Microbiome and Gut Immunity: Innate Immune Cells

  • Till StrowigEmail author
  • Sophie Thiemann
  • Andreas Diefenbach


The innate immune system not only serves as a first line of defense against infections with pathogenic microorganisms but also plays an important role in the balanced interplay with the intestinal microbiota. Distinct subsets of innate immune cells such as macrophages, dendritic cells, granulocytes, mast cells, and innate lymphoid cells are found spread throughout the intestinal tissue as well as organized in tissue-specific lymphoid structures. These cells constantly survey the intestinal tissue for the presence of live microbes to prevent the spread of invading microbes and fine-tune the intestinal barrier. Specifically, metabolites from the commensal microbiota such as short-chain fatty acids have been identified to maintain tolerogenic conditions in the intestine, e.g., promoting regulatory T cells and down-modulating pro-inflammatory signaling pathways. In turn, aberrant recognition and handling of commensal microbes by the innate immune system or the excessive immune activation after pathogen sensing have been demonstrated to promote inflammatory conditions such as inflammatory bowel diseases in the intestine. Hence, the detailed understanding of the interplay between the microbiota and innate immune system may enable novel therapeutic interventions to promote human health and, specifically, to prevent auto-inflammatory diseases.


  1. Bain, C. C., Bravo-Blas, A., Scott, C. L., et al. (2014). Constant replenishment from circulating monocytes maintains the macrophage pool in the intestine of adult mice. Nature Immunology, 15, 929–937.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bauer, S., Groh, V., Wu, J., et al. (1999). Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science, 285, 727–729.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Beura, L. K., Hamilton, S. E., Bi, K., et al. (2016). Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature, 532, 512–516.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bischoff, S. C. (2009). Physiological and pathophysiological functions of intestinal mast cells. Seminars in Immunopathology, 31, 185–205.CrossRefPubMedGoogle Scholar
  5. Björkström, N. K., Ljunggren, H.-G., & Michaëlsson, J. (2016). Emerging insights into natural killer cells in human peripheral tissues. Nature Reviews Immunology, 16, 310–320.CrossRefPubMedGoogle Scholar
  6. Britanova, L., & Diefenbach, A. (2017). Interplay of innate lymphoid cells and the microbiota. Immunological Reviews, 279, 36–51.CrossRefPubMedGoogle Scholar
  7. Brubaker, S. W., Bonham, K. S., Zanoni, I., & Kagan, J. C. (2015). Innate immune pattern recognition: A cell biological perspective. Annual Review of Immunology, 33, 257–290.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bryceson, Y. T., March, M. E., Ljunggren, H.-G., & Long, E. O. (2006). Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood, 107, 159–166.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Buonomo, E. L., Cowardin, C. A., Wilson, M. G., et al. (2016). Microbiota-regulated IL-25 increases eosinophil number to provide protection during Clostridium difficile infection. Cell Reports, 16, 432–443.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Cebra, J. J., Periwal, S. B., Lee, G., et al. (1998). Development and maintenance of the gut-associated lymphoid tissue (GALT): The roles of enteric bacteria and viruses. Developmental Immunology, 6, 13–18.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Cerovic, V., Houston, S. A., Scott, C. L., et al. (2013). Intestinal CD103(-) dendritic cells migrate in lymph and prime effector T cells. Mucosal Immunology, 6, 104–113.CrossRefPubMedGoogle Scholar
  12. Cerovic, V., Bain, C. C., Mowat, A. M., & Milling, S. W. F. (2014). Intestinal macrophages and dendritic cells: What’s the difference? Trends in Immunology, 35, 270–277.CrossRefPubMedGoogle Scholar
