Commensal gut flora reduces susceptibility to experimentally induced colitis via T‐cell‐derived interleukin‐101

Background: Regulatory cytokines are well known to modify experimental colitis in mice. The aim of this study was to elucidate the effect of interleukin (IL)‐10 derived from different cellular sources and the effect of commensal gut flora in dextran sulfate sodium (DSS)‐induced colitis in mice. Methods: Wildtype (WT) and IL‐10 deficient (IL‐10−/−) mice either harboring a characterized specific pathogen‐free (SPF) gut flora or germfree were exposed to 2% DSS. Moreover, cell type‐specific IL‐10, IL‐4, and IL‐12 knockout mice and animals combining the T‐cell‐specific IL‐10 knockout with a deficiency in IL‐12 or IL‐4 were exposed to DSS. Results: SPF IL‐10−/− mice showed an increased susceptibility to DSS‐induced colitis compared to WT mice determined by histopathology and proinflammatory cytokine and chemokine responses. Under germfree conditions, both WT and IL‐10−/− mice were highly susceptible to DSS. IL‐10 mRNA was increased upon DSS exposure in WT SPF but not in germfree mice. Mice carrying a specific deletion of IL‐10 in T‐cells exhibited a tendency towards an enhanced susceptibility to DSS. The lack of T‐cell‐derived IL‐10 in combination with the lack of IL‐4 increased the susceptibility to DSS colitis, as did the lack of IL‐12 alone. Conclusions: IL‐10 is a crucial factor inhibiting the innate proinflammatory immune response induced by DSS. Intestinal bacteria are necessary for the induction of protective IL‐10, which is mainly T‐cell‐derived. T‐cell‐derived IL‐10 can only mediate its protective effect in a Th1‐dominated milieu. If the balance is shifted towards a Th2 response, IL‐10 is not protective. (Inflamm Bowel Dis 2011;)

[1]  L. Groebe,et al.  Monocytes/macrophages and/or neutrophils are the target of IL‐10 in the LPS endotoxemia model , 2010, European journal of immunology.

[2]  A. Schäffer,et al.  Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. , 2009, The New England journal of medicine.

[3]  H. Blöcker,et al.  Charles River altered Schaedler flora (CRASF®) remained stable for four years in a mouse colony housed in individually ventilated cages , 2009, Laboratory animals.

[4]  J. Hansen,et al.  Gene expression patterns in experimental colitis in IL‐10‐deficient mice , 2009, Inflammatory Bowel Diseases.

[5]  F. Gunzer,et al.  Probiotic Escherichia coli Nissle 1917 Inhibits Leaky Gut by Enhancing Mucosal Integrity , 2007, PloS one.

[6]  A. O’Garra,et al.  TH1 cells control themselves by producing interleukin-10 , 2007, Nature Reviews Immunology.

[7]  I. Autenrieth,et al.  Identification of Commensal Bacterial Strains That Modulate Yersinia enterocolitica and Dextran Sodium Sulfate-Induced Inflammatory Responses: Implications for the Development of Probiotics , 2007, Infection and Immunity.

[8]  Werner Müller,et al.  Interleukin‐10 derived from macrophages and/or neutrophils regulates the inflammatory response to LPS but not the response to CpG DNA , 2006, European journal of immunology.

[9]  S. Ahrné,et al.  Bifidobacterium infantis strains with and without a combination of Oligofructose and Inulin (OFI) attenuate inflammation in DSS-induced colitis in rats , 2006, BMC gastroenterology.

[10]  E. Telemo,et al.  Impaired regulatory T cell function in germ‐free mice , 2006, European journal of immunology.

[11]  Young Ho Suh,et al.  Involvement of lymphocytes in dextran sulfate sodium-induced experimental colitis. , 2006, World journal of gastroenterology.

[12]  S. Miura,et al.  Propionibacterium freudenreichii component 1.4-dihydroxy-2-naphthoic acid (DHNA) attenuates dextran sodium sulphate induced colitis by modulation of bacterial flora and lymphocyte homing , 2005, Gut.

[13]  F. Obermeier,et al.  Influence of intestinal bacteria on induction of regulatory T cells: lessons from a transfer model of colitis , 2005, Gut.

[14]  K. Rajewsky,et al.  T Cell–specific Inactivation of the Interleukin 10 Gene in Mice Results in Enhanced T Cell Responses but Normal Innate Responses to Lipopolysaccharide or Skin Irritation , 2004, The Journal of experimental medicine.

