Accounting for reciprocal host–microbiome interactions in experimental science

Abstract

Mammals are defined by their metagenome, a combination of host and microbiome genes. This knowledge presents opportunities to further basic biology with translation to human diseases. However, the now-documented influence of the metagenome on experimental results and the reproducibility of in vivo mammalian models present new challenges. Here we provide the scientific basis for calling on all investigators, editors and funding agencies to embrace changes that will enhance reproducible and interpretable experiments by accounting for metagenomic effects. Implementation of new reporting and experimental design principles will improve experimental work, speed discovery and translation, and properly use substantial investments in biomedical research.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The role of the metagenome on determining phenotypes.
Figure 2: Determining the role of the microbiome within genetically equivalent but phenotypically different mice (as in ref.12).
Figure 3: Use of littermate controls as a gold standard to control for the effects of the microbiome and metagenome.
Figure 4: Additional experiments to test for the relative dominance of host chromosomal or microbiome traits.

References

  1. 1

    Brodin, P. et al. Variation in the human immune system is largely driven by non-heritable influences. Cell 160, 37–47 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Lee, M. N. et al. Common genetic variants modulate pathogen-sensing responses in human dendritic cells. Science 343, 1246980 (2014)

    PubMed  PubMed Central  Google Scholar 

  3. 3

    Norman, J. M., Handley, S. A. & Virgin, H. W. Kingdom-agnostic metagenomics and the importance of complete characterization of enteric microbial communities. Gastroenterology 146, 1459–1469 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Moon, C. & Stappenbeck, T. S. Viral interactions with the host and microbiota in the intestine. Curr. Opin. Immunol. 24, 405–410 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Virgin, H. W. The virome in mammalian physiology and disease. Cell 157, 142–150 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Beck, J. M. et al. Multicenter comparison of lung and oral microbiomes of HIV-infected and HIV-uninfected individuals. Am. J. Respir. Crit. Care Med. 192, 1335–1344 (2015)

    PubMed  PubMed Central  Google Scholar 

  8. 8

    Anahtar, M. N. et al. Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract. Immunity 42, 965–976 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Oh, J. et al. Biogeography and individuality shape function in the human skin metagenome. Nature 514, 59–64 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    MacDuff, D. A. et al. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection. eLife 4, (2015)

  11. 11

    Virgin, H. W. & Todd, J. A. Metagenomics and personalized medicine. Cell 147, 44–56 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Moon, C. et al. Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature 521, 90–93 (2015).Demonstrates that indigenous intestinal bacteria dominantly influence phenotypes through degradation of fecal IgA and emphasizes the need for control of the metagenome and microbiome in mouse experiments.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Bloom, S. M. et al. Commensal Bacteroides species induce colitis in host-genotype-specific fashion in a mouse model of inflammatory bowel disease. Cell Host Microbe 9, 390–403 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Cadwell, K. et al. Virus-plus-susceptibility gene interaction determines Crohn’s disease gene Atg16L1 phenotypes in intestine. Cell 141, 1135–1145 (2010).With ref. 13 , experimental proof of concept that one cannot only separately consider the effects of host genes or microbiome genes on mouse phenotypes; one must consider the entire metagenome including bacteria and viruses.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Basic, M. et al. Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice. Inflamm. Bowel Dis. 20, 431–443 (2014)

    PubMed  PubMed Central  Google Scholar 

  16. 16

    Metchnikoff, O. Life of Elie Metchnikoff 1845–1916. (Houghton Mifflin Company, 1921)

  17. 17

    Wang, Z. et al. Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis. Cell 163, 1585–1595 (2015).Demonstrates the concept that intestinal metabolites can have dramatic effects on distant organ systems (here blood vessels) and emphasize that the effect of the metagenome and microbiome must be considered in all mouse experiments.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Gevers, D. et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe 15, 382–392 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Reyes, A., Wu, M., McNulty, N. P., Rohwer, F. L. & Gordon, J. I. Gnotobiotic mouse model of phage-bacterial host dynamics in the human gut. Proc. Natl Acad. Sci. USA 110, 20236–20241 (2013)

    ADS  CAS  Google Scholar 

  20. 20

    Norman, J. M. et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 160, 447–460 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Haberman, Y. et al. Pediatric Crohn disease patients exhibit specific ileal transcriptome and microbiome signature. J. Clin. Invest. 124, 3617–3633 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22

    Handley, S. A. et al. Pathogenic simian immunodeficiency virus infection is associated with expansion of the enteric virome. Cell 151, 253–266 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23

