The gut microbiota in mouse models of inflammatory bowel disease

REVIEW ARTICLE published: 28 February 2014 doi: 10.3389/fcimb.2014.00028 CELLULAR AND INFECTION MICROBIOLOGY The gut microbiota in mouse models of inflammatory bowel disease Kalliopi K. Gkouskou 1,2† , Chrysoula Deligianni 3† , Christos Tsatsanis 3 and Aristides G. Eliopoulos 1,2,4* 1 Molecular and Cellular Biology Laboratory, Division of Basic Sciences, University of Crete Medical School, Heraklion, Greece Laboratory of Translational Medicine and Experimental Therapeutics, University of Crete Medical School, Heraklion, Greece 3 Department of Clinical Chemistry, University of Crete Medical School, Heraklion, Greece 4 Laboratory of Cancer Biology, Institute of Molecular Biology and Biotechnology–FORTH, Heraklion, Greece 2 Edited by: Yiorgos Apidianakis, University of Cyprus, Cyprus Reviewed by: Triantafyllos Chavakis, Technische Univerasität Dresden, Germany Christos Polytarchou, University of California Los Angeles, USA *Correspondence: Aristides G. Eliopoulos, University of Crete Medical School, GR-71003 Heraklion, Crete, Greece e-mail: † These authors have contributed equally to this work. 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: microbiota, colitis, mouse models, IBD, Crohn’s disease INTRODUCTION The lower gastrointestinal tract of healthy adult humans contains more than 100 trillion bacteria (Ley et al., 2008), termed the gut “microbiota,” which are involved in complex interactions with host mucosal epithelial and immune cells and shape fundamental physiological processes such as digestion, energy homeostasis, and development of gut-associated lymphoid tissues (Bakhtiar et al., 2013). Surface antigens and metabolic end-products of gut microbiota modulate the activation of resident immune cells and the production of cytokines which protect against potential pathogens (Cario, 2013). However, this homeostatic relationship is perturbed in inflammatory bowel diseases (IBD), a group of chronic relapsing and remitting disorders of the gastrointestinal tract manifesting as Crohn’s disease (CD) or ulcerative colitis (UC). UC usually affects only the rectum and shows continuous inflammation, whereas CD may occur anywhere along the gastrointestinal tract and is characterized by discontinuous lesions in the intestinal wall. One of the most important and devastating complications of the long-standing inflammation in IBD is colorectal cancer development. The first case of UC-associated carcinoma of the intestine was reported by Crohn and Rosenberg (1925), and CD was connected to cancer in 1945 (Warren and Sommers, 1948). Subsequent studies confirmed that patients with IBD, especially UC, have increased risk for developing colorectal cancer and this risk increases further with the severity of inflammation (reviewed in Danese and Mantovani, 2010; Rubin et al., 2012). Frontiers in Cellular and Infection Microbiology The realization of the intimate relationship between the microbiota and intestinal homeostasis has spurred large collaborative efforts aiming to identify and characterize the microorganisms which associate with health and disease in humans. The European MetaHIT [Metagenomics of the Human Intestinal Tract, (Qin et al., 2010)] project and the Human Microbiome Project [HMP, (Peterson et al., 2009)] explore multi-“omic” data to define the role of human microbiome in health and disease along with the development of a reference set of microbial genome sequences. However, experimental model systems such as the mouse and Drosophila continue to provide critical insight into how hostmicrobiota homeostasis is established, maintained or perturbed (Kostic et al., 2013). Herein, we review the phenotypic, cellular, and molecular characteristics of some of the most widely-used mouse models of experimental IBD and colitis-associated cancer (CAC) and the impact of microbiota on these pathologies (Figure 1). CHEMICAL AND GENETIC MOUSE MODELS OF INFLAMMATORY BOWEL DISEASE AND COLITIS-ASSOCIATED COLON CANCER DEXTRAN SODIUM SULFATE-INDUCED COLITIS An established model of IBD employs the chemical Dextran Sodium Sulfate (DSS). DSS administered to the drinking water in repeated cycles triggers a state of chronic intestinal inflammation by binding to medium-chain-length fatty acids present in the mouse colon, inducing disruption of colonic epithelial barrier (Laroui et al., 2012). The ensuing tissue damage www.frontiersin.org February 2014 | Volume 4 | Article 28 | 1 Gkouskou et al. Gut microbiota in IBD 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 (Treg ) 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 gastroint (...truncated)