The gut microbiota — masters of host development and physiology

Key Points

  • Animals are closely associated with a vast and diverse microbiota, most members of which reside in the gastrointestinal tract. Two gradients of microbial distribution exist in the gastrointestinal tract: the proximal–distal axis and the tissue–lumen axis.

  • Several parameters, including diet, lifestyle, antibiotics and other drugs, hygiene, and the genetics and immune status of the host, shape the microbiota composition, with various consequences for host physiology.

  • The gut microbiota is required for the development and maturation of the intestinal epithelium and immune system of the host. This microbiota affects properties of the mucus layer, promotes the development of lymphoid structures, modulates activation and differentiation of several lymphocyte populations and balances the production of immunoglobulin A and antimicrobial peptides.

  • The gut microbiota facilitates host metabolism and adiposity by expanding nutrient sources, producing essential vitamins and carrying out xenobiotic metabolism, but also affects a wide range of other host physiological aspects, including organ morphogenesis, intestinal vascularization, tissue homeostasis, carcinogenesis, bone mass and behaviour.

  • There is increasing evidence for a tight cross-species homeostatic interaction between the host and its microbiota, and research in this field has been facilitated by recent progress in the description and isolation of gut microbiota members, as well as in gnotobiology and host genetics. Elucidation of the molecular targets and causative connections in these host–microbiota interactions promises to reveal new possibilities to treat chronic inflammatory diseases and maintain human health.


Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host–microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Factors shaping intestinal microbial composition and effects of dysbiosis on host health.
Figure 2: Microbiota-induced maturation of the gastrointestinal tract.
Figure 3: Microbial impact on host physiology.


  1. 1

    Clemente, J. C., Ursell, L. K., Parfrey, L. W. & Knight, R. The impact of the gut microbiota on human health: an integrative view. Cell 148, 1258–1270 (2012).

  2. 2

    Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature 486, 207–214 (2012). A detailed catalogue of the human gut microbiome.

  3. 3

    Qin, J. et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature 464, 59–65 (2010). The first catalogue of the human microbiome.

  4. 4

    Sekirov, I., Russell, S. L., Antunes, L. C. & Finlay, B. B. Gut microbiota in health and disease. Physiol. Rev. 90, 859–904 (2010).

  5. 5

    Sina, C. et al. Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice. Gut 22 Mar 2012 (doi:10.1136/gutjnl-2011-300076).

  6. 6

    Swidsinski, A., Loening-Baucke, V., Lochs, H. & Hale, L. P. Spatial organization of bacterial flora in normal and inflamed intestine: a fluorescence in situ hybridization study in mice. World J. Gastroenterol. 11, 1131–1140 (2005).

  7. 7

    Xu, J. & Gordon, J. I. Honor thy symbionts. Proc. Natl Acad. Sci. USA 100, 10452–10459 (2003).

  8. 8

    Human Microbiome Project Consortium. A framework for human microbiome research. Nature 486, 215–221 (2012).

  9. 9

    Gill, S. R. et al. Metagenomic analysis of the human distal gut microbiome. Science 312, 1355–1359 (2006).

  10. 10

    Smith, K., McCoy, K. D. & Macpherson, A. J. Use of axenic animals in studying the adaptation of mammals to their commensal intestinal microbiota. Semin. Immunol. 19, 59–69 (2007).

  11. 11

    Sjogren, K. et al. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367 (2012). A study demonstrating that the gut microbiota affects bone mass, possibly by inhibiting osteoclastogenesis through modulation of the T cell profile.

  12. 12

    Lederberg, J. Infectious history. Science 288, 287–293 (2000).

  13. 13

    Arrieta, M. C. & Finlay, B. B. The commensal microbiota drives immune homeostasis. Front. Immunol. 3, 33 (2012).

  14. 14

    McFall-Ngai, M. Adaptive immunity: care for the community. Nature 445, 153 (2007).

  15. 15

    Hooper, L. V., Littman, D. R. & Macpherson, A. J. Interactions between the microbiota and the immune system. Science 336, 1268–1273 (2012).

