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The microbiome and innate immunity

Abstract

The intestinal microbiome is a signalling hub that integrates environmental inputs, such as diet, with genetic and immune signals to affect the host's metabolism, immunity and response to infection. The haematopoietic and non-haematopoietic cells of the innate immune system are located strategically at the host–microbiome interface. These cells have the ability to sense microorganisms or their metabolic products and to translate the signals into host physiological responses and the regulation of microbial ecology. Aberrations in the communication between the innate immune system and the gut microbiota might contribute to complex diseases.

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Figure 1: Intestinal epithelial cells orchestrate the host–microbiota interface.
Figure 2: The integration of microbial signals by myeloid cells.
Figure 3: The integration of microbial signals by ILCs.
Figure 4: The hierarchy of anatomy in microbiome–innate-immune-system interactions.
Figure 5: Microbiome–innate-immune-system interactions are involved in multifactorial diseases.

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References

  1. Thaiss, C. A., Levy, M., Itav, S. & Elinav, E. Integration of innate immune signaling. Trends Immunol. 37, 84–101 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  3. Shibolet, O. & Podolsky, D. K. TLRs in the gut. IV. Negative regulation of Toll-like receptors and intestinal homeostasis: addition by subtraction. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1469–G1473 (2007).

    Article  CAS  PubMed  Google Scholar 

  4. 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). Refs 4 and 5 highlight the importance of innate-immune-system recognition of the microbiota for host–microbiota homeostasis.

    Article  CAS  PubMed  Google Scholar 

  5. Slack, E. et al. Innate and adaptive immunity cooperate flexibly to maintain host–microbiota mutualism. Science 325, 617–620 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Pfeiffer, J. K. & Virgin, H. W. Transkingdom control of viral infection and immunity in the mammalian intestine. Science 351, aad5872 (2016).

    Article  PubMed  CAS  Google Scholar 

  7. Underhill, D. M. & Pearlman, E. Immune interactions with pathogenic and commensal fungi: a two-way street. Immunity 43, 845–858 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Thaiss, C. A., Levy, M., Suez, J. & Elinav, E. The interplay between the innate immune system and the microbiota. Curr. Opin. Immunol. 26, 41–48 (2014).

    Article  CAS  PubMed  Google Scholar 

  9. Pott, J. & Hornef, M. Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep. 13, 684–698 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Vaishnava, S. et al. The antibacterial lectin RegIIIγ promotes the spatial segregation of microbiota and host in the intestine. Science 334, 255–258 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Vlantis, K. et al. TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice. Gut http://dx.doi.org/10.1136/gutjnl-2014-308323 (2015).

  13. Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. Günther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  15. Takahashi, N. et al. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513, 95–99 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  16. Welz, P.-S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Couturier-Maillard, A. et al. NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J. Clin. Invest. 123, 700–711 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Nigro, G., Rossi, R., Commere, P. H., Jay, P. & Sansonetti, P. J. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 15, 792–798 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Ramanan, D., Tang, M. S., Bowcutt, R., Loke, P. & Cadwell, K. Bacterial sensor Nod2 prevents inflammation of the small intestine by restricting the expansion of the commensal Bacteroides vulgatus. Immunity 41, 311–324 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).

    Article  ADS  CAS  PubMed  Google Scholar 

  21. Nordlander, S., Pott, J. & Maloy, K. J. NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen. Mucosal Immunol. 7, 775–785 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Sellin, M. E. et al. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16, 237–248 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Allam, R. et al. Epithelial NAIPs protect against colonic tumorigenesis. J. Exp. Med. 212, 369–383 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hu, B. et al. Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc. Natl Acad. Sci. USA 107, 21635–21640 (2010).

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  25. Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015). Refs 25–29 demonstrate the role of epithelial NLRP6 in orchestrating antimicrobial peptide production, mucus secretion and viral recognition.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wlodarska, M. et al. NLRP6 inflammasome orchestrates the colonic host–microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045–1059 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Elinav, E. et al. NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745–757 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Normand, S. et al. Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc. Natl Acad. Sci. USA 108, 9601–9606 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang, P. et al. Nlrp6 regulates intestinal antiviral innate immunity. Science 350, 826–830 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  30. Macia, L. et al. Metabolite-sensing receptors GPR43 and GPR109A facilitate dietary fibre-induced gut homeostasis through regulation of the inflammasome. Nature Commun. 6, 6734 (2015).

