Resident Enteric Bacteria Are Necessary for Development of Spontaneous Colitis and Immune System Activation in Interleukin-10-Deficient Mice

Abstract

Mice with targeted deletion of the gene for interleukin-10 (IL-10) spontaneously develop enterocolitis when maintained in conventional conditions but develop only colitis when kept in specific-pathogen-free (SPF) environments. This study tested the hypothesis that enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in IL-10-deficient mice. IL-10-deficient mice were maintained in either SPF conditions or germfree conditions or were populated with bacteria known to cause colitis in other rodent models. IL-10-deficient mice kept in SPF conditions developed colitis in all segments of the colon (cecum and proximal and distal colon). These mice exhibited immune system activation as evidenced by increased expression of CD44 on CD4+ T cells; increased mesenteric lymph node cell numbers; and increased production of immunoglobulin A (IgA), IgG1, and IL-12 p40 from colon fragment cultures. Mice populated with bacterial strains, including Bacteroides vulgatus, known to induce colitis in other rodent models had minimal colitis. Germfree IL-10-deficient mice had no evidence of colitis or immune system activation. We conclude therefore that resident enteric bacteria are necessary for the development of spontaneous colitis and immune system activation in IL-10-deficient mice.

IL-10: A Multifunctional Cytokine in Viral Infections

“…IL-10-deficient mice develop spontaneous enterocolitis typically driven by microbial insult and dependent on T cell responses [16][17][18]. When these mice are bred in pathogen-free environments or when MyD88 (a key component for pathogen recognition receptor (PRR) signaling) is also knocked out, colitis does not occur implicating the gut microflora as a causal agent [16][17][18][19][20]. IL-10 thus maintains T cell tolerance to commensal 2 Journal of Immunology Research microflora in the gut.…”

The role of infection in the aetiology of inflammatory bowel disease

“…With regards to IBD, it has long been recognised that bacteria are essential to the development of the disease [41], and historical animal models of Crohn's disease have initiated granulomatous change in both mice and rabbits by infiltrating healthy animal tissue with human Crohn's tissue [42,43]. The lack of transmissibility of disease by transfer of stool from human IBD patients to the monkey colon has however been cited as demonstrating a lack of evidence for a specific pathogen [44].…”

Immune regulation and cytotoxic T cell activation of IL-10 agonists – Preclinical and clinical experience

“…This anti-inflammatory role of IL-10 was earliest demonstrated in IL-10 knockout mice who spontaneously develop inflammatory bowel disease (IBD) [31]. Removal of commensal intestinal bacteria by antibiotic treatment protected IL-10 -/-mice from colitis [32], and the prevalence and severity of IBD in IL-10-/-mice is attenuated in SPF facilities. The relevance of this finding has been confirmed in patients carrying a somatic mutation in the IL-10 or the IL10R gene, who spontaneously develop severe, very early onset IBD [16].…”