  13. Cerwenka, A., Bakker, A. B., McClanahan, T., et al. (2000). Retinoic acid early inducible genes define a ligand family for the activating NKG2D receptor in mice. Immunity, 12, 721–727.CrossRefPubMedGoogle Scholar
  14. Chang, P. V., Hao, L., Offermanns, S., & Medzhitov, R. (2014). The microbial metabolite butyrate regulates intestinal macrophage function via histone deacetylase inhibition. Proceedings of the National Academy of Sciences of the United States of America, 111, 2247–2252.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Chapuy, L., Bsat, M., Mehta, H., et al. (2014). Basophils increase in Crohn disease and ulcerative colitis and favor mesenteric lymph node memory TH17/TH1 response. Journal of Allergy and Clinical Immunology, 134, 978–981.e1.CrossRefPubMedGoogle Scholar
  16. Chu, V. T., Beller, A., Rausch, S., et al. (2014). Eosinophils promote generation and maintenance of immunoglobulin-A-expressing plasma cells and contribute to gut immune homeostasis. Immunity, 40, 582–593 d.CrossRefPubMedGoogle Scholar
  17. Clarke, T. B., Davis, K. M., Lysenko, E. S., et al. (2010). Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nature Medicine, 16, 228–231.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Constantinides, M. G., McDonald, B. D., Verhoef, P. A., & Bendelac, A. (2014). A committed precursor to innate lymphoid cells. Nature, 508, 397–401.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Cording, S., Fleissner, D., Heimesaat, M. M., et al. (2013). Commensal microbiota drive proliferation of conventional and Foxp3(+) regulatory CD4(+) T cells in mesenteric lymph nodes and Peyer’s patches. European Journal of Microbiology and Immunology, 3, 1–10.CrossRefPubMedGoogle Scholar
  20. Daussy, C., Faure, F., Mayol, K., et al. (2014). T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. The Journal of Experimental Medicine, 211, 563–577.CrossRefPubMedPubMedCentralGoogle Scholar
  21. Diefenbach, A., & Raulet, D. H. (2003). Innate immune recognition by stimulatory immunoreceptors. Current Opinion in Immunology, 15, 37–44.CrossRefPubMedGoogle Scholar
  22. Diefenbach, A., Jamieson, A. M., Liu, S. D., et al. (2000). Ligands for the murine NKG2D receptor: Expression by tumor cells and activation of NK cells and macrophages. Nature Immunology, 1, 119–126.CrossRefPubMedGoogle Scholar
  23. Diefenbach, A., Colonna, M., & Koyasu, S. (2014). Development, differentiation, and diversity of innate lymphoid cells. Immunity, 41, 354–365.CrossRefPubMedPubMedCentralGoogle Scholar
  24. Eberl, G., & Lochner, M. (2009). The development of intestinal lymphoid tissues at the interface of self and microbiota. Mucosal Immunology, 2, 478–485.CrossRefPubMedGoogle Scholar
  25. Elinav, E., Strowig, T., Kau, A. L., et al. (2011). NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell, 145, 745–757.CrossRefPubMedPubMedCentralGoogle Scholar
  26. Erny, D., Hrabě de Angelis, A. L., Jaitin, D., et al. (2015). Host microbiota constantly control maturation and function of microglia in the CNS. Nature Neuroscience, 18, 965–977.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Fung, T. C., Bessman, N. J., Hepworth, M. R., et al. (2016). Lymphoid-tissue-resident commensal bacteria promote members of the IL-10 cytokine family to establish mutualism. Immunity, 44, 634–646.CrossRefPubMedPubMedCentralGoogle Scholar
  28. Ganal, S. C., Sanos, S. L., Kallfass, C., et al. (2012). Priming of natural killer cells by nonmucosal mononuclear phagocytes requires instructive signals from commensal microbiota. Immunity, 37, 171–186.CrossRefPubMedGoogle Scholar
  29. Gieseck, R. L., Wilson, M. S., & Wynn, T. A. (2018). Type 2 immunity in tissue repair and fibrosis. Nature Reviews Immunology, 18, 62–76.CrossRefPubMedGoogle Scholar
  30. Gomez de Agüero, M., Ganal-Vonarburg, S. C., Fuhrer, T., et al. (2016). The maternal microbiota drives early postnatal innate immune development. Science, 351, 1296–1302.CrossRefPubMedGoogle Scholar
  31. Gomez, M. R., Talke, Y., Hofmann, C., et al. (2014). Basophils control T-cell responses and limit disease activity in experimental murine colitis. Mucosal Immunology, 7, 188–199.CrossRefPubMedGoogle Scholar
