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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).
Gismera, C. S. & Aladren, B. S. Inflammatory bowel diseases: a disease (s) of modern times? Is incidence still increasing? World J. Gastroenterol. 14, 5491–5498 (2008).
Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).
Anderson, C. A. et al. Investigation of Crohn's disease risk loci in ulcerative colitis further defines their molecular relationship. Gastroenterology 136, 523–529 (2009).
Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nature Genet. 40, 955–962 (2008).
Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease. Nature Rev. Immunol. 8, 458–466 (2008).
Gaya, D. R., Russell, R. K., Nimmo, E. R. & Satsangi, J. New genes in inflammatory bowel disease: lessons for complex diseases? Lancet 367, 1271–1284 (2006).
Honda, K. & Takeda, K. Regulatory mechanisms of immune responses to intestinal bacteria. Mucosal Immunol. 2, 187–196 (2009).
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S. & Medzhitov, R. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118, 229–241 (2004). An influential study that establishes the role of innate immune recognition of the intestinal microbiota in gut homeostasis.
Coombes, J. L., Robinson, N. J., Maloy, K. J., Uhlig, H. H. & Powrie, F. Regulatory T cells and intestinal homeostasis. Immunol. Rev. 204, 184–194 (2005).
Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).
Salzman, N. H. et al. Analysis of 16S libraries of mouse gastrointestinal microflora reveals a large new group of mouse intestinal bacteria. Microbiology 148, 3651–3660 (2002).
Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010). The most comprehensive metagenomic analysis of the human gut microbiome to date.
Frank, D. N. & Pace, N. R. Gastrointestinal microbiology enters the metagenomics era. Curr. Opin. Gastroenterol. 24, 4–10 (2008).
Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).
Frank, D. N. et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 104, 13780–13785 (2007). One of the first large culture-independent studies showing reduced diversity of intestinal microbiota in patients with IBDs.
Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).
Zoetendal, E. G., Rajilic-Stojanovic, M. & de Vos, W. M. High-throughput diversity and functionality analysis of the gastrointestinal tract microbiota. Gut 57, 1605–1615 (2008).
Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716–1724 (2009).
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009). A landmark study characterizing the composition dynamics and stability of the predicted functional capacity of the intestinal microbiome.
Gophna, U., Sommerfeld, K., Gophna, S., Doolittle, W. F. & Veldhuyzen van Zanten, S. J. Differences between tissue-associated intestinal microfloras of patients with Crohn's disease and ulcerative colitis. J. Clin. Microbiol. 44, 4136–4141 (2006).
Bibiloni, R., Mangold, M., Madsen, K. L., Fedorak, R. N. & Tannock, G. W. The bacteriology of biopsies differs between newly diagnosed, untreated, Crohn's disease and ulcerative colitis patients. J. Med. Microbiol. 55, 1141–1149 (2006).
Kassinen, A. et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133, 24–33 (2007).
Othman, M., Aguero, R. & Lin, H. C. Alterations in intestinal microbial flora and human disease. Curr. Opin. Gastroenterol. 24, 11–16 (2008).
Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).
Sokol, H. et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183–1189 (2009).
Hoffmann, C. et al. Community-wide response of the gut microbiota to enteropathogenic Citrobacter rodentium infection revealed by deep sequencing. Infect. Immun. 77, 4668–4678 (2009). One of the first large studies showing that pathogen colonization induces changes in the intestinal microbiota.
Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007).
Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).
Heimesaat, M. M. et al. Shift towards pro-inflammatory intestinal bacteria aggravates acute murine colitis via Toll-like receptors 2 and 4. PLoS ONE 2, e662 (2007).
Petersen, A. M. et al. A phylogenetic group of Escherichia coli associated with active left-sided inflammatory bowel disease. BMC Microbiol. 9, 171 (2009).
Packey, C. D. & Sartor, R. B. Commensal bacteria, traditional and opportunistic pathogens, dysbiosis and bacterial killing in inflammatory bowel diseases. Curr. Opin. Infect. Dis. 22, 292–301 (2009).