    Mutlu, E. A. et al. A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects. PLoS Pathog. 10, e1003829 (2014)

    PubMed  PubMed Central  Google Scholar 

  24. 24

    Handley, S. A. et al. SIV infection-mediated changes in gastrointestinal bacterial microbiome and virome are associated with immunodeficiency and prevented by vaccination. Cell Host Microbe 19, 323–335 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Monaco, C. L. et al. Altered virome and bacterial microbiome in human immunodeficiency virus-associated acquired immunodeficiency syndrome. Cell Host Microbe 19, 311–322 (2016)

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26

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

    PubMed  PubMed Central  Google Scholar 

  27. 27

    Reyes, A. et al. Gut DNA viromes of Malawian twins discordant for severe acute malnutrition. Proc. Natl Acad. Sci. USA 112, 11941–11946 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28

    Smith, M. I. et al. Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science 339, 548–554 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Ridaura, V. K. et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science 341, 1241214 (2013)

    Google Scholar 

  30. 30

    Jenq, R. R. et al. Regulation of intestinal inflammation by microbiota following allogeneic bone marrow transplantation. J. Exp. Med. 209, 903–911 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Davis-Richardson, A. G. et al. Bacteroides dorei dominates gut microbiome prior to autoimmunity in Finnish children at high risk for type 1 diabetes. Front. Microbiol. 5, 678 (2014)

    PubMed  PubMed Central  Google Scholar 

  32. 32

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

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33

    Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).With refs 34, 35, 36 , demonstrates the need to consider the effects of the metagenome and microbiome of all organs including the brain.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Yano, J. M. et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 161, 264–276 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

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

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36

    Sampson, T. R. & Mazmanian, S. K. Control of brain development, function, and behavior by the microbiome. Cell Host Microbe 17, 565–576 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  37. 37

    Vétizou, M. et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350, 1079–1084 (2015)

    ADS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Sjogren, K. et al. The gut microbiota regulates bone mass in mice. J. Bone Miner. Res. 27, 1357–1367 (2012)

    PubMed  PubMed Central  Google Scholar 

  39. 39

    De Vlaminck, I. et al. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell 155, 1178–1187 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Arpaia, N. et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504, 451–455 (2013).With refs 41, 42, 43 and 47 , shows the diverse effects and mechanisms of microbial metabolites (here short chain fatty acids) and emphasizes that mechanisms underlying the metagenome and microbiome require investigation in multiple cell types.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Atarashi, K. et al. Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500, 232–236 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Sefik, E. et al. Individual intestinal symbionts induce a distinct population of RORγ+ regulatory T cells. Science (2015)

  43. 43

    Smith, P. M. et al. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341, 569–573 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Kernbauer, E., Ding, Y. & Cadwell, K. An enteric virus can functionally replace the beneficial cues provided by commensal bacteria. Nature 516, 94–98 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Reinhardt, C. et al. Tissue factor and PAR1 promote microbiota-induced intestinal vascular remodelling. Nature 483, 627–631 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46

    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)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47

    Kaiko, G. E. et al. The colonic crypt protects stem cells from microbiota-derived metabolites. Cell 165, 1–13 (2016)

    Google Scholar 

  48. 48

    Osborne, L. C. et al. Virus-helminth coinfection reveals a microbiota-independent mechanism of immunomodulation. Science 345, 578–582 (2014)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Reese, T. A. et al. Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter. Science 345, 573–577 (2014).Emphasizes that phenotypes driven by the metagenome can be polymicrobial and are not exclusively bacterial; here viral and protozoan interactions are important.

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51

    Arrieta, M. C. et al. Early infancy microbial and metabolic alterations affect risk of childhood asthma. Sci. Transl. Med. 7, 307ra152 (2015)

    PubMed  PubMed Central  Google Scholar 

  52. 52

    Thorburn, A. N. et al. Evidence that asthma is a developmental origin disease influenced by maternal diet and bacterial metabolites. Nat. Commun. 6, 7320 (2015).With ref. 51 , shows that intestinal metabolites can affect disease pathogenesis in distant organs (here asthma models in the lung).

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53

    Buffie, C. G. et al. Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile. Nature 517, 205–208 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    Reese, T. A. et al. Sequential infection with common pathogens promotes human-like immune gene expression and altered vaccine response. Cell Host Microbe 19, 1–7 (2016).This report emphasizes the history of microbial interactions with an organism additionally shapes phenotypes and this needs to be modelled in mouse experiments.

