Journal Article

The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models

Josenhans, Christine, Suerbaum, Sebastian, Nell, Sandra

2010

Overview

Key Points Inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis, are important human health problems. Their pathogenesis involves both the genetic predisposition of the host and the intestinal microbiota, the highly complex community of bacteria that live in the gut. In addition, infections with certain intestinal pathogens have been shown to increase the risk of IBD development. Experimental models of intestinal inflammation using gene-targeted mice and defined bacteria have proven extremely valuable in dissecting the roles of host and bacterial factors in IBD pathogenesis. Knowledge gained from such models is the central topic of this Review, with a special focus on the role of bacteria and bacterial components in determining the risk of chronic intestinal inflammation. Germ-free mice monoassociated with several specific bacteria have provided insight into particular mechanisms of gut inflammation; some bacteria are not by themselves sufficient to induce intestinal inflammation in germ-free mice, whereas other pathogenic bacteria can induce chronic inflammatory disease alone. For example, Bacteroides fragilis toxin (BFT)-expressing bacteria can cause IBD alone. Mouse models using the Gram-negative enterobacteria Citrobacter rodentium and Salmonella enterica subspecies enterica serovar Typhimurium established that the composition of the intestinal microbiota determines susceptibility to infection, and that a gut infection itself can alter the accompanying microbiota. These models suggest that the reduction of bacterial density and diversity of the intestinal microbiota is likely to determine susceptibility to pathogen infection and chronic disease. These models also provided seminal evidence of the importance of innate immune recognition in the control of inflammatory responses elicited by these organisms. Host susceptibility by genetic deficiencies in the experimentally infected mice was also proven to be a crucial factor that can turn acute into chronic disease. The group of enterohepatic Helicobacter spp., and in particular Helicobacter hepaticus , has been investigated to dissect the role of bacterial and host components in the development of gut inflammation during chronic pathogen infection. Important findings from these models include the importance of different T cell subsets in the control of intestinal immune homeostasis and the development of IBD and colitis, the observation that T cells recognizing a single bacterial antigen can trigger colitis, and that bacterial factors such as the genotoxic cytotoxic distending toxin or the functions encoded on a pathogenicity island can affect disease. These models have also helped to recognize the contribution of the resident microbiota for the development of chronic inflammatory disease and the importance of coinfections. Other models discussed in this Review include enterotoxic B. fragilis (ETBF), Campylobacter spp. and association studies of diverse commensal bacteria, all of which — in our view — contribute unique and relevant perspectives on the complex interactions of bacteria and host cells in the intestine that decide between health and acute or chronic disease. A better understanding of the role of harmful and potentially beneficial microorganisms in IBD pathogenesis could open up new avenues for prevention and therapy of IBD, for example by probiotics; we review results obtained from mouse models that investigate mechanisms of probiotic intervention in IBD and effects of probiotics and their products on gut homeostasis. In this article the authors review what mouse models of intestinal inflammation using gene-targeted mice and defined bacteria have contributed to our understanding of the mechanisms underlying inflammatory bowel disease (IBD), focusing on the specific contribution of bacteria and bacterial components. Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a major human health problem. The bacteria that live in the gut play an important part in the pathogenesis of IBD. However, owing to the complexity of the gut microbiota, our understanding of the roles of commensal and pathogenic bacteria in establishing a healthy intestinal barrier and in its disruption is evolving only slowly. In recent years, mouse models of intestinal inflammatory disorders based on defined bacterial infections have been used intensively to dissect the roles of individual bacterial species and specific bacterial components in the pathogenesis of IBD. In this Review, we focus on the impact of pathogenic and commensal bacteria on IBD-like pathogenesis in mouse infection models and summarize important recent developments.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/1647/767/1424 / 631/326/41/2531 / 692/698/2741/2135 / 692/699/1503/1581/257 / Animals / Bacteria / Bacteria - pathogenicity / Bacterial diseases / Bacterial Physiological Phenomena / Biomedical and Life Sciences / Causes of / Diagnosis / Disease Models, Animal / Gastrointestinal Tract - microbiology / Health aspects / Humans / Infectious Diseases / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory Bowel Diseases - microbiology / Life Sciences / Medical Microbiology / Mice / Microbiology / Microbiota (Symbiotic organisms) / Parasitology / review-article / Virology