Chow, J. & Mazmanian, S. K. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe 7, 265–276 (2010).
Eckmann, L. Animal models of inflammatory bowel disease: lessons from enteric infections. Ann. N. Y. Acad. Sci. 1072, 28–38 (2006).
Uhlig, H. H. & Powrie, F. Mouse models of intestinal inflammation as tools to understand the pathogenesis of inflammatory bowel disease. Eur. J. Immunol. 39, 2021–2026 (2009). One of the most comprehensive reviews on mouse models of intestinal inflammatory diseases, with a focus on immunological mechanisms.
Elson, C. O. et al. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol. Rev. 206, 260–276 (2005).
Pizarro, T. T., Arseneau, K. O., Bamias, G. & Cominelli, F. Mouse models for the study of Crohn's disease. Trends Mol. Med. 9, 218–222 (2003).
Sellon, R. K. et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect. Immun. 66, 5224–5231 (1998).
Mundy, R., MacDonald, T. T., Dougan, G., Frankel, G. & Wiles, S. Citrobacter rodentium of mice and man. Cell. Microbiol. 7, 1697–1706 (2005).
Borenshtein, D., McBee, M. E. & Schauer, D. B. Utility of the Citrobacter rodentium infection model in laboratory mice. Curr. Opin. Gastroenterol. 24, 32–37 (2008). A thoughtful and comprehensive review of the Citrobacter rodentium model and its impact on the study of bacterium-induced intestinal inflammation.
Savkovic, S. D., Villanueva, J., Turner, J. R., Matkowskyj, K. A. & Hecht, G. Mouse model of enteropathogenic Escherichia coli infection. Infect. Immun. 73, 1161–1170 (2005).
Simmons, C. P. et al. Central role for B lymphocytes and CD4+ T cells in immunity to infection by the attaching and effacing pathogen Citrobacter rodentium. Infect. Immun. 71, 5077–5086 (2003).
Wiles, S. et al. Organ. specificity, colonization and clearance dynamics in vivo following oral challenges with the murine pathogen Citrobacter rodentium. Cell. Microbiol. 6, 963–972 (2004).
Maaser, C. et al. Clearance of Citrobacter rodentium requires B cells but not secretory immunoglobulin A (IgA) or IgM antibodies. Infect. Immun. 72, 3315–3324 (2004).
Dennis, A. et al. The p50 subunit of NF-kB is critical for in vivo clearance of the noninvasive enteric pathogen Citrobacter rodentium. Infect. Immun. 76, 4978–4988 (2008).
Gibson, D. L. et al. Toll-like receptor 2 plays a critical role in maintaining mucosal integrity during Citrobacter rodentium-induced colitis. Cell. Microbiol. 10, 388–403 (2008).
Gibson, D. L. et al. MyD88 signalling plays a critical role in host defence by controlling pathogen burden and promoting epithelial cell homeostasis during Citrobacter rodentium-induced colitis. Cell. Microbiol. 10, 618–631 (2008).
Lebeis, S. L., Bommarius, B., Parkos, C. A., Sherman, M. A. & Kalman, D. TLR signaling mediated by MyD88 is required for a protective innate immune response by neutrophils to Citrobacter rodentium. J. Immunol. 179, 566–577 (2007).
Bry, L. & Brenner, M. B. Critical role of T cell-dependent serum antibody, but not the gut-associated lymphoid tissue, for surviving acute mucosal infection with Citrobacter rodentium, an attaching and effacing pathogen. J. Immunol. 172, 433–441 (2004).
Guttman, J. A., Samji, F. N., Li, Y., Vogl, A. W. & Finlay, B. B. Evidence that tight junctions are disrupted due to intimate bacterial contact and not inflammation during attaching and effacing pathogen infection in vivo. Infect. Immun. 74, 6075–6084 (2006).
Haraga, A., Ohlson, M. B. & Miller, S. I. Salmonellae interplay with host cells. Nature Rev. Microbiol. 6, 53–66 (2008).
