Box 1: Transmissible murine crypt hyperplasia
Transmissible murine crypt hyperplasia (TMCH) is a hallmark pathological feature of Citrobacter rodentium infection; it accompanies intestinal inflammation during colitis and is defined by a thickening of the colonic mucosa, which is caused by excessive induction of epithelial regeneration and repair mechanisms1, 2, 15, 28. In uninfected mice (see the figure, part a), colonic epithelial cells are continually renewed by Lgr5+ progenitor stem cells, which are found at the base of the crypt. The production of Wingless (WNT) by pericryptal myofibroblasts triggers asymmetric cell division of the colonic stem cells, which forms a replacement stem cell and an undifferentiated transit amplifying (TA) cell108. Following stimulation, TA cells undergo a limited number of cell divisions and migrate from the bottom of the crypt to the luminal surface, where they terminally differentiate and are later lost by shedding and replaced by new cells108. The progression of TMCH varies between mouse strains that are resistant to C. rodentium and those that are susceptible to C. rodentium. Susceptible mouse strains encode the C. rodentium infection 1 (CRI1) locus on chromosome 15, which is ~4 mb and encompasses five genes (rspo2 (which encodes R-spondin 2), eif3e, gm10373, ttc35 and tmem74)20, 109. During C. rodentium infection of susceptible mice (see the figure, part b), pericryptal myofibroblasts secrete the mitogen R-spondin 2, which targets Lgr5+ stem cells and undifferentiated TA cells near the base of the crypts and triggers an excessive intestinal epithelial repair response, which results in an accumulation of undifferentiated colonocytes at the luminal surface and a reduction in the number of goblet cells20. The large increase in TA cell number, combined with bacterial inhibition of colonocyte detachment, causes dramatic crypt elongation44 and characteristic thickening of the colonic mucosa. Importantly, the undifferentiated colonocytes at the luminal surface have decreased expression of the solute carrier family 26, member 3 (SLc26a3) HCO3–Cl− exchanger and carbonic anhydrase IV (Car4), which causes impaired electrolyte absorption and profuse diarrhoea that results in death20, 22. In resistant mice (see the figure, part c), TMCH typically lasts 2–3 weeks and follows a biphasic response, with progressive and regressive phases28, 110. During the progressive phase, mitogens (such as fibroblast growth factor 7 (FGF7)111) and cytokines (for example, Toll-like receptor 2 (TLR2)-dependent production of IL-11 (Ref. 100)) produced by pericryptal myofibroblasts, and other uncharacterized signals trigger cell proliferation via activation of WNT–β-catenin20, STAT3 (signal transducer and activator of transcription 3)100 and phosphatidylinositol 3-kinase–AKT–β-catenin signalling pathways112. TMCH is triggered by the loss of epithelial barrier integrity and the transit of bacteria into the sterile lamina propria100, 108. In mice that have a disrupted colonic epithelium as a result of intrarectal administration of ethanol, heat killed bacteria that express β-intimin trigger TMCH in an interferon-γ (IFNγ)-dependent process that is mediated by interactions between the bacterium and β1 integrins on T cells in the lamina propria111. In response to infection-induced epithelial damage, TLR2 (Refs 57, 100), TLR4 (Refs 58, 100) and myeloid differentiation primary-response protein 88 (MYD88)55 induce inflammation via the MEK, ERK and nuclear factor κB (NF-κB)110 pathways in both epithelial cells and pericryptal myofibroblasts. These innate immune responses, including epithelial repair mechanisms, are modulated by environmental factors, including diet110, probiotic treatment and undefined microbial species that are present in the colonic microbiota of resistant mice25. The regressive phase involves pathogen clearance, the resolution of colitis and inflammation and a return to normal intestinal homeostasis28, 110. Importantly, the epithelial regenerative and repair pathways that are associated with TMCH replicate the pathology and cellular signalling events that are observed in human diseases such as inflammatory bowel disease (IBD), ulcerative colitis and colon tumorigenesis13, 14. Thus, TMCH is a suitable model for the study of such diseases. Figure modified from Ref. 20, Nature Publishing Group.
Medical Research Council (MRC) Centre for Molecular Bacteriology and Infection, Department of Life Sciences, Flowers Building, Imperial College, London SW7 2AZ, UK.
- James W. Collins,
- Valerie F. Crepin &
- Gad Frankel
Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
- Kristie M. Keeney &
- B. Brett Finlay
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
- Vijay A. K. Rathinam &
- Katherine A. Fitzgerald
Competing interests statement
The authors declare no competing interests.
James W. Collins
James W. Collins obtained his Ph.D. from the University of Reading, UK, and is currently a postdoctoral research associate in the Frankel laboratory at Imperial College, London, UK.
Kristie M. Keeney
Kristie M. Keeney obtained her Ph.D. from the University of Michigan, USA, and is currently a Kirschstein National Institutes of Health postdoctoral research fellow in the Finlay laboratory at University of British Columbia, Canada.
Valerie F. Crepin
Valerie F. Crepin obtained her Ph.D. from Nottingham University, UK; she started her postdoctoral training at Imperial College, London, UK, in 2003, and is now a senior research associate in the Frankel laboratory at Imperial College.
Vijay A. K. Rathinam
Vijay A. K. Rathinam received his Veterinary Medicine degree from Madras Veterinary College, India, and his Ph.D from Michigan State University, USA. He carried out his postdoctoral training in the laboratory of Kate Fitzgerald at the University of Massachusetts Medical School, USA. In 2014, he joined the University of Connecticut Health Center, USA, as Assistant Professor in the Department of Immunology.