  16. 16

    O'Hara, A. M. & Shanahan, F. The gut flora as a forgotten organ. EMBO Rep. 7, 688–693 (2006).

  17. 17

    Johansson, M. E. et al. The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria. Proc. Natl Acad. Sci. USA 105, 15064–15069 (2008). An article showing that the inner mucus layer shields the intestinal epithelium from bacterial contact.

  18. 18

    Johansson, M. E., Larsson, J. M. & Hansson, G. C. The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4659–4665 (2011).

  19. 19

    Juge, N. Microbial adhesins to gastrointestinal mucus. Trends Microbiol. 20, 30–39 (2012).

  20. 20

    Derrien, M. et al. Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes 1, 254–268 (2010).

  21. 21

    Ambort, D. et al. Calcium and pH-dependent packing and release of the gel-forming MUC2 mucin. Proc. Natl Acad. Sci. USA 109, 5645–5650 (2012).

  22. 22

    Sharma, R., Schumacher, U., Ronaasen, V. & Coates, M. Rat intestinal mucosal responses to a microbial flora and different diets. Gut 36, 209–214 (1995).

  23. 23

    Petersson, J. et al. Importance and regulation of the colonic mucus barrier in a mouse model of colitis. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G327–G333 (2011).

  24. 24

    An, G. et al. Increased susceptibility to colitis and colorectal tumors in mice lacking core 3-derived O-glycans. J. Exp. Med. 204, 1417–1429 (2007).

  25. 25

    Fu, J. et al. Loss of intestinal core 1-derived O-glycans causes spontaneous colitis in mice. J. Clin. Invest. 121, 1657–1666 (2011).

  26. 26

    van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nature Rev. Immunol. 10, 664–674 (2010).

  27. 27

    Mebius, R. E. Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003).

  28. 28

    Renz, H., Brandtzaeg, P. & Hornef, M. The impact of perinatal immune development on mucosal homeostasis and chronic inflammation. Nature Rev. Immunol. 12, 9–23 (2012).

  29. 29

    Round, J. L. & Mazmanian, S. K. The gut microbiota shapes intestinal immune responses during health and disease. Nature Rev. Immunol. 9, 313–323 (2009).

  30. 30

    Kanamori, Y. et al. Identification of novel lymphoid tissues in murine intestinal mucosa where clusters of c-kit+ IL-7R+ Thy1+ lympho-hemopoietic progenitors develop. J. Exp. Med. 184, 1449–1459 (1996).

  31. 31

    Eberl, G. Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway? Nature Rev. Immunol. 5, 413–420 (2005).

  32. 32

    Eberl, G. & Littman, D. R. Thymic origin of intestinal αβ T cells revealed by fate mapping of RORγt+ cells. Science 305, 248–251 (2004).

  33. 33

    Hamada, H. et al. Identification of multiple isolated lymphoid follicles on the antimesenteric wall of the mouse small intestine. J. Immunol. 168, 57–64 (2002).

  34. 34

    Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008). A study which reveals that microbial induction of ileal lymphoid follicles is mediated via peptidoglycans that are recognized mainly by the intracellular NOD1 receptor.

  35. 35

    Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nature Immunol. 10, 66–74 (2009).

  36. 36

    Luci, C. et al. Influence of the transcription factor RORγt on the development of NKp46+ cell populations in gut and skin. Nature Immunol. 10, 75–82 (2009).

  37. 37

    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).

  38. 38

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

  39. 39

    Cohen, N. R., Garg, S. & Brenner, M. B. Antigen presentation by CD1 lipids, T cells, and NKT cells in microbial immunity. Adv. Immunol. 102, 1–94 (2009).

  40. 40

    Van Kaer, L., Parekh, V. V. & Wu, L. Invariant natural killer T cells: bridging innate and adaptive immunity. Cell Tissue Res. 343, 43–55 (2011).

  41. 41

    Olszak, T. et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 336, 489–493 (2012). An elegant study demonstrating that the gut microbiota is required for normal development of iNKT cells in neonates and thereby protects from inflammatory diseases, thus confirming the hygiene hypothesis.