Grassl, G. A. & Finlay, B. B. Pathogenesis of enteric Salmonella infections. Curr. Opin. Gastroenterol. 24, 22–26 (2008).
Halle, S. et al. Solitary intestinal lymphoid tissue provides a productive port of entry for Salmonella enterica serovar Typhimurium. Infect. Immun. 75, 1577–1585 (2007).
Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).
Vazquez-Torres, A. et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401, 804–808 (1999).
Stecher, B. et al. Comparison of Salmonella enterica serovar Typhimurium colitis in germfree mice and mice pretreated with streptomycin. Infect. Immun. 73, 3228–3241 (2005).
Barthel, M. et al. Pretreatment of mice with streptomycin provides a Salmonella enterica serovar Typhimurium colitis model that allows analysis of both pathogen and host. Infect. Immun. 71, 2839–2858 (2003).
Coombes, B. K. et al. Analysis of the contribution of Salmonella pathogenicity islands 1 and 2 to enteric disease progression using a novel bovine ileal loop model and a murine model of infectious enterocolitis. Infect. Immun. 73, 7161–7169 (2005).
Hapfelmeier, S. & Hardt, W. D. A mouse model for S. Typhimurium-induced enterocolitis. Trends Microbiol. 13, 497–503 (2005).
Hapfelmeier, S. et al. The Salmonella pathogenicity island (SPI)-2 and SPI-1 type III secretion systems allow Salmonella serovar Typhimurium to trigger colitis via MyD88-dependent and MyD88-independent mechanisms. J. Immunol. 174, 1675–1685 (2005).
Uematsu, S. et al. Detection of pathogenic intestinal bacteria by Toll-like receptor 5 on intestinal CD11c+ lamina propria cells. Nature Immunol. 7, 868–874 (2006).
Gazouli, M. et al. Role of functional polymorphisms of NRAMP1 gene for the development of Crohn's disease. Inflamm. Bowel Dis. 14, 1323–1330 (2008).
Valdez, Y. et al. Nramp1 drives an accelerated inflammatory response during Salmonella-induced colitis in mice. Cell. Microbiol. 11, 351–362 (2009).
Stecher, B. et al. Chronic Salmonella enterica serovar Typhimurium-induced colitis and cholangitis in streptomycin-pretreated Nramp1+/+ mice. Infect. Immun. 74, 5047–5057 (2006).
Rieder, F. & Fiocchi, C. Intestinal fibrosis in IBD – a dynamic, multifactorial process. Nature Rev. Gastroenterol. Hepatol. 6, 228–235 (2009).
Grassl, G. A., Valdez, Y., Bergstrom, K. S., Vallance, B. A. & Finlay, B. B. Chronic enteric Salmonella infection in mice leads to severe and persistent intestinal fibrosis. Gastroenterology 134, 768–780 (2008).
Sartor, R. B. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clin. Pract. Gastroenterol. Hepatol. 3, 390–407 (2006).
Sears, C. L. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin. Microbiol. Rev. 22, 349–369 (2009).
Sears, C. L. et al. Association of enterotoxigenic Bacteroides fragilis infection with inflammatory diarrhea. Clin. Infect. Dis. 47, 797–803 (2008).
Sack, R. B. et al. Enterotoxigenic Bacteroides fragilis: epidemiologic studies of its role as a human diarrhoeal pathogen. J. Diarrhoeal Dis. Res. 10, 4–9 (1992).
Prindiville, T. P. et al. Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease. Emerg. Infect. Dis. 6, 171–174 (2000).
Toprak, N. U. et al. A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin. Microbiol. Infect. 12, 782–786 (2006).
Wu, S. et al. A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nature Med. 15, 1016–1022 (2009). An elegant study establishing a mechanistic link between chronic colonization with ETBF and colon tumour induction in a mouse model.
Wu, S. et al. The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infect. Immun. 74, 5382–5390 (2006).