Katherine A. Fitzgerald
Katherine A. Fitzgerald obtained her Ph.D. from Trinity College Dublin, Ireland. She joined the University of Massachusetts Medical School, USA, in 2002 and is currently Professor of Medicine and Co-director of the Program in Innate Immunity.
B. Brett Finlay
B. Brett Finlay obtained his Ph.D. from the University of Alberta, Canada, and did his postdoctoral training at Stanford University, California, USA. He joined the University of British Columbia, Canada, in 1989 and is currently Professor in the Michael Smith Laboratories and in the Departments of Biochemistry and Molecular Biology and of Microbiology and Immunology. He is a Canadian Institutes of Health Distinguished Investigator and a University of British Columbia Peter Wall Distinguished Professor.
Gad Frankel obtained his Ph.D. from the Hebrew University of Jerusalem, Israel; he did his postdoctoral training at Stanford University, California, USA, the Weizmann Institute, Rehovot, Israel, and Imperial College, London, UK. He was appointed Lecturer at Imperial College in 1998 and was promoted to Reader in 2000 and to Professor in 2002.
- Crohn's disease
A chronic inflammatory disease of the gastrointestinal tract; it primarily affects the ileum and colon and causes recurrent abdominal pain, fatigue, weight loss, blood and mucus in the faeces, and diarrhoea.
- Ulcerative colitis
A chronic inflammatory disease of the colon and rectum that is characterized by recurrent abdominal pain, chills, fever, colitis and diarrhoea.
- Sterilizing immunity
An immune response that completely prevents an infection.
The consumption of faeces.
- H-NS family
(Histone-like nucleoid-structuring family). A family of DNA-binding proteins that bind to AT-rich double-stranded DNA and are involved in transcriptional silencing and bacterial chromosome organization.
- Integration host factor
(IHF). A histone-like DNA-binding protein that binds to consensus sites and bends the DNA to form a nucleoprotein complex that promotes transcription.
- AHL-type quorum sensing system
(N-Acyl-homoserine lactone quorum sensing system). A dedicated communication system that is present in Gram-negative bacteria and is used to regulate specific genes in response to population density via the production of autoinducer 1.
- LuxS quorum sensing system
A communication system that is found in both Gram-positive and Gram-negative bacteria; it controls the expression of virulence genes in a cell density-dependent manner via the production of the signalling molecule autoinducer 2 by luxS.
- C3H/HeJ mice
A substrain of the widely used laboratory mouse strain C3H; they carry a mutation in Tlr4 and are resistant to endotoxin exposure.
- BarA–SirA two-component regulatory system
A two-component system that is present in Salmonella enterica subsp. enterica serovar Typhimurium. BarA encodes a histidine kinase and SirA encodes the response regulator. Following activation, the system triggers a signalling cascade that results in increased expression of virulence genes and decreased expression of motility genes.
(Inducible nitric oxide synthase). A cytosolic enzyme that is found in multiple cell types and that produces nitrous oxide (NO) from L-arginine, following induction by lipopolysaccharide and pro-inflammatory cytokines. It is presumed that the production of NO, in conjunction with superoxide radicals, leads to the formation of antimicrobial reactive nitrogen intermediates, such as peroxynitrite and nitrosothiols, which restrict the growth of invading pathogens.
Macromolecular complexes that are found in the cytosol of haematopoietic cells and are assembled in response to a range of microbial and endogenous danger signals, which leads to the proteolytic activation of the effector protein caspase 1. Inflammasomes typically consist of a receptor, an adaptor molecule (apoptosis-associated speck-like protein containing caspase activation and recruitment domain), and the effector caspase 1.
- Specific pathogen-free mice
Mice that are provided by laboratory animal vendors or are generated in a home laboratory, that have a guaranteed health status and are free of particular pathogens.
- Faecal microbiota transplantation
(FMT). A transplantation process in which the faecal material (including the faecal microbiota) from a healthy donor is transferred into a recipient. Patients are often treated by enema infusion or the consumption of capsules containing donor faeces.
- Intestinal lymphoid follicles
A type of lymphoid tissue that consists of aggregates of B cells, CD4+ T cells and IgA-producing plasma cells, which are found directly underneath the associated epithelium. These follicles are induced following environmental cues from the intestinal microbiota and dietary components.
- RegIII antimicrobial peptides
Secreted antimicrobial peptides that are produced in the gastrointestinal tract and pancreas and consist of a signal peptide and a single C-type lectin domain; they bind to peptidoglycan and are bactericidal for Gram-positive bacteria.
- Trefoil factor
A secretory protein that contains a trefoil motif and is produced by goblet cells in the gastrointestinal mucosa; it is thought to protect against mucosal damage by stabilizing the mucus layer.
- Resistin-like molecule B
A protein that is produced by intestinal goblet cells and is induced by microorganisms; it is thought to regulate innate mucosal immune responses, such as macrophage activation and antimicrobial lectin expression.
- Altered Schaedler flora
(ASF). A cocktail of eight culturable bacterial strains that is used to colonize the gastrointestinal tract of germ-free mice, thereby generating a defined low-complexity microbiota. Notably, different variations of ASF are commercially available.
- Monocolonized mice
Former germ-free mice that have been colonized with a single bacterial strain.
- Humanized microbiota
A term used to describe human microbiota colonizing the mouse gastrointestinal tract.
The complete profile of small-molecule metabolites, such as amino acids, nucleotides, antioxidants, organic acids, vitamins, hormones, drugs and food components that are found within a cell, tissue, organ or entire organism.