  32. Gorjifard, S., & Goldszmid, R. S. (2016). Microbiota-myeloid cell crosstalk beyond the gut. Journal of Leukocyte Biology, 100, 865–879.CrossRefPubMedGoogle Scholar
  33. Guerra, N., Tan, Y. X., Joncker, N. T., et al. (2008). NKG2D-deficient mice are defective in tumor surveillance in models of spontaneous malignancy. Immunity, 28, 571–580.CrossRefPubMedPubMedCentralGoogle Scholar
  34. Hill, D. A., Siracusa, M. C., Abt, M. C., et al. (2012). Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nature Medicine, 18, 538–546.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Hoyler, T., Klose, C. S. N., Souabni, A., et al. (2012). The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity, 37, 634–648.CrossRefPubMedPubMedCentralGoogle Scholar
  36. Humbles, A. A., Lu, B., Friend, D. S., et al. (2002). The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proceedings of the National Academy of Sciences of the United States of America, 99, 1479–1484.CrossRefPubMedPubMedCentralGoogle Scholar
  37. Jia, W., Xie, G., & Jia, W. (2017). Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis. Nature Reviews Gastroenterology & Hepatology, 5, 172ra122.Google Scholar
  38. Joeris, T., Müller-Luda, K., Agace, W. W., & Mowat, A. M. (2017). Diversity and functions of intestinal mononuclear phagocytes. Mucosal Immunology, 10, 845–864.CrossRefPubMedGoogle Scholar
  39. Kärre, K., Ljunggren, H. G., Piontek, G., & Kiessling, R. (1986). Selective rejection of H-2-deficient lymphoma variants suggests alternative immune defence strategy. Nature, 319, 675–678.CrossRefPubMedGoogle Scholar
  40. Khosravi, A., Yáñez, A., Price, J. G., et al. (2014). Gut microbiota promote hematopoiesis to control bacterial infection. Cell Host & Microbe, 15, 374–381.CrossRefGoogle Scholar
  41. Kiss, E. A., & Vonarbourg, C. (2012). Aryl hydrocarbon receptor: A molecular link between postnatal lymphoid follicle formation and diet. Gut Microbes, 3, 577–582.CrossRefPubMedPubMedCentralGoogle Scholar
  42. Klose, C. S. N., Flach, M., Möhle, L., et al. (2014). Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell, 157, 340–356. Scholar
  43. Knoop, K. A., Gustafsson, J. K., McDonald, K. G., et al. (2017). Microbial antigen encounter during a preweaning interval is critical for tolerance to gut bacteria. Science Immunology, 2, eaao1314.CrossRefPubMedGoogle Scholar
  44. Kunii, J., Takahashi, K., Kasakura, K., et al. (2011). Commensal bacteria promote migration of mast cells into the intestine. Immunobiology, 216, 692–697.CrossRefPubMedGoogle Scholar
  45. Lavin, Y., Mortha, A., Rahman, A., & Merad, M. (2015). Regulation of macrophage development and function in peripheral tissues. Nature Reviews Immunology, 15, 731–744.CrossRefPubMedPubMedCentralGoogle Scholar
  46. Leiding, J. W. (2017). Neutrophil evolution and their diseases in humans. Frontiers in Immunology, 8, 1009.CrossRefPubMedPubMedCentralGoogle Scholar
  47. Lelouard, H., Fallet, M., de Bovis, B., et al. (2012). Peyer’s patch dendritic cells sample antigens by extending dendrites through M cell-specific transcellular pores. Gastroenterology, 142, 592–601.e3.CrossRefPubMedGoogle Scholar
  48. Luu, T. T., Ganesan, S., Wagner, A. K., et al. (2016). Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells. Scientific Reports, 6, 37996.CrossRefPubMedPubMedCentralGoogle Scholar
  49. Magalhaes, J. G., Tattoli, I., & Girardin, S. E. (2007). The intestinal epithelial barrier: How to distinguish between the microbial flora and pathogens. Seminars in Immunology, 19, 106–115.CrossRefPubMedGoogle Scholar
  50. Masterson, J. C., McNamee, E. N., Jedlicka, P., et al. (2011). CCR3 blockade attenuates eosinophilic ileitis and associated remodeling. The American Journal of Pathology, 179, 2302–2314.CrossRefPubMedPubMedCentralGoogle Scholar
  51. McDole, J. R., Wheeler, L. W., McDonald, K. G., et al. (2012). Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature, 483, 345–349.CrossRefPubMedPubMedCentralGoogle Scholar