Wu, S., Rhee, K. J., Zhang, M., Franco, A. & Sears, C. L. Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and g-secretase-dependent E-cadherin cleavage. J. Cell Sci. 120, 1944–1952 (2007).
Wu, S., Morin, P. J., Maouyo, D. & Sears, C. L. Bacteroides fragilis enterotoxin induces c-Myc expression and cellular proliferation. Gastroenterology 124, 392–400 (2003).
Rhee, K. J. et al. Induction of persistent colitis by a human commensal, enterotoxigenic Bacteroides fragilis, in wild-type C57BL/6 mice. Infect. Immun. 77, 1708–1718 (2009).
D'Inca, R. et al. Increased intestinal permeability and NOD2 variants in familial and sporadic Crohn's disease. Aliment. Pharmacol. Ther. 23, 1455–1461 (2006).
Buhner, S. et al. Genetic basis for increased intestinal permeability in families with Crohn's disease: role of CARD15 3020insC mutation? Gut 55, 342–347 (2006).
Garcia Rodriguez, L. A., Ruigomez, A. & Panes, J. Acute gastroenteritis is followed by an increased risk of inflammatory bowel disease. Gastroenterology 130, 1588–1594 (2006).
Gradel, K. O. et al. Increased short- and long-term risk of inflammatory bowel disease after Salmonella or Campylobacter gastroenteritis. Gastroenterology 137, 495–501 (2009).
Man, S. M. et al. Campylobacter concisus and other Campylobacter species in children with newly diagnosed Crohn's disease. Inflamm. Bowel Dis. 16, 1008–1016 (2010).
Mansfield, L. S. et al. C57BL/6 and congenic interleukin-10-deficient mice can serve as models of Campylobacter jejuni colonization and enteritis. Infect. Immun. 75, 1099–1115 (2007).
Kalischuk, L. D., Inglis, G. D. & Buret, A. G. Campylobacter jejuni induces transcellular translocation of commensal bacteria via lipid rafts. Gut Pathog. 1, 2 (2009).
Fox, J. G. et al. Gastroenteritis in NF-kB-deficient mice is produced with wild-type Camplyobacter jejuni but not with C. jejuni lacking cytolethal distending toxin despite persistent colonization with both strains. Infect. Immun. 72, 1116–1125 (2004). Important early work on a specific bacterial factor, CDT, with colitogenic potential in susceptible mice.
Fox, J. G. The non-H pylori helicobacters: their expanding role in gastrointestinal and systemic diseases. Gut 50, 273–283 (2002).
On, S. L., Hynes, S. & Wadstrom, T. Extragastric Helicobacter species. Helicobacter 7, (Suppl. 1) 63–67 (2002).
Solnick, J. V. & Schauer, D. B. Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases. Clin. Microbiol. Rev. 14, 59–97 (2001).
Suerbaum, S. et al. The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus. Proc. Natl Acad. Sci. USA 100, 7901–7906 (2003).
Fox, J. G. et al. Helicobacter hepaticus sp. nov., a microaerophilic bacterium isolated from livers and intestinal mucosal scrapings from mice. J. Clin. Microbiol. 32, 1238–1245 (1994).
Ward, J. M. et al. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Lab. Anim. Sci. 46, 15–20 (1996).
Taylor, N. S., Xu, S., Nambiar, P., Dewhirst, F. E. & Fox, J. G. Enterohepatic Helicobacter species are prevalent in mice from commercial and academic institutions in Asia, Europe, and North America. J. Clin. Microbiol. 45, 2166–2172 (2007).
Kullberg, M. C. et al. Helicobacter hepaticus triggers colitis in specific-pathogen-free interleukin-10 (IL-10)-deficient mice through an IL-12- and gamma interferon-dependent mechanism. Infect. Immun. 66, 5157–5166 (1998).
Cahill, R. J. et al. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus. Infect. Immun. 65, 3126–3131 (1997). First description of the H. hepaticus IBD model.