    Google Scholar 

  55. 55

    McCafferty, J. et al. Stochastic changes over time and not founder effects drive cage effects in microbial community assembly in a mouse model. ISME J. 7, 2116–2125 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  56. 56

    Pantoja-Feliciano, I. G. et al. Biphasic assembly of the murine intestinal microbiota during early development. ISME J. 7, 1112–1115 (2013)

    PubMed  PubMed Central  Google Scholar 

  57. 57

    Farkas, A. M. et al. Induction of Th17 cells by segmented filamentous bacteria in the murine intestine. J. Immunol. Methods 421, 104–111 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Campbell, J. H. et al. Host genetic and environmental effects on mouse intestinal microbiota. ISME J. 6, 2033–2044 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  59. 59

    Yurkovetskiy, L. et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 39, 400–412 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Markle, J. G. et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science 339, 1084–1088 (2013)

    ADS  CAS  Google Scholar 

  61. 61

    Langille, M. G. et al. Microbial shifts in the aging mouse gut. Microbiome 2, 50 (2014)

    PubMed  PubMed Central  Google Scholar 

  62. 62

    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)

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Thaiss, C. A. et al. Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159, 514–529 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  64. 64

    McInnes, E. F. et al. Prevalence of viral, bacterial and parasitological diseases in rats and mice used in research environments in Australasia over a 5-y period. Lab Anim. (NY) 40, 341–350 (2011)

    Google Scholar 

  65. 65

    Karp, C. L. Unstressing intemperate models: how cold stress undermines mouse modeling. J. Exp. Med. 209, 1069–1074 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  66. 66

    Gaskill, B. N. et al. Heat or insulation: behavioral titration of mouse preference for warmth or access to a nest. PLoS One 7, e32799 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67

    Huang, E. Y. et al. Using corticosteroids to reshape the gut microbiome: implications for inflammatory bowel diseases. Inflamm. Bowel Dis. 21, 963–972 (2015)

    PubMed  PubMed Central  Google Scholar 

  68. 68

    Chevalier, C. et al. Gut microbiota orchestrates energy homeostasis during cold. Cell 163, 1360–1374 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Wolf, K. J. et al. Consumption of acidic water alters the gut microbiome and decreases the risk of diabetes in NOD mice. J. Histochem. Cytochem. 62, 237–250 (2014)

    PubMed  PubMed Central  Google Scholar 

  70. 70

    Hall, J. E., White, W. J. & Lang, C. M. Acidification of drinking water: its effects on selected biologic phenomena in male mice. Lab. Anim. Sci. 30, 643–651 (1980)

    PubMed Central  CAS  PubMed  Google Scholar 

  71. 71

    Carmody, R. N. et al. Diet dominates host genotype in shaping the murine gut microbiota. Cell Host Microbe 17, 72–84 (2015).One example of many cited here that shows in detail the potential rapid effects on environmental influences such as diet on the composition of the microbiome and emphasizes the need to report environmental variables in all experiments.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Ijssennagger, N. et al. Gut microbiota facilitates dietary heme-induced epithelial hyperproliferation by opening the mucus barrier in colon. Proc. Natl Acad. Sci. USA 112, 10038–10043 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73

    Zenewicz, L. A. et al. IL-22 deficiency alters colonic microbiota to be transmissible and colitogenic. J. Immunol. 190, 5306–5312 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

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

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Garrett, W. S. et al. Communicable ulcerative colitis induced by T-bet deficiency in the innate immune system. Cell 131, 33–45 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77

    Cox, L. M. et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 158, 705–721 (2014).With ref. 76 , emphasizes the early life effects of the microbiota that must be considered in experimental design to control for the metagenome and microbiome.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. 78

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

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Sun, J. et al. Pancreatic β-cells limit autoimmune diabetes via an immunoregulatory antimicrobial peptide expressed under the influence of the gut Microbiota. Immunity 43, 304–317 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  80. 80

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

    CAS  PubMed  PubMed Central  Google Scholar 

  81. 81

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Ryu, S. H. & Stappenbeck, T. S. Gut–pancreatic axis AMPlified in islets of Langerhans. Immunity 43, 216–218 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Levy, M. et al. Microbiota-modulated metabolites shape the intestinal microenvironment by regulating NLRP6 inflammasome signaling. Cell 163, 1428–1443 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  84. 84

    Eberl, G. Addressing the experimental variability associated with the microbiota. Mucosal Immunol. 8, 487–490 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85

    Macpherson, A. J. & McCoy, K. D. Standardised animal models of host microbial mutualism. Mucosal Immunol. 8, 476–486 (2015).Excellent review on the methodology and use of isobiotic mice in experiments.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. 86