[15]  M. Neurath,et al.  Anti-interleukin-12 antibody for active Crohn's disease. , 2004, The New England journal of medicine.

[16]  J. Sundberg,et al.  Refined histopathologic scoring system improves power todetect colitis QTL in mice , 2004, Mammalian Genome.

[17]  Si-young Song,et al.  Retinoic acid imprints gut-homing specificity on T cells. , 2004, Immunity.

[18]  M. Teixeira,et al.  The Essential Role of the Intestinal Microbiota in Facilitating Acute Inflammatory Responses1 , 2004, The Journal of Immunology.

[19]  E. Leiter,et al.  Genetic and environmental context determines the course of colitis developing in IL-10-deficient mice. , 2002, Inflammatory bowel diseases.

[20]  W. M. Weaver,et al.  A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival. , 2001, Immunity.

[21]  S. Kitajima,et al.  Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. , 2001, Experimental animals.

[22]  P. Rutgeerts,et al.  Role of interleukin‐12 in the induction of mucosal inflammation and abrogation of regulatory T cell function in chronic experimental colitis , 2001, European journal of immunology.

[23]  J. Schölmerich,et al.  Different Subsets of Enteric Bacteria Induce and Perpetuate Experimental Colitis in Rats and Mice , 2001, Infection and Immunity.

[24]  M. Büchler,et al.  Characterisation of Acute Murine Dextran Sodium Sulphate Colitis: Cytokine Profile and Dose Dependency , 2000, Digestion.

[25]  J. Schölmerich,et al.  The role of the resident intestinal flora in acute and chronic dextran sulfate sodium‐induced colitis in mice , 2000, European journal of gastroenterology & hepatology.

[26]  W. Reith,et al.  Conditional gene targeting in macrophages and granulocytes using LysMcre mice , 1999, Transgenic Research.

[27]  S. Kitajima,et al.  Changes in colonic mucosal permeability in mouse colitis induced with dextran sulfate sodium. , 1999, Experimental animals.

[28]  R. Sartor,et al.  Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice , 1998, Infection and Immunity.

[29]  H. Okamura,et al.  Role of interleukin-10 in a murine model of dextran sulfate sodium-induced colitis. , 1998, Scandinavian journal of gastroenterology.

[30]  R Morawetz,et al.  Analysis of granuloma formation in double cytokine-deficient mice reveals a central role for IL-10 in polarizing both T helper cell 1- and T helper cell 2-type cytokine responses in vivo. , 1997, Journal of immunology.

[31]  K. Rajewsky,et al.  B lymphocyte-specific, Cre-mediated mutagenesis in mice. , 1997, Nucleic acids research.

[32]  J. Ni,et al.  Effects of dextran sulphate sodium on intestinal epithelial cells and intestinal lymphocytes. , 1996, Gut.

[33]  D. Carvajal,et al.  IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses , 1996 .

[34]  A. Grönberg,et al.  Dextran sulfate sodium (DSS) induced experimental colitis in immunodeficient mice: Effects in CD4+-cell depleted, athymic and NK-cell depleted SCID mice , 1996, Inflammation Research.

[35]  K. Rajewsky,et al.  Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. , 1995, The Journal of clinical investigation.

[36]  M. Neurath,et al.  Antibodies to interleukin 12 abrogate established experimental colitis in mice , 1995, The Journal of experimental medicine.

[37]  C. Elson,et al.  Dextran sulfate sodium-induced colitis occurs in severe combined immunodeficient mice. , 1994, Gastroenterology.

[38]  K. Rajewsky,et al.  Interleukin-10-deficient mice develop chronic enterocolitis , 1993, Cell.

[39]  K. Rajewsky,et al.  Generation and analysis of interleukin-4 deficient mice. , 1991, Science.

[40]  Shizuo Akira,et al.  MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis , 2004, Journal of Gastroenterology.

[41]  J. Lindeberg,et al.  Conditional gene targeting. , 2003, Upsala journal of medical sciences.

[42]  S. Kitajima,et al.  Histological analysis of murine colitis induced by dextran sulfate sodium of different molecular weights. , 2000, Experimental animals.

[43]  D. Carvajal,et al.  IL-12-deficient mice are defective in IFN gamma production and type 1 cytokine responses. , 1996, Immunity.

[44]  T. Ohkusa,et al.  A novel method in the induction of reliable experimental acute and chronic ulcerative colitis in mice. , 1990, Gastroenterology.

[45]  M. Walport,et al.  Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted Mice , 2004, PLoS biology.