Home LiteratureArticle Details
PMID: 19343057 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

The gut microbiota shapes intestinal immune responses during health and disease.

Nature reviews. Immunology ·Vol. 9 ·No. 5 ·2009-05-00 ·Pages 313-23

Round JL, Mazmanian SK

Abstract

Immunological dysregulation is the cause of many non-infectious human diseases such as autoimmunity, allergy and cancer. The gastrointestinal tract is the primary site of interaction between the host immune system and microorganisms, both symbiotic and pathogenic. In this Review we discuss findings indicating that developmental aspects of the adaptive immune system are influenced by bacterial colonization of the gut. We also highlight the molecular pathways that mediate host-symbiont interactions that regulate proper immune function. Finally, we present recent evidence to support that disturbances in the bacterial microbiota result in dysregulation of adaptive immune cells, and this may underlie disorders such as inflammatory bowel disease. This raises the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.

MeSH Terms
Animals Disease Health Homeostasis/immunology Humans Immune System Phenomena/immunology Inflammatory Bowel Diseases/immunology,microbiology Intestines/immunology,microbiology
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Round June L
Division of Biology, California Institute of Technology, Pasadena, California 91125, USA.
Mazmanian Sarkis K
References (104)
104 references, click to expand
  1. Biodiversity of the mucosa-associated microbiota is stable along the distal digestive tract in healthy individuals and patients with IBD.
    Inflamm Bowel Dis. 2005 May;11(5):473-80 PMID: 15867587
  2. Probiotics ameliorate recurrent Th1-mediated murine colitis by inducing IL-10 and IL-10-dependent TGF-beta-bearing regulatory cells.
    J Immunol. 2005 Mar 15;174(6):3237-46 PMID: 15749854
  3. Increased susceptibility to primary infection with Listeria monocytogenes in germfree mice may be due to lack of accumulation of L-selectin+ CD44+ T cells in sites of inflammation.
    Infect Immun. 1996 Aug;64(8):3280-7 PMID: 8757865
  4. Effect of intestinal microbiota on the induction of regulatory CD25+ CD4+ T cells.
    Clin Exp Immunol. 2008 Jul;153(1):127-35 PMID: 18460018
  5. Defects in mucosal immunity leading to ulcerative colitis.
    Immunol Rev. 2005 Aug;206:296-305 PMID: 16048556
  6. Gastrointestinal microbiology enters the metagenomics era.
    Curr Opin Gastroenterol. 2008 Jan;24(1):4-10 PMID: 18043225
  7. A model of host-microbial interactions in an open mammalian ecosystem.
    Science. 1996 Sep 6;273(5280):1380-3 PMID: 8703071
  8. Immune responses that adapt the intestinal mucosa to commensal intestinal bacteria.
    Immunology. 2005 Jun;115(2):153-62 PMID: 15885120
  9. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3.
    Nat Immunol. 2005 Apr;6(4):331-7 PMID: 15785758
  10. Commensal host-bacterial relationships in the gut.
    Science. 2001 May 11;292(5519):1115-8 PMID: 11352068
  11. How regulatory T cells work.
    Nat Rev Immunol. 2008 Jul;8(7):523-32 PMID: 18566595
  12. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice.
    Infect Immun. 1998 Nov;66(11):5224-31 PMID: 9784526
  13. Pathways of T cell pathology in models of chronic intestinal inflammation.
    Int Rev Immunol. 2000;19(1):1-37 PMID: 10723675
  14. Specific microbiota direct the differentiation of IL-17-producing T-helper cells in the mucosa of the small intestine.
    Cell Host Microbe. 2008 Oct 16;4(4):337-49 PMID: 18854238
  15. An ecological and evolutionary perspective on human-microbe mutualism and disease.
    Nature. 2007 Oct 18;449(7164):811-8 PMID: 17943117
  16. IL-23 plays a key role in Helicobacter hepaticus-induced T cell-dependent colitis.
    J Exp Med. 2006 Oct 30;203(11):2485-94 PMID: 17030948
  17. Interactions between commensal intestinal bacteria and the immune system.
    Nat Rev Immunol. 2004 Jun;4(6):478-85 PMID: 15173836
  18. Role of intestinal microflora in chronic inflammation and ulceration of the rat colon.
    Gut. 1994 Aug;35(8):1090-7 PMID: 7926912
  19. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria.