Chin, E. Y., Dangler, C. A., Fox, J. G. & Schauer, D. B. Helicobacter hepaticus infection triggers inflammatory bowel disease in T cell receptor alphabeta mutant mice. Comp. Med. 50, 586–594 (2000).
Burich, A. et al. Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G764-G778 (2001).
Maggio-Price, L. et al. Dual infection with Helicobacter bilis and Helicobacter hepaticus in p-glycoprotein-deficient mdr1a−/− mice results in colitis that progresses to dysplasia. Am. J. Pathol. 166, 1793–1806 (2005).
Ge, Z. et al. Helicobacter hepaticus HHGI1 is a pathogenicity island associated with typhlocolitis in B6.129-IL10tm1Cgn mice. Microbes Infect. 10, 726–733 (2008).
Dieleman, L. A. et al. Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. Infect. Immun. 68, 5107–5113 (2000).
Whary, M. T. et al. Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response. Infect. Immun. 66, 3142–3148 (1998).
Kullberg, M. C. et al. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis. J. Exp. Med. 203, 2485–2494 (2006).
Engle, S. J. et al. Elimination of colon cancer in germ-free transforming growth factor beta 1-deficient mice. Cancer Res. 62, 6362–6366 (2002).
Erdman, S. E. et al. CD4+CD25+ regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 63, 6042–6050 (2003).
Kullberg, M. C. et al. Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope. Proc. Natl Acad. Sci. USA 100, 15830–15835 (2003). Study showing that a T cell clone recognizing a single bacterial epitope of a chronic intestinal pathogen can elicit colitis in H. hepaticus -infected mice.
Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).
Young, V. B. et al. In vitro and in vivo characterization of Helicobacter hepaticus cytolethal distending toxin mutants. Infect. Immun. 72, 2521–2527 (2004).
Sterzenbach, T. et al. Inhibitory effect of enterohepatic Helicobacter hepaticus on innate immune responses of mouse intestinal epithelial cells. Infect. Immun. 75, 2717–2728 (2007).
Fox, J. G. et al. Helicobacter bilis sp. nov., a novel Helicobacter species isolated from bile, livers, and intestines of aged, inbred mice. J. Clin. Microbiol. 33, 445–454 (1995).
Maggio-Price, L. et al. Helicobacter bilis infection accelerates and H. hepaticus infection delays the development of colitis in multiple drug resistance-deficient (mdr1a−/−) mice. Am. J. Pathol. 160, 739–751 (2002).
Shen, Z. et al. Cytolethal distending toxin promotes Helicobacter cinaedi-associated typhlocolitis in interleukin-10-deficient mice. Infect. Immun. 77, 2508–2516 (2009).
Jergens, A. E. et al. Helicobacter bilis triggers persistent immune reactivity to antigens derived from the commensal bacteria in gnotobiotic C3H/HeN mice. Gut 56, 934–940 (2007).
Dubinsky, M. C. et al. Increased immune reactivity predicts aggressive complicating Crohn's disease in children. Clin. Gastroenterol. Hepatol. 6, 1105–1111 (2008).
Niess, J. H., Leithauser, F., Adler, G. & Reimann, J. Commensal gut flora drives the expansion of proinflammatory CD4 T cells in the colonic lamina propria under normal and inflammatory conditions. J. Immunol. 180, 559–568 (2008).
Kim, S. C., Tonkonogy, S. L., Karrasch, T., Jobin, C. & Sartor, R. B. Dual-association of gnotobiotic IL-10−/− mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis. Inflamm. Bowel Dis. 13, 1457–1466 (2007). Seminal study showing that commensal bacteria can induce IBD in predisposed germ-free mice.
Nemoto, Y. et al. Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis. J. Immunol. 183, 5059–5068 (2009).
Karrasch, T., Kim, J. S., Muhlbauer, M., Magness, S. T. & Jobin, C. Gnotobiotic IL-10−/−;NF-kB(EGFP) mice reveal the critical role of TLR/NF-kB signaling in commensal bacteria-induced colitis. J. Immunol. 178, 6522–6532 (2007).
Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).
Balish, E. & Warner, T. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am. J. Pathol. 160, 2253–2257 (2002).
Stecher, B. et al. Like will to like: abundances of closely related species can predict susceptibility to intestinal colonization by pathogenic and commensal bacteria. PLoS Pathog. 6, e1000711 (2010).
Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007). Shows development of a colitogenic microbiota in a predisposed mouse strain that can induce IBD after transfer into wild-type mice.
Prisciandaro, L., Geier, M., Butler, R., Cummins, A. & Howarth, G. Probiotics and their derivatives as treatments for inflammatory bowel disease. Inflamm. Bowel Dis. 15, 1906–1914 (2009).
Behm, B. W. & Bickston, S. J. Tumor necrosis factor-a antibody for maintenance of remission in Crohn's disease. Cochrane Database Syst. Rev. CD006893 (2008).
Damaskos, D. & Kolios, G. Probiotics and prebiotics in inflammatory bowel disease: microflora 'on the scope'. Br. J. Clin. Pharmacol. 65, 453–467 (2008).
Isaacs, K. & Herfarth, H. Role of probiotic therapy in IBD. Inflamm. Bowel Dis. 14, 1597–1605 (2008).
Llopis, M. et al. Lactobacillus casei downregulates commensals' inflammatory signals in Crohn's disease mucosa. Inflamm. Bowel Dis. 15, 275–283 (2009).
Sherman, P. M., Ossa, J. C. & Johnson-Henry, K. Unraveling mechanisms of action of probiotics. Nutr. Clin. Pract. 24, 10–14 (2009).
Lee, H. S. et al. Lactic acid bacteria inhibit proinflammatory cytokine expression and bacterial glycosaminoglycan degradation activity in dextran sulfate sodium-induced colitic mice. Int. Immunopharmacol. 8, 574–580 (2008).
Chen, C. C., Louie, S., Shi, H. N. & Walker, W. A. Preinoculation with the probiotic Lactobacillus acidophilus early in life effectively inhibits murine Citrobacter rodentium colitis. Pediatr. Res. 58, 1185–1191 (2005).
Chen, C. C., Chiu, C. H., Lin, T. Y., Shi, H. N. & Walker, W. A. Effect of probiotics Lactobacillus acidophilus on Citrobacter rodentium colitis: the role of dendritic cells. Pediatr. Res. 65, 169–175 (2009).
Johnson-Henry, K. C. et al. Amelioration of the effects of Citrobacter rodentium infection in mice by pretreatment with probiotics. J. Infect. Dis. 191, 2106–2117 (2005).
Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).
Gaboriau-Routhiau, V. et al. The key role of segmented filamentous bacteria in the coordinated maturation of gut helper T cell responses. Immunity 31, 677–689 (2009).
Waidmann, M. et al. Bacteroides vulgatus protects against Escherichia coli-induced colitis in gnotobiotic interleukin-2-deficient mice. Gastroenterology 125, 162–177 (2003). An important early study showing that probiotic bacteria can prevent bacterium-induced IBD.
Guslandi, M., Giollo, P. & Testoni, P. A. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur. J. Gastroenterol. Hepatol. 15, 697–698 (2003).
Wu, X. et al. Saccharomyces boulardii ameliorates Citrobacter rodentium-induced colitis through actions on bacterial virulence factors. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G295–G306 (2008).
Dalmasso, G. et al. Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes. Gastroenterology 131, 1812–1825 (2006).
Mazmanian, S. K., Round, J. L. & Kasper, D. L. A microbial symbiosis factor prevents intestinal inflammatory disease. Nature 453, 620–625 (2008). Shows that a single bacterial factor, polysaccharide A, produced by B. fragilis , strongly influences susceptibility to intestinal inflammation elicited by a chronic bacterial pathogen.
Feller, M. et al. Mycobacterium avium subspecies paratuberculosis and Crohn's disease: a systematic review and meta-analysis. Lancet Infect. Dis. 7, 607–613 (2007).