  42. 42

    Kieper, W. C. et al. Recent immune status determines the source of antigens that drive homeostatic T cell expansion. J. Immunol. 174, 3158–3163 (2005).

  43. 43

    Smith, P. M. & Garrett, W. S. The gut microbiota and mucosal T cells. Front. Microbiol. 2, 111 (2011).

  44. 44

    Hooper, L. V. & Macpherson, A. J. Immune adaptations that maintain homeostasis with the intestinal microbiota. Nature Rev. Immunol. 10, 159–169 (2010).

  45. 45

    Round, J. L. et al. The Toll-like receptor 2 pathway establishes colonization by a commensal of the human microbiota. Science 332, 974–977 (2011).

  46. 46

    Maynard, C. L. et al. Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10. Nature Immunol. 8, 931–941 (2007).

  47. 47

    Atarashi, K. et al. Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331, 337–341 (2011).

  48. 48

    Geuking, M. B. et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity 34, 794–806 (2011).

  49. 49

    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).

  50. 50

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

  51. 51

    Lee, Y. K., Menezes, J. S., Umesaki, Y. & Mazmanian, S. K. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 108 (Suppl. 1), 4615–4622 (2011).

  52. 52

    Wu, H. J. et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010).

  53. 53

    Macpherson, A. J. & Uhr, T. Induction of protective IgA by intestinal dendritic cells carrying commensal bacteria. Science 303, 1662–1665 (2004).

  54. 54

    Uematsu, S. et al. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5. Nature Immunol. 9, 769–776 (2008).

  55. 55

    Macpherson, A. J. et al. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science 288, 2222–2226 (2000).

  56. 56

    Kawamoto, S. et al. The inhibitory receptor PD-1 regulates IgA selection and bacterial composition in the gut. Science 336, 485–489 (2012). An article which shows that the gut microbiota is required for the development of completely functional IgA-producing cells and thereby maintains microbial homeostasis in the intestine.

  57. 57

    Gallo, R. L. & Hooper, L. V. Epithelial antimicrobial defence of the skin and intestine. Nature Rev. Immunol. 12, 503–516 (2012).

  58. 58

    Putsep, K. et al. Germ-free and colonized mice generate the same products from enteric prodefensins. J. Biol. Chem. 275, 40478–40482 (2000).

  59. 59

    Cash, H. L., Whitham, C. V., Behrendt, C. L. & Hooper, L. V. Symbiotic bacteria direct expression of an intestinal bactericidal lectin. Science 313, 1126–1130 (2006).

  60. 60

    Hooper, L. V., Stappenbeck, T. S., Hong, C. V. & Gordon, J. I. Angiogenins: a new class of microbicidal proteins involved in innate immunity. Nature Immunol. 4, 269–273 (2003).

  61. 61

    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). Work revealing that intestinal phagocytes discriminate commensals from pathogens using the intracellular NLRC4 (NOD-, LRR- and CARD-containing 4) inflammasome and by being hyporesponsive to commensal-derived TLR stimuli.

  62. 62

    Schauber, J. et al. Expression of the cathelicidin LL-37 is modulated by short chain fatty acids in colonocytes: relevance of signalling pathways. Gut 52, 735–741 (2003).

  63. 63

    Liang, S. C. et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J. Exp. Med. 203, 2271–2279 (2006).

  64. 64

    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).

  65. 65

    Salzman, N. H. et al. Enteric defensins are essential regulators of intestinal microbial ecology. Nature Immunol. 11, 76–83 (2010).

  66. 66

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

  67. 67

    Shin, S. C. et al. Drosophila microbiome modulates host developmental and metabolic homeostasis via insulin signaling. Science 334, 670–674 (2011). A detailed analysis revealing the molecular pathway of a symbiotic interaction between the fruit fly and one of its gut bacteria; this interaction is required for a normal developmental rate, body size, wing area and metabolism, as well as for normal stem cell activity.