    Article  ADS  CAS  Google Scholar 

  31. Singh, N. et al. Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40, 128–139 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hu, S. et al. The DNA sensor AIM2 maintains intestinal homeostasis via regulation of epithelial antimicrobial host defense. Cell Rep. 13, 1922–1936 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Man, S. M. et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell 162, 45–58 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Song-Zhao, G. X. et al. Nlrp3 activation in the intestinal epithelium protects against a mucosal pathogen. Mucosal Immunol. 7, 763–774 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Kelly, C. J. et al. Crosstalk between microbiota-derived short-chain fatty acids and intestinal epithelial HIF augments tissue barrier function. Cell Host Microbe 17, 662–671 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Venkatesh, M. et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 41, 296–310 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chimerel, C. et al. Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 9, 1202–1208, (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mukherji, A., Kobiita, A., Ye, T. & Chambon, P. Homeostasis in intestinal epithelium is orchestrated by the circadian clock and microbiota cues transduced by TLRs. Cell 153, 812–827 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Thaiss, C. A. & Elinav, E. Exploring new horizons in microbiome research. Cell Host Microbe 15, 662–667 (2014).

    Article  CAS  Google Scholar 

  40. Zarrinpar, A., Chaix, A., Yooseph, S. & Panda, S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab. 20, 1006–1017 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Khosravi, A. et al. Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host Microbe 15, 374–381 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Balmer, M. L. et al. Microbiota-derived compounds drive steady-state granulopoiesis via MyD88/TICAM signaling. J. Immunol. 193, 5273–5283 (2014).

    Article  CAS  PubMed  Google Scholar 

  43. Trompette, A. et al. Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis. Nature Med. 20, 159–166 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Deshmukh, H. S. et al. The microbiota regulates neutrophil homeostasis and host resistance to Escherichia coli K1 sepsis in neonatal mice. Nature Med. 20, 524–530 (2014).

    Article  CAS  PubMed  Google Scholar 

  45. Gomez de Agüero, M. et al. The maternal microbiota drives early postnatal innate immune development. Science 351, 1296–1302 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  46. Zhang, D. et al. Neutrophil ageing is regulated by the microbiome. Nature 525, 528–532 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hill, D. A. et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nature Med. 18, 538–546 (2012).

    Article  CAS  PubMed  Google Scholar 

  48. Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nature Neurosci. 18, 965–977 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Tamoutounour, S. et al. Origins and functional specialization of macrophages and of conventional and monocyte-derived dendritic cells in mouse skin. Immunity 39, 925–938 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Kim, Y. G. et al. Gut dysbiosis promotes M2 macrophage polarization and allergic airway inflammation via fungi-induced PGE2. Cell Host Microbe 15, 95–102 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Chang, P. V., Hao, L., Offermanns, S. & Medzhitov, R. The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proc. Natl Acad. Sci. USA 111, 2247–2252 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Bain, C. C. et al. Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nature Immunol. 15, 929–937 (2014).

    Article  CAS  Google Scholar 

  53. Muller, P. A. et al. Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158, 300–313 (2014); erratum 158, 1210 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fonseca, D. M. et al. Microbiota-dependent sequelae of acute infection compromise tissue-specific immunity. Cell 163, 354–366 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Ganal, S. C. et al. Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity 37, 171–186 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Schwab, L. et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nature Med. 20, 648–654 (2014).

    Article  CAS  PubMed  Google Scholar 

  57. Oh, J. Z. et al. TLR5-mediated sensing of gut microbiota is necessary for antibody responses to seasonal influenza vaccination. Immunity 41, 478–492 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Iida, N. et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342, 967–970 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).

    Article  ADS  CAS  PubMed  Google Scholar 

  60. Sanos, S. L. et al. RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22-producing NKp46+ cells. Nature Immunol. 10, 83–91 (2009).

    Article  ADS  CAS  Google Scholar 

  61. Satoh-Takayama, N. et al. Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29, 958–970 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Sawa, S. et al. RORγt+ innate lymphoid cells regulate intestinal homeostasis by integrating negative signals from the symbiotic microbiota. Nature Immunol. 12, 320–326 (2011).

