The gut microbiota in mouse models of inflammatory bowel disease

Abstract

The intestine and the intestinal immune system have evolved through a symbiotic homeostasis under which a highly diverse microbial flora is maintained in the gastrointestinal tract while pathogenic bacteria are recognized and eliminated. Disruption of the balance between the immune system and the gut microbiota results in the development of multiple pathologies in humans. Inflammatory bowel diseases (IBD) have been associated with alterations in the composition of intestinal flora but whether these changes are causal or result of inflammation is still under dispute. Various chemical and genetic models of IBD have been developed and utilized to elucidate the complex relationship between intestinal epithelium, immune system and the gut microbiota. In this review we describe some of the most commonly used mouse models of colitis and Crohn's disease (CD) and summarize the current knowledge of how changes in microbiota composition may affect intestinal disease pathogenesis. The pursuit of gut-microbiota interactions will no doubt continue to provide invaluable insight into the complex biology of IBD.

Keywords: Crohn's disease; IBD; colitis; microbiota; mouse models.

Figure 1

Schematic representation of known pathogenic events in experimental IBD. Defective TLR and NOD signaling in Paneth epithelial cells leads to reduced “sensing” of bacterial products (yellow and blue circles) and reduced production of anti-microbial peptides. The ensuing disruption of microbiota balance which may also be influenced by the frequent use of antibiotics and/or diet stimulates inflammation that is largely orchestrated by resident dendritic cells (DCs). Their activation by products of pathogenic bacteria induces IL-23 which in turn engages innate lymphoid cells (ILC) to produce IL-22 and IL-17. Inflammation also results in the recruitment of inflammatory DCs which secrete IL-12 and TNF and increase IFNγ, TNF and IL-17-producing Th1/Th17 cells. Cytokines secreted by ILCs and Th1/Th17 cells promote both the recruitment of neutrophils that produce DNA-damaging reactive oxygen species (ROS) and the survival of intestinal epithelial cells (IEC) by the engagement of STAT3 signal transduction, eventually leading to malignant transformation. Suppression of regulatory T cell (T_reg) activity by pro-inflammatory M1 macrophages which secrete high TNF and IL-1 but low IL-10 levels unleashes inflammation and allows macrophages to produce oxidative products and mutagens which are believed to contribute to carcinogenesis. Reduced production of mucus by Goblet cells impacts on microbial composition and gastrointestinal barrier function.