestine: implications for inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:462–478.

    Article  PubMed  Google Scholar 

  4. Kappler JW, Roehm N, Marrack P. T cell tolerance by clonal elimination in the thymus. Cell. 1987;49:273–280.

    Article  PubMed  CAS  Google Scholar 

  5. Jenkins MK, Pardoll DM, Mizuguchi J, et al. T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol Rev. 1987;95:113–135.

    Article  PubMed  CAS  Google Scholar 

  6. Sakaguchi S. Immunologic tolerance maintained by regulatory T cells: implications for autoimmunity, tumor immunity and transplantation tolerance. Vox Sang. 2002;83:151–153.

    Article  PubMed  Google Scholar 

  7. Walker LS, Abbas AK. The enemy within: keeping self-reactive T cells at bay in the periphery. Nat Rev Immunol. 2002;2:11–19.

    Article  PubMed  CAS  Google Scholar 

  8. Ridge JP, Fuchs EJ, Matzinger P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science. 1996;271:1723–1726.

    Article  PubMed  CAS  Google Scholar 

  9. Sydora BC, Macfarlane SM, Doyle JS, et al. Neonatal exposure to fecal antigens reduces intestinal inflammation. Inflamm Bowel Dis. 2010;17:899–906.

    Article  PubMed  Google Scholar 

  10. Verdu EF, Bercik P, Cukrowska B, et al. Oral administration of antigens from intestinal flora anaerobic bacteria reduces the severity of experimental acute colitis in BALB/c mice. Clin Exp Immunol. 2000;120:46–50.

    Article  PubMed  CAS  Google Scholar 

  11. Konrad A, Mahler M, Flogerzi B, et al. Amelioration of murine colitis by feeding a solution of lysed Escherichia coli. Scand J Gastroenterol. 2003;38:172–179.

    PubMed  CAS  Google Scholar 

  12. Wirtz S, Neufert C, Weigmann B, et al. Chemically induced mouse models of intestinal inflammation. Nat Protoc. 2007;2:541–546.

    Article  PubMed  CAS  Google Scholar 

  13. Yan Y, Kolachala V, Dalmasso G, et al. Temporal and spatial analysis of clinical and molecular parameters in dextran sodium sulfate induced colitis. PLoS ONE. 2009;4:6073.

    Article  Google Scholar 

  14. Kitajima S, Takuma S, Morimoto M. Histological analysis of murine colitis induced by dextran sulfate sodium of different molecular weights. Exp Anim. 2000;49:9–15.

    Article  PubMed  CAS  Google Scholar 

  15. Dieleman LA, Hoentjen F, Qian BF, et al. Reduced ratio of protective versus proinflammatory cytokine responses to commensal bacteria in HLA-B27 transgenic rats. Clin Exp Immunol. 2004;136:30–39.

    Article  PubMed  CAS  Google Scholar 

  16. Sydora BC, Tavernini MM, Wessler A, et al. Lack of interleukin-10 leads to intestinal inflammation, independent of the time at which luminal microbial colonization occurs. Inflamm Bowel Dis. 2003;9:87–97.

    Article  PubMed  Google Scholar 

  17. Madsen KL, Doyle JS, Jewell LD, et al. Lactobacillus species prevents colitis in interleukin 10 gene-deficient mice. Gastroenterology. 1999;116:1107–1114.

    Article  PubMed  CAS  Google Scholar 

  18. Alex P, Zachos NC, Nguyen T, et al. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm Bowel Dis. 2009;15:341–352.

    Article  PubMed  Google Scholar 

  19. Egger B, Bajaj-Elliott M, MacDonald TT, et al. Characterisation of acute murine dextran sodium sulphate colitis: cytokine profile and dose dependency. Digestion. 2000;62:240–248.

    Article  PubMed  CAS  Google Scholar 

  20. Duchmann R, Kaiser I, Hermann E, et al. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol. 1995;102:448–455.

    Article  PubMed  CAS  Google Scholar 

  21. Sakaguchi S. Naturally arising CD4 + regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004;22:531–562.

    Article  PubMed  CAS  Google Scholar 

  22. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.

    Article  PubMed  CAS  Google Scholar 

  23. Uhlig HH, Powrie F. The role of mucosal T lymphocytes in regulating intestinal inflammation. Springer Semin Immunopathol. 2005;27:167–180.

    Article  PubMed  Google Scholar 

  24. Maul J, Loddenkemper C, Mundt P, et al. Peripheral and intestinal regulatory CD4 + CD25(high) T cells in inflammatory bowel disease. Gastroenterology. 2005;128:1868–1878.

    Article  PubMed  CAS  Google Scholar 

  25. O’Mahony C, van der Kleij H, Bienenstock J, et al. Loss of vagal anti-inflammatory effect: in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol. 2009;297:R1118–R1126.