    Article  ADS  CAS  Google Scholar 

  63. Sonnenberg, G. F. et al. Innate lymphoid cells promote anatomical containment of lymphoid-resident commensal bacteria. Science 336, 1321–1325 (2012). Refs 63–65 demonstrate a role for innate lymphoid cells in the local containment of the microbiota and in regulating T-cell responses to the microbiota.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hepworth, M. R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hepworth, M. R. et al. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348, 1031–1035 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mortha, A. et al. Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343, 1249288 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  67. Kinnebrew, M. A. et al. Interleukin 23 production by intestinal CD103+CD11b+ dendritic cells in response to bacterial flagellin enhances mucosal innate immune defense. Immunity 36, 276–287 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kruglov, A. A. et al. Nonredundant function of soluble LTα3 produced by innate lymphoid cells in intestinal homeostasis. Science 342, 1243–1246 (2013).

    Article  ADS  CAS  PubMed  Google Scholar 

  69. Goto, Y. et al. Innate lymphoid cells regulate intestinal epithelial cell glycosylation. Science 345, 1254009 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Sonnenberg, G. F. & Artis, D. Innate lymphoid cell interactions with microbiota: implications for intestinal health and disease. Immunity 37, 601–610 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. von Moltke, J., Ji, M., Liang, H. E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature 529, 221–225 (2016).

    Article  ADS  CAS  PubMed  Google Scholar 

  72. Powell, N. et al. The transcription factor T-bet regulates intestinal inflammation mediated by interleukin-7 receptor+ innate lymphoid cells. Immunity 37, 674–684 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Levy, M., Thaiss, C. A. & Elinav, E. Metagenomic cross-talk: the regulatory interplay between immunogenomics and the microbiome. Genome Med. 7, 120 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Petnicki-Ocwieja, T. et al. Nod2 is required for the regulation of commensal microbiota in the intestine. Proc. Natl Acad. Sci. USA 106, 15813–15818 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  75. Vijay-Kumar, M. et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228–231 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  76. Pickard, J. M. et al. Rapid fucosylation of intestinal epithelium sustains host-commensal symbiosis in sickness. Nature 514, 638–641 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. Kamdar, K. et al. Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease. Cell Host Microbe 19, 21–31 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Ubeda, C. et al. Familial transmission rather than defective innate immunity shapes the distinct intestinal microbiota of TLR-deficient mice. J. Exp. Med. 209, 1445–1456 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001). This study provided initial insight into the effects of commensal bacteria on genome-wide transcriptional reprogramming.

    Article  ADS  CAS  PubMed  Google Scholar 

  80. Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can replace the beneficial function of commensal bacteria. Nature 516, 94–98 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  81. Rakoff-Nahoum, S. et al. Analysis of gene-environment interactions in postnatal development of the mammalian intestine. Proc. Natl Acad. Sci. USA 112, 1929–1936 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. Sommer, F., Nookaew, I., Sommer, N., Fogelstrand, P. & Backhed, F. Site-specific programming of the host epithelial transcriptome by the gut microbiota. Genome Biol. 16, 62 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Leone, V. et al. Effects of diurnal variation of gut microbes and high-fat feeding on host circadian clock function and metabolism. Cell Host Microbe 17, 681–689 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Rawls, J. F., Mahowald, M. A., Ley, R. E. & Gordon, J. I. Reciprocal gut microbiota transplants from zebrafish and mice to germ-free recipients reveal host habitat selection. Cell 127, 423–433 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Chung, H. et al. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 149, 1578–1593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Patrick, S. et al. A unique homologue of the eukaryotic protein-modifier ubiquitin present in the bacterium Bacteroides fragilis, a predominant resident of the human gastrointestinal tract. Microbiology 157, 3071–3078 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Neish, A. S. et al. Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science 289, 1560–1563 (2000).

    Article  ADS  CAS  PubMed  Google Scholar 

  88. Kumar, A. et al. Commensal bacteria modulate cullin-dependent signaling via generation of reactive oxygen species. EMBO J. 26, 4457–4466 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kelly, D. et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nature Immunol. 5, 104–112 (2004).

    Article  CAS  Google Scholar 

  90. Zhang, Q. et al. Commensal bacteria direct selective cargo sorting to promote symbiosis. Nature Immunol. 16, 918–926 (2015).

    Article  CAS  Google Scholar 

  91. Camp, J. G. et al. Microbiota modulate transcription in the intestinal epithelium without remodeling the accessible chromatin landscape. Genome Res. 24, 1504–1516 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Takahashi, K. et al. Epigenetic control of the host gene by commensal bacteria in large intestinal epithelial cells. J. Biol. Chem. 286, 35755–35762 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  94. Alenghat, T. et al. Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis. Nature 504, 153–157 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chen, G. Y., Liu, M., Wang, F., Bertin, J. & Nunez, G. A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J. Immunol. 186, 7187–7194 (2011).