  68. 68

    Koropatnick, T. A. et al. Microbial factor-mediated development in a host-bacterial mutualism. Science 306, 1186–1188 (2004).

  69. 69

    Troll, J. V. et al. Peptidoglycan induces loss of a nuclear peptidoglycan recognition protein during host tissue development in a beneficial animal–bacterial symbiosis. Cell. Microbiol. 11, 1114–1127 (2009).

  70. 70

    McFall-Ngai, M. Host-microbe symbiosis: the squid-Vibrio association—a naturally occurring, experimental model of animal/bacterial partnerships. Adv. Exp. Med. Biol. 635, 102–112 (2008).

  71. 71

    Wagner, C. L., Taylor, S. N. & Johnson, D. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin. Rev. Allergy Immunol. 34, 191–204 (2008).

  72. 72

    Reinhardt, C., Reigstad, C. S. & Bäckhed, F. Intestinal microbiota during infancy and its implications for obesity. J. Pediatr. Gastroenterol. Nutr. 48, 249–256 (2009).

  73. 73

    Wostmann, B. S. The germfree animal in nutritional studies. Annu. Rev. Nutr. 1, 257–279 (1981).

  74. 74

    Gordon, H. A. & Bruckner-Kardoss, E. Effect of normal microbial flora on intestinal surface area. Am. J. Physiol. 201, 175–178 (1961).

  75. 75

    Abrams, G. D., Bauer, H. & Sprinz, H. Influence of the normal flora on mucosal morphology and cellular renewal in the ileum. A comparison of germ-free and conventional mice. Lab. Invest. 12, 355–364 (1963).

  76. 76

    Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012). An investigation which demonstrates that bacteria promote vessel formation in the intestinal epithelium by modulating tissue factor signalling.

  77. 77

    Banasaz, M., Norin, E., Holma, R. & Midtvedt, T. Increased enterocyte production in gnotobiotic rats mono-associated with Lactobacillus rhamnosus GG. Appl. Environ. Microbiol. 68, 3031–3034 (2002).

  78. 78

    Alam, M., Midtvedt, T. & Uribe, A. Differential cell kinetics in the ileum and colon of germfree rats. Scand. J. Gastroenterol. 29, 445–451 (1994).

  79. 79

    Wikoff, W. R. et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc. Natl Acad. Sci. USA 106, 3698–3703 (2009).

  80. 80

    Husebye, E., Hellstrom, P. M. & Midtvedt, T. Intestinal microflora stimulates myoelectric activity of rat small intestine by promoting cyclic initiation and aboral propagation of migrating myoelectric complex. Dig. Dis. Sci. 39, 946–956 (1994).

  81. 81

    Samuel, B. S. et al. Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proc. Natl Acad. Sci. USA 105, 16767–16772 (2008).

  82. 82

    Hooper, L. V. et al. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881–884 (2001).

  83. 83

    Lutgendorff, F., Akkermans, L. M. & Soderholm, J. D. The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr. Mol. Med. 8, 282–298 (2008).

  84. 84

    Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).

  85. 85

    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).

  86. 86

    Stappenbeck, T. S., Hooper, L. V. & Gordon, J. I. Developmental regulation of intestinal angiogenesis by indigenous microbes via Paneth cells. Proc. Natl Acad. Sci. USA 99, 15451–15455 (2002).

  87. 87

    Buchon, N., Broderick, N. A., Chakrabarti, S. & Lemaitre, B. Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev. 23, 2333–2344 (2009).

  88. 88

    Crawford, P. A. & Gordon, J. I. Microbial regulation of intestinal radiosensitivity. Proc. Natl Acad. Sci. USA 102, 13254–13259 (2005).

  89. 89

    Savage, D. C., Siegel, J. E., Snellen, J. E. & Whitt, D. D. Transit time of epithelial cells in the small intestines of germfree mice and ex-germfree mice associated with indigenous microorganisms. Appl. Environ. Microbiol. 42, 996–1001 (1981).

  90. 90

    Blumberg, R. & Powrie, F. Microbiota, disease, and back to health: a metastable journey. Sci. Transl. Med. 4, 137rv7 (2012).