  52. Merad, M., Sathe, P., Helft, J., et al. (2013). The dendritic cell lineage: Ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annual Review of Immunology, 31, 563–604.CrossRefPubMedGoogle Scholar
  53. Mori, Y., Iwasaki, H., Kohno, K., et al. (2009). Identification of the human eosinophil lineage-committed progenitor: Revision of phenotypic definition of the human common myeloid progenitor. The Journal of Experimental Medicine, 206, 183–193.CrossRefPubMedPubMedCentralGoogle Scholar
  54. Mowat, A. M., Scott, C. L., & Bain, C. C. (2017). Barrier-tissue macrophages: Functional adaptation to environmental challenges. Nature Medicine, 23, 1258–1270.CrossRefPubMedGoogle Scholar
  55. Niess, J. H., Brand, S., Gu, X., et al. (2005). CX3CR1-mediated dendritic cell access to the intestinal lumen and bacterial clearance. Science, 307, 254–258.CrossRefPubMedGoogle Scholar
  56. Ohkubo, T., Tsuda, M., Suzuki, S., et al. (1999). Peripheral blood neutrophils of germ-free rats modified by in vivo granulocyte-colony-stimulating factor and exposure to natural environment. Scandinavian Journal of Immunology, 49, 73–77.CrossRefPubMedGoogle Scholar
  57. Ohno, H. (2016). Intestinal M cells. Journal of Biochemistry, 159, 151–160.CrossRefPubMedGoogle Scholar
  58. Palm, N. W., & Medzhitov, R. (2009). Pattern recognition receptors and control of adaptive immunity. Immunological Reviews, 227, 221–233.CrossRefPubMedGoogle Scholar
  59. Park, J.-S., Lee, E.-J., Lee, J.-C., et al. (2007). Anti-inflammatory effects of short chain fatty acids in IFN-gamma-stimulated RAW 264.7 murine macrophage cells: Involvement of NF-kappaB and ERK signaling pathways. International Immunopharmacology, 7, 70–77.CrossRefPubMedGoogle Scholar
  60. Parlato, M., & Yeretssian, G. (2014). NOD-like receptors in intestinal homeostasis and epithelial tissue repair. International Journal of Molecular Sciences, 15, 9594–9627.CrossRefPubMedPubMedCentralGoogle Scholar
  61. Patten, D. A., & Collett, A. (2013). Exploring the immunomodulatory potential of microbial-associated molecular patterns derived from the enteric bacterial microbiota. Microbiology (Reading, England), 159, 1535–1544.CrossRefGoogle Scholar
  62. Platt, A. M., Bain, C. C., Bordon, Y., et al. (2010). An independent subset of TLR expressing CCR2-dependent macrophages promotes colonic inflammation. Journal of Immunology, 184, 6843–6854.CrossRefGoogle Scholar
  63. Raab, Y., Fredens, K., Gerdin, B., & Hallgren, R. (1998). Eosinophil activation in ulcerative colitis: Studies on mucosal release and localization of eosinophil granule constituents. Digestive Diseases and Sciences, 43, 1061–1070.CrossRefPubMedGoogle Scholar
  64. Rathinam, V. A. K., & Fitzgerald, K. A. (2016). Inflammasome complexes: Emerging mechanisms and effector functions. Cell, 165, 792–800.CrossRefPubMedPubMedCentralGoogle Scholar
  65. Raulet, D. H., Vance, R. E., & McMahon, C. W. (2001). Regulation of the natural killer cell receptor repertoire. Annual Review of Immunology, 19, 291–330.CrossRefPubMedGoogle Scholar
  66. Rivollier, A., He, J., Kole, A., et al. (2012). Inflammation switches the differentiation program of Ly6Chi monocytes from antiinflammatory macrophages to inflammatory dendritic cells in the colon. The Journal of Experimental Medicine, 209, 139–155.CrossRefPubMedPubMedCentralGoogle Scholar
  67. Robertson, S. J., & Girardin, S. E. (2013). Nod-like receptors in intestinal host defense: Controlling pathogens, the microbiota, or both? Current Opinion in Gastroenterology, 29, 15–22.CrossRefPubMedGoogle Scholar
  68. Rosshart, S. P., Vassallo, B. G., Angeletti, D., et al. (2017). Wild mouse gut microbiota promotes host fitness and improves disease resistance. Cell, 171, 1015–1028.e13.CrossRefPubMedGoogle Scholar
  69. Russell, S. L., Gold, M. J., Willing, B. P., et al. (2013). Perinatal antibiotic treatment affects murine microbiota, immune responses and allergic asthma. Gut Microbes, 4, 158–164.CrossRefPubMedPubMedCentralGoogle Scholar
  70. Saitoh, O., Kojima, K., Sugi, K., et al. (1999). Fecal eosinophil granule-derived proteins reflect disease activity in inflammatory bowel disease. The American Journal of Gastroenterology, 94, 3513–3520.CrossRefPubMedGoogle Scholar