Snydman, D. R. The safety of probiotics. Clin. Infect. Dis. 46, (Suppl. 2) S104–S111 (2008).
Cannon, J. P., Lee, T. A., Bolanos, J. T. & Danziger, L. H. Pathogenic relevance of Lactobacillus: a retrospective review of over 200 cases. Eur. J. Clin. Microbiol. Infect. Dis. 24, 31–40 (2005).
Magalhaes, J. G., Tattoli, I. & Girardin, S. E. The intestinal epithelial barrier: how to distinguish between the microbial flora and pathogens. Semin. Immunol. 19, 106–115 (2007).
Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).
Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).
Alex, P. et al. Distinct cytokine patterns identified from multiplex profiles of murine DSS and TNBS-induced colitis. Inflamm. Bowel Dis. 15, 341–352 (2009).
Kitajima, S., Morimoto, M., Sagara, E., Shimizu, C. & Ikeda, Y. Dextran sodium sulfate-induced colitis in germ-free IQI/Jic mice. Exp. Anim. 50, 387–395 (2001).
Beckwith, J., Cong, Y., Sundberg, J. P., Elson, C. O. & Leiter, E. H. Cdcs1, a major colitogenic locus in mice, regulates innate and adaptive immune response to enteric bacterial antigens. Gastroenterology 129, 1473–1484 (2005).
Klapproth, J. M. et al. Citrobacter rodentium lifA/efa1 is essential for colonic colonization and crypt cell hyperplasia in vivo. Infect. Immun. 73, 1441–1451 (2005).
Deng, W., Vallance, B. A., Li, Y., Puente, J. L. & Finlay, B. B. Citrobacter rodentium translocated intimin receptor (Tir) is an essential virulence factor needed for actin condensation, intestinal colonization and colonic hyperplasia in mice. Mol. Microbiol. 48, 95–115 (2003).
Newman, J. V., Zabel, B. A., Jha, S. S. & Schauer, D. B. Citrobacter rodentium espB is necessary for signal transduction and for infection of laboratory mice. Infect. Immun. 67, 6019–6025 (1999).
Hardwidge, P. R. et al. Modulation of host cytoskeleton function by the enteropathogenic Escherichia coli and Citrobacter rodentium effector protein EspG. Infect. Immun. 73, 2586–2594 (2005).
Coulthurst, S. J. et al. Quorum sensing has an unexpected role in virulence in the model pathogen Citrobacter rodentium. EMBO Rep. 8, 698–703 (2007).
Hapfelmeier, S. et al. Role of the Salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice. Infect. Immun. 72, 795–809 (2004).
Stecher, B. et al. Flagella and chemotaxis are required for efficient induction of Salmonella enterica serovar Typhimurium colitis in streptomycin-pretreated mice. Infect. Immun. 72, 4138–4150 (2004).
Nakano, V., Gomes, D. A., Arantes, R. M., Nicoli, J. R. & Avila-Campos, M. J. Evaluation of the pathogenicity of the Bacteroides fragilis toxin gene subtypes in gnotobiotic mice. Curr. Microbiol. 53, 113–117 (2006).
Ge, Z. et al. Cytolethal distending toxin is essential for Helicobacter hepaticus colonization in outbred Swiss Webster mice. Infect. Immun. 73, 3559–3567 (2005).
Pratt, J. S., Sachen, K. L., Wood, H. D., Eaton, K. A. & Young, V. B. Modulation of host immune responses by the cytolethal distending toxin of Helicobacter hepaticus. Infect. Immun. 74, 4496–4504 (2006).
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.
The authors declare no competing financial interests.
Entrez Genome Project
- 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.
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.
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.
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.
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.
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.
About this article
Cite this article
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
Mammalian Genome (2021)
Neurochemistry International (2021)
Life Sciences (2021)
Treatment of Intestinal Inflammation With Epicutaneous Immunotherapy Requires TGF-β and IL-10 but Not Foxp3+ Tregs
Frontiers in Immunology (2021)