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  • Review Article
  • Published:

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

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.

Abstract

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.

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Figure 1: Interactions between the gut microbiota and the intestinal mucosa.
Figure 2: Mouse models of infectious colitis.

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Acknowledgements

We dedicate this Review to the late D. B. Schauer, our long-time friend and colleague, who was an individual striving for perfection, not only in research. He made invaluable contributions to the field of infection-related intestinal inflammation. We sorely miss him. We thank M. Hornef for many helpful discussions and the three anonymous reviewers for expert suggestions. Funding of the work carried out in our laboratory by the SFB621 from the German Research Foundation, the German Ministry of Education and Research (research network Pathogenomics HELDIVNET), the INCA network from the European Union and by the Center of Infection Biology at Hannover Medical School is gratefully acknowledged.

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Supplementary information S1 (table)

Overview of murine models of chronic intestinal inflammation and experimental colitisa (PDF 376 kb)

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DATABASES

Entrez Genome Project

Bacteroides fragilis

Campylobacter jejuni

Citrobacter rodentium

Helicobacter bilis

Helicobacter cinaedi

Helicobacter hepaticus

Helicobacter pylori

Salmonella enterica subspecies enterica serovar Typhimurium

FURTHER INFORMATION

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Christine Josenhans' homepage

Glossary

Crohn's disease

A clinical form of IBD in humans. It is characterized by segmental and transmural granulomatous inflammation that can affect any part of the gastrointestinal tract.

Ulcerative colitis

The second major clinical form of IBD in humans. It causes continuous and mucosal non-granulomatous inflammation restricted to the colon.

Intestinal microbiota

All of the microbial species present in the entire gastrointestinal tract, with density and diversity increasing from stomach to colon.

Commensal

A term derived from the Latin word mensa, meaning “at the table together”, which generally refers to microorganisms that live in symbiotic or mutually beneficial relationships with their mammalian hosts.

Microorganism-associated molecular patterns

Conserved molecular motifs, also known as pathogen-associated molecular patterns, that are characteristic of and common to many species of non-pathogenic and pathogenic microorganisms. They are recognized by PRRs and activate the mammalian innate immune system.

Gut-associated lymphoid tissue

Mucosa-associated lymphoid tissue in the gastrointestinal tract and the principal inductive site for mucosal immune responses in the intestine. It comprises Peyer's patches, the appendix, isolated lymphoid follicles and solitary intestinal lymphoid tissue.

Gut microbiome

The complete set of genes and genomes of the microorganisms present in the intestine, and their phenotypic properties.

Intestinal mucosa

Gastrointestinal tissue composed of a single layer of columnar intestinal epithelial cells and the underlying connective tissue (lamina propria), which contains blood and lymphoid vessels and various types of innate and adaptive immune cells.

Germ-free

Animals that have been raised in a sterile environment without a microbiota and thus are free of microorganisms. Germ-free mice, in contrast to colonized mice, show an underdeveloped immune system, no colonization resistance and require higher caloric intake to maintain body weight.

Specific-pathogen-free

Animals that are free of defined specific pathogenic microorganisms but otherwise are colonized with an undefined microbiota. Using SPF animals guarantees that specific microorganisms do not interfere with an experiment.

Gnotobiotic

A mouse that has been derived from aseptic birth, and in which all life forms are completely defined. This includes both germ-free animals and animals that are colonized after birth with a well-defined microbiota.

Goblet cell

A specific type of differentiated intestinal epithelial cell. They secrete mucus forming the glycocalyx, which strengthens the barrier effect of the intestinal epithelium, and are localized along the whole intestine, with increasing numbers from the small intestine to the colon.

Microfold cell

A specialized cell present in the intestinal epithelium overlying Peyer's patches or smaller lymphoid accumulations. Microfold cells sample antigens from the intestinal lumen and deliver them by transcytosis to antigen-presenting cells and lymphocytes.

Dendritic cell

An antigen-presenting cell. After activation, dendritic cells migrate to lymphoid tissues, where they interact with B and T cells to initiate and shape the adaptive immune response.

Probiotic

A dietary supplement of live microorganisms (bacteria or yeast) that is thought to confer a health benefit to the host organism when ingested in adequate amounts.

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Nell, S., Suerbaum, S. & Josenhans, C. The impact of the microbiota on the pathogenesis of IBD: lessons from mouse infection models. Nat Rev Microbiol 8, 564–577 (2010). https://doi.org/10.1038/nrmicro2403

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