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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.

References

  1. 1

    Xavier, R. J. & Podolsky, D. K. Unravelling the pathogenesis of inflammatory bowel disease. Nature 448, 427–434 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Medzhitov, R. Recognition of microorganisms and activation of the immune response. Nature 449, 819–826 (2007).

    CAS  Google Scholar 

  4. 4

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5

    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).

    CAS  Article  Google Scholar 

  6. 6

    Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease. Nature Rev. Immunol. 8, 458–466 (2008).

    CAS  Article  Google Scholar 

  7. 7

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Honda, K. & Takeda, K. Regulatory mechanisms of immune responses to intestinal bacteria. Mucosal Immunol. 2, 187–196 (2009).

    CAS  Article  Google Scholar 

  9. 9

    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.

    CAS  Article  Google Scholar 

  10. 10

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Frank, D. N. & Pace, N. R. Gastrointestinal microbiology enters the metagenomics era. Curr. Opin. Gastroenterol. 24, 4–10 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Ley, R. E. et al. Obesity alters gut microbial ecology. Proc. Natl Acad. Sci. USA 102, 11070–11075 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16

    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.

    CAS  Article  Google Scholar 

  17. 17

    Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    Hildebrandt, M. A. et al. High-fat diet determines the composition of the murine gut microbiome independently of obesity. Gastroenterology 137, 1716–1724 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20

    Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).

    CAS  Article  Google Scholar 

  21. 21

    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.

    CAS  Article  Google Scholar 

  22. 22

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Kassinen, A. et al. The fecal microbiota of irritable bowel syndrome patients differs significantly from that of healthy subjects. Gastroenterology 133, 24–33 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25

    Othman, M., Aguero, R. & Lin, H. C. Alterations in intestinal microbial flora and human disease. Curr. Opin. Gastroenterol. 24, 11–16 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. 26

    Manichanh, C. et al. Reduced diversity of faecal microbiota in Crohn's disease revealed by a metagenomic approach. Gut 55, 205–211 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 27

    Sokol, H. et al. Low counts of Faecalibacterium prausnitzii in colitis microbiota. Inflamm. Bowel Dis. 15, 1183–1189 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29

    Lupp, C. et al. Host-mediated inflammation disrupts the intestinal microbiota and promotes the overgrowth of Enterobacteriaceae. Cell Host Microbe 2, 119–129 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30

    Stecher, B. et al. Salmonella enterica serovar Typhimurium exploits inflammation to compete with the intestinal microbiota. PLoS Biol. 5, 2177–2189 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32

    Petersen, A. M. et al. A phylogenetic group of Escherichia coli associated with active left-sided inflammatory bowel disease. BMC Microbiol. 9, 171 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Chow, J. & Mazmanian, S. K. A pathobiont of the microbiota balances host colonization and intestinal inflammation. Cell Host Microbe 7, 265–276 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 35

    Eckmann, L. Animal models of inflammatory bowel disease: lessons from enteric infections. Ann. N. Y. Acad. Sci. 1072, 28–38 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  38. 38

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Mundy, R., MacDonald, T. T., Dougan, G., Frankel, G. & Wiles, S. Citrobacter rodentium of mice and man. Cell. Microbiol. 7, 1697–1706 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 43

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. 45

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52

    Haraga, A., Ohlson, M. B. & Miller, S. I. Salmonellae interplay with host cells. Nature Rev. Microbiol. 6, 53–66 (2008).

    CAS  Article  Google Scholar 

  53. 53

    Grassl, G. A. & Finlay, B. B. Pathogenesis of enteric Salmonella infections. Curr. Opin. Gastroenterol. 24, 22–26 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. 54

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Niess, J. H. et al. CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science 307, 254–258 (2005).

    CAS  Article  Google Scholar 

  56. 56

    Vazquez-Torres, A. et al. Extraintestinal dissemination of Salmonella by CD18-expressing phagocytes. Nature 401, 804–808 (1999).

    CAS  Article  Google Scholar 

  57. 57

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 58

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 60

    Hapfelmeier, S. & Hardt, W. D. A mouse model for S. Typhimurium-induced enterocolitis. Trends Microbiol. 13, 497–503 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    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).

    CAS  Article  Google Scholar 

  63. 63

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64

    Valdez, Y. et al. Nramp1 drives an accelerated inflammatory response during Salmonella-induced colitis in mice. Cell. Microbiol. 11, 351–362 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 65

    Stecher, B. et al. Chronic Salmonella enterica serovar Typhimurium-induced colitis and cholangitis in streptomycin-pretreated Nramp1+/+ mice. Infect. Immun. 74, 5047–5057 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 66

    Rieder, F. & Fiocchi, C. Intestinal fibrosis in IBD – a dynamic, multifactorial process. Nature Rev. Gastroenterol. Hepatol. 6, 228–235 (2009).

    CAS  Article  Google Scholar 

  67. 67

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 68

    Sartor, R. B. Mechanisms of disease: pathogenesis of Crohn's disease and ulcerative colitis. Nature Clin. Pract. Gastroenterol. Hepatol. 3, 390–407 (2006).