  91. 91

    Hope, M. E., Hold, G. L., Kain, R. & El-Omar, E. M. Sporadic colorectal cancer – role of the commensal microbiota. FEMS Microbiol. Lett. 244, 1–7 (2005).

  92. 92

    Swidsinski, A. et al. Association between intraepithelial Escherichia coli and colorectal cancer. Gastroenterology 115, 281–286 (1998).

  93. 93

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

  94. 94

    Sanapareddy, N. et al. Increased rectal microbial richness is associated with the presence of colorectal adenomas in humans. ISME J. 6, 1858–1868 (2012).

  95. 95

    Uronis, J. M. & Jobin, C. Microbes and colorectal cancer: is there a relationship? Curr. Oncol. 16, 22–24 (2009).

  96. 96

    Dove, W. F. et al. Intestinal neoplasia in the ApcMin mouse: independence from the microbial and natural killer (beige locus) status. Cancer Res. 57, 812–814 (1997).

  97. 97

    Breuer, N. & Goebell, H. The role of bile acids in colonic carcinogenesis. Klin. Wochenschr. 63, 97–105 (1985).

  98. 98

    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).

  99. 99

    Abdulamir, A. S., Hafidh, R. R. & Abu Bakar, F. The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J. Exp. Clin. Cancer Res. 30, 11 (2011).

  100. 100

    Kostic, A. D. et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 22, 292–298 (2012).

  101. 101

    Del Fattore, A., Teti, A. & Rucci, N. Bone cells and the mechanisms of bone remodelling. Front. Biosci. (Elite Ed.) 4, 2302–2321 (2012).

  102. 102

    Bliziotes, M. et al. Serotonin transporter and receptor expression in osteocytic MLO-Y4 cells. Bone 39, 1313–1321 (2006).

  103. 103

    Yadav, V. K. et al. Lrp5 controls bone formation by inhibiting serotonin synthesis in the duodenum. Cell 135, 825–837 (2008).

  104. 104

    Kong, Y. Y. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999).

  105. 105

    Sato, K. et al. Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J. Exp. Med. 203, 2673–2682 (2006).

  106. 106

    Wei, S., Kitaura, H., Zhou, P., Ross, F. P. & Teitelbaum, S. L. IL-1 mediates TNF-induced osteoclastogenesis. J. Clin. Invest. 115, 282–290 (2005).

  107. 107

    Zwerina, J. et al. TNF-induced structural joint damage is mediated by IL-1. Proc. Natl Acad. Sci. USA 104, 11742–11747 (2007).

  108. 108

    Turnbaugh, P. J. et al. A core gut microbiome in obese and lean twins. Nature 457, 480–484 (2009).

  109. 109

    Ley, R. E. Obesity and the human microbiome. Curr. Opin. Gastroenterol. 26, 5–11 (2010).

  110. 110

    Turnbaugh, P. J. et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027–1031 (2006).

  111. 111

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

  112. 112

    Qin, J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012). A report which reveals that there are alterations in the gut microbiome in Chinese patients with type 2 diabetes, and that these alterations can predict the occurrence of diabetes.

  113. 113

    Bäckhed, F. et al. The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl Acad. Sci. USA 101, 15718–15723 (2004). The first demonstration that the gut microbiota modulates adiposity.

  114. 114

    Bäckhed, F., Manchester, J. K., Semenkovich, C. F. & Gordon, J. I. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl Acad. Sci. USA 104, 979–984 (2007).

  115. 115

    Caesar, R. et al. Gut-derived lipopolysaccharide augments adipose macrophage accumulation but is not essential for impaired glucose or insulin tolerance in mice. Gut 61, 1701–1707 (2012).

  116. 116

    Cani, P. D. et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56, 1761–1772 (2007).

  117. 117

    Karlsson, F. H. et al. Symptomatic atherosclerosis is associated with an altered gut metagenome. Nature Commun. 3, 1245 (2012).

  118. 118

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

  119. 119

    Tremaroli, V. & Bäckhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).