    Article  PubMed  Google Scholar 

  26. Kitajima S, Morimoto M, Sagara E, et al. Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp Anim. 2001;50:387–395.

    Article  PubMed  CAS  Google Scholar 

  27. Weigle WO. Immunological unresponsiveness. Adv Immunol. 1973;16:61–122.

    Article  PubMed  CAS  Google Scholar 

  28. Webb S, Morris C, Sprent J. Extrathymic tolerance of mature T cells: clonal elimination as a consequence of immunity. Cell. 1990;63:1249–1256.

    Article  PubMed  CAS  Google Scholar 

  29. Rocha B, von Boehmer H. Peripheral selection of the T cell repertoire. Science. 1991;251:1225–1228.

    Article  PubMed  CAS  Google Scholar 

  30. Liblau RS, Tisch R, Shokat K, et al. Intravenous injection of soluble antigen induces thymic and peripheral T-cells apoptosis. Proc Natl Acad Sci USA. 1996;93:3031–3036.

    Article  PubMed  CAS  Google Scholar 

  31. Burstein HJ, Abbas AK. In vivo role of interleukin 4 in T cell tolerance induced by aqueous protein antigen. J Exp Med. 1993;177:457–463.

    Article  PubMed  CAS  Google Scholar 

  32. Rizzo LV, Morawetz RA, Miller-Rivero NE, et al. IL-4 and IL-10 are both required for the induction of oral tolerance. J Immunol. 1999;162:2613–2622.

    PubMed  CAS  Google Scholar 

  33. Chen Y, Inobe J, Marks R, et al. Peripheral deletion of antigen-reactive T cells in oral tolerance. Nature. 1995;376:177–180.

    Article  PubMed  CAS  Google Scholar 

  34. Troy AE, Zaph C, Du Y, et al. IL-27 regulates homeostasis of the intestinal CD4 + effector T cell pool and limits intestinal inflammation in a murine model of colitis. J Immunol. 2009;183:2037–2044.

    Article  PubMed  CAS  Google Scholar 

  35. Veltkamp C, Ruhwald R, Giesem T, et al. CD4 + CD25 + cell depletion from the normal CD4 + T cell pool prevents tolerance toward the intestinal flora and leads to chronic colitis in immunodeficient mice. Inflamm Bowel Dis. 2006;12:437–446.

    Article  PubMed  Google Scholar 

  36. Ohkawara T, Nishihira J, Takeda H, et al. Amelioration of dextran sulfate sodium-induced colitis by anti-macrophage migration inhibitory factor antibody in mice. Gastroenterology. 2002;123:256–270.

    Article  PubMed  CAS  Google Scholar 

  37. Horino J, Fujimoto M, Terabe F, et al. Suppressor of cytokine signaling-1 ameliorates dextran sulfate sodium-induced colitis in mice. Int Immunol. 2008;20:753–762.

    Article  PubMed  CAS  Google Scholar 

  38. Dieleman LA, Ridwan BU, Tennyson GS, et al. Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. Gastroenterology. 1994;107:1643–1652.

    PubMed  CAS  Google Scholar 

  39. Kim TW, Seo JN, Suh YH, et al. Involvement of lymphocytes in dextran sulfate sodium-induced experimental colitis. World J Gastroenterol. 2006;12:302–305.

    PubMed  Google Scholar 

  40. Moskophidis D, Lechner F, Pircher H, et al. Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells. Nature. 1993;362:758–761.

    Article  PubMed  CAS  Google Scholar 

  41. Oxenius A, Zinkernagel RM, Hengartner H. Comparison of activation versus induction of unresponsiveness of virus-specific CD4 + and CD8 + T cells upon acute versus persistent viral infection. Immunity. 1998;9:449–457.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Center of Excellence for Gastrointestinal Inflammation and Immunity Research, University of Alberta, Edmonton, AB, T6G 2E1, Canada

    Beate C. Sydora, Eric J. Albert, Rae R. Foshaug & Richard N. Fedorak

  2. Department of Surgery, University of Alberta, Edmonton, AB, Canada

    Thomas A. Churchill

  3. Department of Laboratory Medicine and Pathology, Vernon Jubilee Hospital, Vernon, BC, Canada

    Jason S. G. Doyle

Authors
  1. Beate C. Sydora
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eric J. Albert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rae R. Foshaug
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jason S. G. Doyle
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Thomas A. Churchill
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Richard N. Fedorak
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Beate C. Sydora.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sydora, B.C., Albert, E.J., Foshaug, R.R. et al. Intravenous Injection of Endogenous Microbial Components Abrogates DSS-Induced Colitis. Dig Dis Sci 57, 345–354 (2012). https://doi.org/10.1007/s10620-011-1878-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-011-1878-5

Keywords

Search

Navigation