    Science. 2004 Mar 12;303(5664):1662-5 PMID: 15016999
  20. Impaired regulatory T cell function in germ-free mice.
    Eur J Immunol. 2006 Sep;36(9):2336-46 PMID: 16897813
  21. Complex genetics of obesity in mouse models.
    Annu Rev Nutr. 2008;28:331-45 PMID: 18435591
  22. An obesity-associated gut microbiome with increased capacity for energy harvest.
    Nature. 2006 Dec 21;444(7122):1027-31 PMID: 17183312
  23. CEACAM6 acts as a receptor for adherent-invasive E. coli, supporting ileal mucosa colonization in Crohn disease.
    J Clin Invest. 2007 Jun;117(6):1566-74 PMID: 17525800
  24. Inflammatory bowel disease: an immunity-mediated condition triggered by bacterial infection with Helicobacter hepaticus.
    Infect Immun. 1997 Aug;65(8):3126-31 PMID: 9234764
  25. Evolution of mammals and their gut microbes.
    Science. 2008 Jun 20;320(5883):1647-51 PMID: 18497261
  26. Crohn's disease.
    Lancet. 2002 Jan 5;359(9300):62-9 PMID: 11809204
  27. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system.
    Cell. 2007 Oct 5;131(1):33-45 PMID: 17923086
  28. The response of the germfree guinea pig to oral bacterial challenge with Escherichia coli and Shigella flexneri.
    Am J Pathol. 1961 Dec;39:681-95 PMID: 13915950
  29. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.
    Immunol Rev. 2006 Aug;212:8-27 PMID: 16903903
  30. Experimental Shigella infections in laboratory animals. I. Antagonism by human normal flora components in gnotobiotic mice.
    Infect Immun. 1972 Aug;6(2):168-73 PMID: 4631914
  31. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis.
    Nature. 2008 Nov 27;456(7221):507-10 PMID: 18987631
  32. Commensal bacteria as targets in Crohn's disease.
    Gastroenterology. 2000 Jul;119(1):254-7 PMID: 10889177
  33. Host-bacterial coevolution and the search for new drug targets.
    Curr Opin Chem Biol. 2008 Feb;12(1):109-14 PMID: 18280814
  34. Influence of intestinal bacteria on induction of regulatory T cells: lessons from a transfer model of colitis.
    Gut. 2005 Nov;54(11):1546-52 PMID: 15987795
  35. Development of the human infant intestinal microbiota.
    PLoS Biol. 2007 Jul;5(7):e177 PMID: 17594176
  36. Exploring the relationships between intestinal microflora and inflammatory conditions of the human bowel and spine.
    Antonie Van Leeuwenhoek. 2002 Aug;81(1-4):529-35 PMID: 12448748
  37. B-1 cells and their reactivity with the murine intestinal microflora.
    Semin Immunol. 1996 Feb;8(1):11-8 PMID: 8850294
  38. Induction of colitis by a CD4+ T cell clone specific for a bacterial epitope.
    Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15830-5 PMID: 14673119
  39. The human microbiome: eliminating the biomedical/environmental dichotomy in microbial ecology.
    Environ Microbiol. 2007 Jan;9(1):3-4 PMID: 17227400
  40. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients.
    Proc Natl Acad Sci U S A. 2008 Oct 28;105(43):16731-6 PMID: 18936492
  41. Commensal-induced regulatory T cells mediate protection against pathogen-stimulated NF-kappaB activation.
    PLoS Pathog. 2008 Aug 01;4(8):e1000112 PMID: 18670628
  42. Commensal-dependent expression of IL-25 regulates the IL-23-IL-17 axis in the intestine.
    J Exp Med. 2008 Sep 29;205(10):2191-8 PMID: 18762568
  43. Mucosal immunity and inflammation. II. The yin and yang of T cells in intestinal inflammation: pathogenic and protective roles in a mouse colitis model.
    Am J Physiol. 1999 Jun;276(6):G1317-21 PMID: 10362634
  44. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice.
    Gastroenterology. 2007 Jun;132(7):2359-70 PMID: 17570211
  45. Microbial ecology: human gut microbes associated with obesity.
    Nature. 2006 Dec 21;444(7122):1022-3 PMID: 17183309
  46. The influence of normal microbial flora on the development of chronic mucosal inflammation.
    Res Immunol. 1997 Oct-Dec;148(8-9):567-76 PMID: 9588836
  47. Trawling for treasure: tales of T-bet.
    Nat Immunol. 2007 May;8(5):448-50 PMID: 17440449
  48. Salmonella enterica serovar typhimurium exploits inflammation to compete with the intestinal microbiota.
    PLoS Biol. 2007 Oct;5(10):2177-89 PMID: 17760501
  49. Effect of antibiotics on bacterial flora of rats with intestinal blind loops.
    Proc Soc Exp Biol Med. 1969 Oct;132(1):63-7 PMID: 4310178
  50. Immunology. Regulating the regulators.
    Science. 2003 Feb 14;299(5609):1030-1 PMID: 12586934
  51. Mucosal antibodies in inflammatory bowel disease are directed against intestinal bacteria.
    Gut. 1996 Mar;38(3):365-75 PMID: 8675088
  52. Interleukin-23 drives innate and T cell-mediated intestinal inflammation.
    J Exp Med. 2006 Oct 30;203(11):2473-83 PMID: 17030949
  53. Therapeutic manipulation of the enteric microflora in inflammatory bowel diseases: antibiotics, probiotics, and prebiotics.