  120. 120

    Koch, H. & Schmid-Hempel, P. Socially transmitted gut microbiota protect bumble bees against an intestinal parasite. Proc. Natl Acad. Sci. USA 108, 19288–19292 (2011).

  121. 121

    Boettcher, K. J., Ruby, E. G. & McFall-Ngai, M. J. Bioluminescence in the symbiotic squid Euprymna scolopes is controlled by a daily biological rhythm. J. Comp. Physiol. A Neuroethol. Sens. Neural Behav. Physiol. 179, 65–73 (1996).

  122. 122

    Degnan, P. H. et al. Factors associated with the diversification of the gut microbial communities within chimpanzees from Gombe National Park. Proc. Natl Acad. Sci. USA 109, 13034–13039 (2012).

  123. 123

    Sharon, G. et al. Commensal bacteria play a role in mating preference of Drosophila melanogaster. Proc. Natl Acad. Sci. USA 107, 20051–20056 (2010).

  124. 124

    Huang, Y., Callahan, S. & Hadfield, M. G. Recruitment in the sea: bacterial genes required for inducing larval settlement in a polychaete worm. Sci. Rep. 2, 228 (2012).

  125. 125

    Verhulst, N. O. et al. Composition of human skin microbiota affects attractiveness to malaria mosquitoes. PLoS ONE 6, e28991 (2011).

  126. 126

    Forsythe, P. & Kunze, W. A. Voices from within: gut microbes and the CNS. Cell. Mol. Life Sci. 70, 55–69 (2012).

  127. 127

    Amaral, F. A. et al. Commensal microbiota is fundamental for the development of inflammatory pain. Proc. Natl Acad. Sci. USA 105, 2193–2197 (2008).

  128. 128

    Sudo, N. et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 558, 263–275 (2004).

  129. 129

    Bercik, P. et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609 (2011).

  130. 130

    Lyte, M., Li, W., Opitz, N., Gaykema, R. P. & Goehler, L. E. Induction of anxiety-like behavior in mice during the initial stages of infection with the agent of murine colonic hyperplasia Citrobacter rodentium. Physiol. Behav. 89, 350–357 (2006).

  131. 131

    Heijtz, R. D. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011). The finding that the gut microbiota affects the development of the brain and anxiety-like behaviour.

  132. 132

    Neufeld, K. M., Kang, N., Bienenstock, J. & Foster, J. A. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255–e119 (2011).

  133. 133

    Diamond, B., Huerta, P. T., Tracey, K. & Volpe, B. T. It takes guts to grow a brain: increasing evidence of the important role of the intestinal microflora in neuro- and immune-modulatory functions during development and adulthood. Bioessays 33, 588–591 (2011).

  134. 134

    Collins, S. M., Surette, M. & Bercik, P. The interplay between the intestinal microbiota and the brain. Nature Rev. Microbiol. 10, 735–742 (2012).

  135. 135

    Kellermayer, R. et al. Colonic mucosal DNA methylation, immune response, and microbiome patterns in Toll-like receptor 2-knockout mice. FASEB J. 25, 1449–1460 (2011).

  136. 136

    Ley, R. E. et al. Evolution of mammals and their gut microbes. Science 320, 1647–1651 (2008).

  137. 137

    Dominguez-Bello, M. G. et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl Acad. Sci. USA 107, 11971–11975 (2010).

  138. 138

    Yatsunenko, T. et al. Human gut microbiome viewed across age and geography. Nature 486, 222–227 (2012). An extensive analysis of the gut microbiome of healthy children and adults from three different geographical regions.

  139. 139

    Koboziev, I., Karlsson, F. & Grisham, M. B. Gut-associated lymphoid tissue, T cell trafficking, and chronic intestinal inflammation. Ann. NY Acad. Sci. 1207 (Suppl. 1), e86–e93 (2010).

  140. 140

    Veenbergen, S. & Samsom, J. N. Maintenance of small intestinal and colonic tolerance by IL-10-producing regulatory T cell subsets. Curr. Opin. Immunol. 24, 269–276 (2012).