    Article  CAS  PubMed  Google Scholar 

  96. Jiang, W. et al. Recognition of gut microbiota by NOD2 is essential for the homeostasis of intestinal intraepithelial lymphocytes. J. Exp. Med. 210, 2465–2476 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  98. Franchi, L. et al. NLRC4-driven production of IL-1β discriminates between pathogenic and commensal bacteria and promotes host intestinal defense. Nature Immunol. 13, 449–456 (2012).

    Article  CAS  Google Scholar 

  99. Zheng, Y. et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nature Med. 14, 282–289 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Diehl, G. E. et al. Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells. Nature 494, 116–120 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  101. Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004). This seminal study defined the lymph-node-restricted 'firewall' circuits that control the local containment of the microbiota.

    Article  ADS  CAS  PubMed  Google Scholar 

  102. Sano, T. et al. An IL-23R/IL-22 circuit regulates epithelial serum amyloid A to promote local effector Th17 responses. Cell 163, 381–393 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Naik, S. et al. Commensal–dendritic-cell interaction specifies a unique protective skin immune signature. Nature 520, 104–108 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  104. Balmer, M. L. et al. The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota. Sci. Transl. Med. 6, 237ra66 (2014).

    Article  PubMed  CAS  Google Scholar 

  105. Zeissig, S. & Blumberg, R. S. Life at the beginning: perturbation of the microbiota by antibiotics in early life and its role in health and disease. Nature Immunol. 15, 307–310 (2014).

    Article  CAS  Google Scholar 

  106. Henao-Mejia, J. et al. Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482, 179–185 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  107. Luo, Y. et al. Microbiota from obese mice regulate hematopoietic stem cell differentiation by altering the bone niche. Cell Metab. 22, 886–894 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Abt, M. C. et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 37, 158–170 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ichinohe, T. et al. Microbiota regulates immune defense against respiratory tract influenza A virus infection. Proc. Natl Acad. Sci. USA 108, 5354–5359 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nice, T. J. et al. Interferon-λ cures persistent murine norovirus infection in the absence of adaptive immunity. Science 347, 269–273 (2015).

    Article  ADS  CAS  PubMed  Google Scholar 

  111. Zhang, B. et al. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 346, 861–865 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hernández, P. P. et al. Interferon-λ and interleukin 22 act synergistically for the induction of interferon-stimulated genes and control of rotavirus infection. Nature Immunol. 16, 698–707 (2015).

    Article  CAS  Google Scholar 

  113. Baldridge, M. T. et al. Commensal microbes and interferon-λ determine persistence of enteric murine norovirus infection. Science 347, 266–269 (2015).

    Article  ADS  CAS  PubMed  Google Scholar 

  114. Kane, M. et al. Successful transmission of a retrovirus depends on the commensal microbiota. Science 334, 245–249 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kuss, S. K. et al. Intestinal microbiota promote enteric virus replication and systemic pathogenesis. Science 334, 249–252 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  116. Guo, X. et al. Innate lymphoid cells control early colonization resistance against intestinal pathogens through ID2-dependent regulation of the microbiota. Immunity 42, 731–743 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kamada, N. et al. Regulated virulence controls the ability of a pathogen to compete with the gut microbiota. Science 336, 1325–1329 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  118. Behnsen, J. et al. The cytokine IL-22 promotes pathogen colonization by suppressing related commensal bacteria. Immunity 40, 262–273 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Maekawa, T. et al. Porphyromonas gingivalis manipulates complement and TLR signaling to uncouple bacterial clearance from inflammation and promote dysbiosis. Cell Host Microbe 15, 768–778 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Carvalho, F. A. et al. Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12, 139–152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rigottier-Gois, L. Dysbiosis in inflammatory bowel diseases: the oxygen hypothesis. ISME J. 7, 1256–1261 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hugot, J. P. et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 411, 599–603 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  123. Ogura, Y. et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 411, 603–606 (2001).