    Gastroenterology. 2004 May;126(6):1620-33 PMID: 15168372
  54. Aberrant expansion of segmented filamentous bacteria in IgA-deficient gut.
    Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1981-6 PMID: 14766966
  55. The current future understanding of inflammatory bowel disease.
    Best Pract Res Clin Gastroenterol. 2002 Dec;16(6):933-43 PMID: 12473299
  56. Metagenomic approaches for defining the pathogenesis of inflammatory bowel diseases.
    Cell Host Microbe. 2008 Jun 12;3(6):417-27 PMID: 18541218
  57. Pandemic of atopic diseases--a lack of microbial exposure in early infancy?
    Curr Drug Targets Infect Disord. 2002 Sep;2(3):193-9 PMID: 12462124
  58. Bacteriological and immunological aspects of conventional and germfree mice infected with Salmonella typhimurium.
    Rev Latinoam Microbiol. 1991 Oct-Dec;33(4):239-43 PMID: 1670260
  59. A microbial symbiosis factor prevents intestinal inflammatory disease.
    Nature. 2008 May 29;453(7195):620-5 PMID: 18509436
  60. Intragastric infection of germfree and conventional mice with Salmonella typhimurium.
    Braz J Med Biol Res. 1989;22(11):1389-92 PMID: 2700668
  61. The environmental influence on childhood asthma.
    Allergy. 1999;54 Suppl 49:17-23 PMID: 10422743
  62. Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL.
    Immunity. 2007 Jun;26(6):812-26 PMID: 17570691
  63. ATP drives lamina propria T(H)17 cell differentiation.
    Nature. 2008 Oct 9;455(7214):808-12 PMID: 18716618
  64. The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats.
    J Exp Med. 1994 Dec 1;180(6):2359-64 PMID: 7964509
  65. Generation of antigen-specific, Foxp3-expressing CD4+ regulatory T cells by inhibition of APC proteosome function.
    J Immunol. 2005 Mar 1;174(5):2787-95 PMID: 15728488
  66. Interleukin-23 restrains regulatory T cell activity to drive T cell-dependent colitis.
    Immunity. 2008 Apr;28(4):559-70 PMID: 18400195
  67. Gut microbiota composition and development of atopic manifestations in infancy: the KOALA Birth Cohort Study.
    Gut. 2007 May;56(5):661-7 PMID: 17047098
  68. Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells.
    Nature. 2007 Aug 23;448(7156):929-33 PMID: 17713535
  69. Microbial influences in inflammatory bowel diseases.
    Gastroenterology. 2008 Feb;134(2):577-94 PMID: 18242222
  70. Commensal DNA limits regulatory T cell conversion and is a natural adjuvant of intestinal immune responses.
    Immunity. 2008 Oct 17;29(4):637-49 PMID: 18835196
  71. Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis.
    Cell. 2004 Jul 23;118(2):229-41 PMID: 15260992
  72. The human microbiome project.
    Nature. 2007 Oct 18;449(7164):804-10 PMID: 17943116
  73. Does the microbiota regulate immune responses outside the gut?
    Trends Microbiol. 2004 Dec;12(12):562-8 PMID: 15539116
  74. Genomic and metabolic studies of the impact of probiotics on a model gut symbiont and host.
    PLoS Biol. 2006 Nov;4(12):e413 PMID: 17132046
  75. Linking genetic susceptibility to Crohn's disease with Th17 cell function: IL-22 serum levels are increased in Crohn's disease and correlate with disease activity and IL23R genotype status.
    Inflamm Bowel Dis. 2008 Feb;14(2):204-12 PMID: 18022867
  76. Creating and maintaining the gastrointestinal ecosystem: what we know and need to know from gnotobiology.
    Microbiol Mol Biol Rev. 1998 Dec;62(4):1157-70 PMID: 9841668
  77. Increase in the population of duodenal immunoglobulin A plasmocytes in axenic mice associated with different living or dead bacterial strains of intestinal origin.