  71. Smythies, L. E., Shen, R., Bimczok, D., et al. (2010). Inflammation anergy in human intestinal macrophages is due to Smad-induced IkappaBalpha expression and NF-kappaB inactivation. The Journal of Biological Chemistry, 285, 19593–19604.CrossRefPubMedPubMedCentralGoogle Scholar
  72. Sonnenberg, G. F., & Artis, D. (2012). Innate lymphoid cell interactions with microbiota: Implications for intestinal health and disease. Immunity, 37, 601–610.CrossRefPubMedPubMedCentralGoogle Scholar
  73. St John, A. L., & Abraham, S. N. (2013). Innate immunity and its regulation by mast cells. Journal of Immunology, 190, 4458–4463.CrossRefGoogle Scholar
  74. Steinman, R. M., & Cohn, Z. A. (1973). Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution. The Journal of Experimental Medicine, 137, 1142–1162.CrossRefPubMedPubMedCentralGoogle Scholar
  75. Stewart, M. K., & Cookson, B. T. (2016). Evasion and interference: Intracellular pathogens modulate caspase-dependent inflammatory responses. Nature Reviews Microbiology, 14, 346–359.CrossRefPubMedGoogle Scholar
  76. Strowig, T., Henao-Mejia, J., Elinav, E., & Flavell, R. (2012). Inflammasomes in health and disease. Nature, 481, 278–286.CrossRefPubMedGoogle Scholar
  77. Swiecki, M., Miller, H. L., Sesti-Costa, R., et al. (2017). Microbiota induces tonic CCL2 systemic levels that control pDC trafficking in steady state. Mucosal Immunology, 10, 936–945.CrossRefPubMedGoogle Scholar
  78. Tan, J., McKenzie, C., Potamitis, M., et al. (2014). The role of short-chain fatty acids in health and disease. Advances in Immunology, 121, 91–119.CrossRefPubMedGoogle Scholar
  79. Thaiss, C. A., Levy, M., Itav, S., & Elinav, E. (2016a). Integration of innate immune signaling. Trends in Immunology, 37, 84–101.CrossRefPubMedGoogle Scholar
  80. Thaiss, C. A., Zmora, N., Levy, M., & Elinav, E. (2016b). The microbiome and innate immunity. Nature, 535, 65–74.CrossRefGoogle Scholar
  81. Ueda, Y., Kayama, H., Jeon, S. G., et al. (2010). Commensal microbiota induce LPS hyporesponsiveness in colonic macrophages via the production of IL-10. International Immunology, 22, 953–962.CrossRefPubMedGoogle Scholar
  82. Walton, K. L. W., He, J., Kelsall, B. L., et al. (2006). Dendritic cells in germ-free and specific pathogen-free mice have similar phenotypes and in vitro antigen presenting function. Immunology Letters, 102, 16–24.CrossRefPubMedGoogle Scholar
  83. Wang, S., Xia, P., Chen, Y., et al. (2017). Regulatory innate lymphoid cells control innate intestinal inflammation. Cell, 171, 201–216.e18.CrossRefPubMedGoogle Scholar
  84. Weber, B., Saurer, L., Schenk, M., et al. (2011). CX3CR1 defines functionally distinct intestinal mononuclear phagocyte subsets which maintain their respective functions during homeostatic and inflammatory conditions. European Journal of Immunology, 41, 773–779.CrossRefPubMedGoogle Scholar
  85. Weller, P. F., & Spencer, L. A. (2017). Functions of tissue-resident eosinophils. Nature Reviews Immunology, 17, 746–760.CrossRefPubMedGoogle Scholar
  86. Welty, N. E., Staley, C., Ghilardi, N., et al. (2013). Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. The Journal of Experimental Medicine, 210, 2011–2024.CrossRefPubMedPubMedCentralGoogle Scholar
  87. Wouters, M. M., Vicario, M., & Santos, J. (2016). The role of mast cells in functional GI disorders. Gut, 65, 155–168.CrossRefPubMedGoogle Scholar
  88. Yang, Q., Li, F., Harly, C., et al. (2015). TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nature Immunology, 16, 1044–1050.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Till Strowig
    • 1
    Email author
  • Sophie Thiemann
    • 1
  • Andreas Diefenbach
    • 2
    • 3
  1. 1.Research Group Microbial Immune Regulation, Helmholtz Centre for Infection ResearchBraunschweigGermany
  2. 2.Institute of Microbiology, Charité – Universitätsmedizin BerlinBerlinGermany
  3. 3.Berlin Institute of Health (BIH)BerlinGermany

Personalised recommendations