    Article  ADS  CAS  PubMed  Google Scholar 

  124. Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nature Genet. 39, 207–211 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Rioux, J. D. et al. Genome-wide association study identifies new susceptibility loci for Crohn disease and implicates autophagy in disease pathogenesis. Nature Genet. 39, 596–604 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Iliev, I. D. et al. Interactions between commensal fungi and the C-type lectin receptor Dectin-1 influence colitis. Science 336, 1314–1317 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  127. Kostic, A. D. et al. The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host Microbe 17, 260–273 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Wen, L. et al. Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455, 1109–1113 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  129. Scher, J. U. et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Stefka, A. T. et al. Commensal bacteria protect against food allergen sensitization. Proc. Natl Acad. Sci. USA 111, 13145–13150 (2014).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  131. Ji, Y. et al. Diet-induced alterations in gut microflora contribute to lethal pulmonary damage in TLR2/TLR4-deficient mice. Cell Rep. 8, 137–149 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nature Rev. Immunol. 11, 98–107 (2011).

    Article  CAS  Google Scholar 

  133. Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006). One of the first studies to link dysbiosis to disease.

    Article  ADS  PubMed  Google Scholar 

  134. Wang, X. et al. Interleukin-22 alleviates metabolic disorders and restores mucosal immunity in diabetes. Nature 514, 237–241 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  135. Le Chatelier, E. et al. Richness of human gut microbiome correlates with metabolic markers. Nature 500, 541–546 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Yang, T. et al. Gut dysbiosis is linked to hypertension. Hypertension 65, 1331–1340 (2015).

    Article  CAS  PubMed  Google Scholar 

  137. Rune, I. et al. Modulating the gut microbiota improves glucose tolerance, lipoprotein profile and atherosclerotic plaque development in ApoE-deficient mice. PLoS ONE 11, e0146439 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Koren, O. et al. Human oral, gut, and plaque microbiota in patients with atherosclerosis. Proc. Natl Acad. Sci. USA 108 (suppl.), 4592–4598 (2011).

    Article  ADS  CAS  PubMed  Google Scholar 

  139. Koeth, R. A. et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nature Med. 19, 576–585 (2013). Refs 139–141 explore the causative involvement of specific bacterial metabolites in metabolic disease.

    Article  ADS  CAS  PubMed  Google Scholar 

  140. Wang, Z. et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  141. Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Jin, C., Henao-Mejia, J. & Flavell, R. A. Innate immune receptors: key regulators of metabolic disease progression. Cell Metab. 17, 873–882 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Irrazábal, T., Belcheva, A., Girardin, S. E., Martin, A. & Philpott, D. J. The multifaceted role of the intestinal microbiota in colon cancer. Mol. Cell 54, 309–320 (2014).

    Article  PubMed  CAS  Google Scholar 

  144. Grivennikov, S. I. et al. Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491, 254–258 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sivan, A. et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350, 1084–1089 (2015).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  146. Ahern, P. P., Faith, J. J. & Gordon, J. I. Mining the human gut microbiota for effector strains that shape the immune system. Immunity 40, 815–823 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Zmora, N., Zeevi, D., Korem, T., Segal, E. & Elinav, E. Taking it personally: personalized utilization of the human microbiome in health and disease. Cell Host Microbe 19, 12–20 (2016).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We apologize to those authors whose relevant work could not be included owing to space constraints. We thank the members of the Elinav laboratory for discussions. C.A.T. received a Boehringer Ingelheim Fonds PhD fellowship. N.Z. is supported by the Gilead Sciences International Research Scholars Program in Liver Disease. E.E. is supported by: Y. and R. Ungar; the Abisch Frenkel Foundation for the Promotion of Life Sciences; the Gurwin Family Fund for Scientific Research; the Leona M. and Harry B. Helmsley Charitable Trust; the Crown Endowment Fund for Immunological Research; the estate of J. Gitlitz; the estate of L. Hershkovich; the Benoziyo Endowment Fund for the Advancement of Science; the Adelis Foundation; J. L. and V. Schwartz; A. and G. Markovitz; A. and C. Adelson; the French National Center for Scientific Research (CNRS); D. L. Schwarz; the V. R. Schwartz Research Fellow Chair; L. Steinberg; J. N. Halpern; A. Edelheit; grants funded by the European Research Council; a Marie Curie Career Integration Grant; the German–Israeli Foundation for Scientific Research and Development; the Israel Science Foundation; the Minerva Foundation; the Rising Tide Foundation; the Helmholtz Association; and the European Foundation for the Study of Diabetes. E.E. is the incumbent of the Rina Gudinski Career Development Chair.

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Thaiss, C., Zmora, N., Levy, M. et al. The microbiome and innate immunity. Nature 535, 65–74 (2016). https://doi.org/10.1038/nature18847

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