    Infect Immun. 1978 Aug;21(2):532-9 PMID: 357289
  78. Role of intestinal flora in the development of allergy.
    Curr Opin Allergy Clin Immunol. 2003 Feb;3(1):15-20 PMID: 12582309
  79. IgA response to symbiotic bacteria as a mediator of gut homeostasis.
    Cell Host Microbe. 2007 Nov 15;2(5):328-39 PMID: 18005754
  80. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases.
    Proc Natl Acad Sci U S A. 2007 Aug 21;104(34):13780-5 PMID: 17699621
  81. Role of commensal bacteria in chronic experimental colitis: lessons from the HLA-B27 transgenic rat.
    Pathobiology. 2002-2003;70(3):131-8 PMID: 12571416
  82. Ecological and evolutionary forces shaping microbial diversity in the human intestine.
    Cell. 2006 Feb 24;124(4):837-48 PMID: 16497592
  83. The gut flora as a forgotten organ.
    EMBO Rep. 2006 Jul;7(7):688-93 PMID: 16819463
  84. Microbial interference and colonization of the murine gastrointestinal tract by Listeria monocytogenes.
    Infect Immun. 1979 Jan;23(1):168-74 PMID: 106003
  85. TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function.
    Nature. 2008 May 8;453(7192):236-40 PMID: 18368049
  86. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.
    Lancet. 2001 Jun 16;357(9272):1925-8 PMID: 11425413
  87. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans.
    Nat Rev Immunol. 2007 Aug;7(8):585-98 PMID: 17653126
  88. IL23 differentially regulates the Th1/Th17 balance in ulcerative colitis and Crohn's disease.
    Gut. 2008 Dec;57(12):1682-9 PMID: 18653729
  89. The love-hate relationship between bacterial polysaccharides and the host immune system.
    Nat Rev Immunol. 2006 Nov;6(11):849-58 PMID: 17024229
  90. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism.
    J Exp Med. 2007 Aug 6;204(8):1757-64 PMID: 17620361
  91. Culture-independent analyses of temporal variation of the dominant fecal microbiota and targeted bacterial subgroups in Crohn's disease.
    J Clin Microbiol. 2006 Nov;44(11):3980-8 PMID: 16988018
  92. Dual-association of gnotobiotic IL-10-/- mice with 2 nonpathogenic commensal bacteria induces aggressive pancolitis.
    Inflamm Bowel Dis. 2007 Dec;13(12):1457-66 PMID: 17763473
  93. The regulation of IgA class switching.
    Nat Rev Immunol. 2008 Jun;8(6):421-34 PMID: 18483500
  94. The inhibitory cytokine IL-35 contributes to regulatory T-cell function.
    Nature. 2007 Nov 22;450(7169):566-9 PMID: 18033300
  95. Correlation between in vitro and in vivo immunomodulatory properties of lactic acid bacteria.
    World J Gastroenterol. 2007 Jan 14;13(2):236-43 PMID: 17226902
  96. Symbiotic bacteria direct expression of an intestinal bactericidal lectin.
    Science. 2006 Aug 25;313(5790):1126-30 PMID: 16931762
  97. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene.
    Science. 2006 Dec 1;314(5804):1461-3 PMID: 17068223
  98. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice.
    Lab Invest. 1963 Mar;12:355-64 PMID: 14010768
  99. Diversity of the human intestinal microbial flora.
    Science. 2005 Jun 10;308(5728):1635-8 PMID: 15831718
  100. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system.
    Cell. 2005 Jul 15;122(1):107-18 PMID: 16009137
  101. Bacterial contributions to mammalian gut development.
    Trends Microbiol. 2004 Mar;12(3):129-34 PMID: 15001189
  102. Metagenomic analysis of the human distal gut microbiome.
    Science. 2006 Jun 2;312(5778):1355-9 PMID: 16741115
  103. The immunological and genetic basis of inflammatory bowel disease.
    Nat Rev Immunol. 2003 Jul;3(7):521-33 PMID: 12876555
  104. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses.
    Biol Psychiatry. 2009 Feb 1;65(3):263-7 PMID: 18723164
Article Info
Journal
Nature reviews. Immunology
Abbr.
Nat Rev Immunol
ISSN
1474-1741
DOI
10.1038/nri2515
Published
2009-05-00
Pages
313-23
Language
English
Region
England
NLM ID
101124169
PMCID
PMC4095778
Subset
IM
Grants
NIDDK NIH HHS · R01 DK078938 · United States
NIDDK NIH HHS · R01 DK078938-01A2 · United States
Corrections
ErratumIn
-
External Links
PubMed source DOI: 10.1038/nri2515 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2