  141. 141

    Walker, J. A., Barlow, J. L. & McKenzie, A. N. Innate lymphoid cells - how did we miss them? Nature Rev. Immunol. 13, 75–87 (2013).

Download references


The authors thank R. Perkins for editing the manuscript and A. Hallén for contributions to the figures. Work in the Bäckhed laboratory is supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, the Knut and Alice Wallenberg Foundation, the Swedish Heart Lung foundation, the Swedish Diabetes Foundation, the European Union-funded project TORNADO (grant FP7-KBBE-222720), Ragnar Söderberg's Foundation, Torsten Söderberg's Foundation, the NovoNordisk Foundation, AFA Insurance, IngaBritt and Arne Lundberg's Foundation and a LUA-ALF grant from the Swedish Västra Götalandsregionen.

Author information

Correspondence to Fredrik Bäckhed.

Ethics declarations

Competing interests

F.B. is a scientific founder of MetaboGen AB and owns equity in the company. F.S. declares no competing financial interests.

Related links

Related links


Fredrik Bäckhed's homepage



The sum of all microorganisms (including bacteria, archaea, eukaryotes and viruses) that reside in and/or on a host or a specified part of a host (such as the gastrointestinal tract).


Pertaining to a relationship between two organisms: beneficial to both organisms. The term originates from the Latin word mutuus (lent, borrowed or mutual).


A term that extends the classical biological definition of an organism (a living system capable of autonomous metabolism and reproduction) by including the many microorganisms that live in and on that host organism, thus yielding a superior degree of complexity. The term originates from the Latin supra (above) and the Greek organon (organ, instrument, tool).


Any close physical association between two organisms, usually from different species. This includes mutualism, commensalism and parasitism. The term originates from the Greek words syn (together) and bio (life).


Normally harmless microorganism that can become pathogens under certain environmental conditions.

Somatic hypermutation

A programmed process of mutation affecting the variable regions of immunoglobulin genes during affinity maturation of B cell receptors.

Experimental autoimmune encephalomyelitis

An animal model of T cell-mediated autoimmune disease in general and in particular of demyelinating diseases of the central nervous system, such as multiple sclerosis.

T follicular helper cells

A T cell subtype that resides in the B cell follicles of secondary lymphoid organs and expresses the B cell homing receptor CXC-chemokine receptor 5. These T cells mediate B cell activation and trigger the formation of the germinal centre.

Crypts of Lieberkühn

Tubular invaginations of the intestinal epithelium around the villi. The crypt base contains Paneth cells, which secrete mainly antimicrobial peptides as well as other immune factors, and continually dividing stem cells that are the source of all intestinal epithelial cells.

Xenobiotic metabolism

The metabolism of foreign compounds that are neither produced by nor naturally found in the host, such as drugs.

Enterochromaffin cells

A subtype of enteroendocrine cells in the intestinal or respiratory epithelium. Enterochromaffin cells are the main source of serotonin in the body and are thereby involved in the regulation of intestinal peristalsis and nausea.


A type of junctional complex that is mainly found in epithelia (specifically, in the lateral plasma membrane of the epithelial cell) and mediates cell-to-cell adhesion to allow cells to withstand shearing forces.

Tight junctions

Junctional complexes that are present only in vertebrates (the invertebrate equivalents are the septate junctions) and are located at the transition of the apical and lateral membrane, closely connecting two epithelial cells and thereby making the epithelium impermeable to water and solutes.


An imbalance in the structural and/or functional configuration of the microbiota, leading to a disruption of host–microorganism homeostasis.


Pertaining to an organism: associated with a defined microbiota. For example, laboratory mice can be reared under sterile (germ-free) conditions or colonized with a specific collection of microorganisms. From the Greek gnosis (known or knowledge) and bios (life).

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sommer, F., Bäckhed, F. The gut microbiota — masters of host development and physiology. Nat Rev Microbiol 11, 227–238 (2013) doi:10.1038/nrmicro2974

Download citation

Further reading