    CAS  Article  Google Scholar 

  69. 69

    Sears, C. L. Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin. Microbiol. Rev. 22, 349–369 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 70

    Sears, C. L. et al. Association of enterotoxigenic Bacteroides fragilis infection with inflammatory diarrhea. Clin. Infect. Dis. 47, 797–803 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 71

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Prindiville, T. P. et al. Bacteroides fragilis enterotoxin gene sequences in patients with inflammatory bowel disease. Emerg. Infect. Dis. 6, 171–174 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 74

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Wu, S. et al. The Bacteroides fragilis toxin binds to a specific intestinal epithelial cell receptor. Infect. Immun. 74, 5382–5390 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 77

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 78

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  79. 79

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  82. 82

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  83. 83

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 85

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  87. 87

    Fox, J. G. The non-H pylori helicobacters: their expanding role in gastrointestinal and systemic diseases. Gut 50, 273–283 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 88

    On, S. L., Hynes, S. & Wadstrom, T. Extragastric Helicobacter species. Helicobacter 7, (Suppl. 1) 63–67 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Suerbaum, S. et al. The complete genome sequence of the carcinogenic bacterium Helicobacter hepaticus. Proc. Natl Acad. Sci. USA 100, 7901–7906 (2003).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Ward, J. M. et al. Inflammatory large bowel disease in immunodeficient mice naturally infected with Helicobacter hepaticus. Lab. Anim. Sci. 46, 15–20 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    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.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. 96

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    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).

    Article  Google Scholar 

  98. 98

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100

    Dieleman, L. A. et al. Helicobacter hepaticus does not induce or potentiate colitis in interleukin-10-deficient mice. Infect. Immun. 68, 5107–5113 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 101

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    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).

    CAS  Article  Google Scholar 

  103. 103

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. 104

    Erdman, S. E. et al. CD4+CD25+ regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Res. 63, 6042–6050 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    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.

    CAS  Article  Google Scholar 

  106. 106

    Buonocore, S. et al. Innate lymphoid cells drive interleukin-23-dependent innate intestinal pathology. Nature 464, 1371–1375 (2010).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Young, V. B. et al. In vitro and in vivo characterization of Helicobacter hepaticus cytolethal distending toxin mutants. Infect. Immun. 72, 2521–2527 (2004).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 108

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  109. 109

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. 111

    Shen, Z. et al. Cytolethal distending toxin promotes Helicobacter cinaedi-associated typhlocolitis in interleukin-10-deficient mice. Infect. Immun. 77, 2508–2516 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  113. 113

    Dubinsky, M. C. et al. Increased immune reactivity predicts aggressive complicating Crohn's disease in children. Clin. Gastroenterol. Hepatol. 6, 1105–1111 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  114. 114

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  115. 115

    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.

    Article  Google Scholar 

  116. 116

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 117

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Sadlack, B. et al. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75, 253–261 (1993).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 119

    Balish, E. & Warner, T. Enterococcus faecalis induces inflammatory bowel disease in interleukin-10 knockout mice. Am. J. Pathol. 160, 2253–2257 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 120

    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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  122. 122

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  123. 123

    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).

  124. 124

    Damaskos, D. & Kolios, G. Probiotics and prebiotics in inflammatory bowel disease: microflora 'on the scope'. Br. J. Clin. Pharmacol. 65, 453–467 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  125. 125

    Isaacs, K. & Herfarth, H. Role of probiotic therapy in IBD. Inflamm. Bowel Dis. 14, 1597–1605 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  126. 126

    Llopis, M. et al. Lactobacillus casei downregulates commensals' inflammatory signals in Crohn's disease mucosa. Inflamm. Bowel Dis. 15, 275–283 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Sherman, P. M., Ossa, J. C. & Johnson-Henry, K. Unraveling mechanisms of action of probiotics. Nutr. Clin. Pract. 24, 10–14 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  129. 129

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  130. 130

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  132. 132

    Ivanov, I. I. et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell 139, 485–498 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 133

    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).

    CAS  Article  Google Scholar 

  134. 134

    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.

    Article  PubMed  PubMed Central  Google Scholar 

  135. 135

    Guslandi, M., Giollo, P. & Testoni, P. A. A pilot trial of Saccharomyces boulardii in ulcerative colitis. Eur. J. Gastroenterol. Hepatol. 15, 697–698 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  136. 136

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  137. 137

    Dalmasso, G. et al. Saccharomyces boulardii inhibits inflammatory bowel disease by trapping T cells in mesenteric lymph nodes. Gastroenterology 131, 1812–1825 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  138. 138

    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.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  139. 139

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  140. 140

    Snydman, D. R. The safety of probiotics. Clin. Infect. Dis. 46, (Suppl. 2) S104–S111 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  141. 141

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  142. 142

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  143. 143

    Glocker, E. O. et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361, 2033–2045 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  144. 144

    Kobayashi, K. S. et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 307, 731–734 (2005).

    CAS  Article  Google Scholar 

  145. 145

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  146. 146

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  147. 147

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  148. 148

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  149. 149

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  150. 150

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  152. 152

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  153. 153

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  154. 154

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  155. 155

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  156. 156

    Ge, Z. et al. Cytolethal distending toxin is essential for Helicobacter hepaticus colonization in outbred Swiss Webster mice. Infect. Immun. 73, 3559–3567 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  157. 157

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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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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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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