    Goodman, A. L. et al. Extensive personal human gut microbiota culture collections characterized and manipulated in gnotobiotic mice. Proc. Natl Acad. Sci. USA 108, 6252–6257 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Atkinson, M. A. & Chervonsky, A. Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease. Diabetologia 55, 2868–2877 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  88. 88

    Pozzilli, P., Signore, A., Williams, A. J. & Beales, P. E. NOD mouse colonies around the world–recent facts and figures. Immunol. Today 14, 193–196 (1993)

    CAS  PubMed  PubMed Central  Google Scholar 

  89. 89

    Turnbaugh, P. J. et al. The human microbiome project. Nature 449, 804–810 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Wheeler, M. L. & Underhill, D. M. Time to cast a larger net. Nat. Immunol. 15, 1000–1001 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  91. 91

    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)

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Hajishengallis, G. et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe 10, 497–506 (2011).With ref. 93 , shows that microbiome sequence analysis alone cannot always account for mouse phenotypes; these are examples where low abundance microbes and microbial particles drive phenotypes that would both be missed in sequence analysis.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Hickey, C. A. et al. Colitogenic Bacteroides thetaiotaomicron antigens access host immune cells in a sulfatase-dependent manner via outer membrane vesicles. Cell Host Microbe 17, 672–680 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Segata, N. et al. Metagenomic microbial community profiling using unique clade-specific marker genes. Nat. Methods 9, 811–814 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Whitman, W. B., Coleman, D. C. & Wiebe, W. J. Prokaryotes: the unseen majority. Proc. Natl Acad. Sci. USA 95, 6578–6583 (1998)

    ADS  CAS  Google Scholar 

  96. 96

    Virgin, H. W., Wherry, E. J. & Ahmed, R. Redefining chronic viral infection. Cell 138, 30–50 (2009)

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Young, G. R. et al. Resurrection of endogenous retroviruses in antibody-deficient mice. Nature 491, 774–778 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98

    Ives, A. et al. Leishmania RNA virus controls the severity of mucocutaneous leishmaniasis. Science 331, 775–778 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99

    Underhill, D. M. & Iliev, I. D. The mycobiota: interactions between commensal fungi and the host immune system. Nat. Rev. Immunol. 14, 405–416 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Fletcher, S. M., Stark, D., Harkness, J. & Ellis, J. Enteric protozoa in the developed world: a public health perspective. Clin. Microbiol. Rev. 25, 420–449 (2012)

    PubMed  PubMed Central  Google Scholar 

  101. 101

    Stelekati, E. & Wherry, E. J. Chronic bystander infections and immunity to unrelated antigens. Cell Host Microbe 12, 458–469 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  102. 102

    Pfeiffer, J. K. & Virgin, H. W. Viral immunity. Transkingdom control of viral infection and immunity in the mammalian intestine. Science 351, 239–245 (2016)

    CAS  Google Scholar 

  103. 103

    Dantas, G. & Sommer, M. O. Context matters – the complex interplay between resistome genotypes and resistance phenotypes. Curr. Opin. Microbiol. 15, 577–582 (2012)

    PubMed  PubMed Central  Google Scholar 

  104. 104

    Stern, A. & Sorek, R. The phage–host arms race: shaping the evolution of microbes. BioEssays 33, 43–51 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  105. 105

    Brüssow, H., Canchaya, C. & Hardt, W.-D. Phages and the evolution of bacterial pathogens: from genomic rearrangements to lysogenic conversion. Microbiol. Mol. Biol. Rev. 68, 560–602 (2004)

    PubMed  PubMed Central  Google Scholar 

  106. 106

    Fortier, L.-C. & Sekulovic, O. Importance of prophages to evolution and virulence of bacterial pathogens. Virulence 4, 354–365 (2013)

    PubMed  PubMed Central  Google Scholar 

  107. 107

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Robinson, C. M., Jesudhasan, P. R. & Pfeiffer, J. K. Bacterial lipopolysaccharide binding enhances virion stability and promotes environmental fitness of an enteric virus. Cell Host Microbe 15, 36–46 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

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

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  113. 113

    Furman, D. et al. Cytomegalovirus infection enhances the immune response to influenza. Sci. Transl. Med. 7, 281ra43 (2015)

    PubMed  PubMed Central  Google Scholar 

  114. 114

    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)

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115

    Williams, W. B. et al. HIV-1 vaccines. Diversion of HIV-1 vaccine-induced immunity by gp41-microbiota cross-reactive antibodies. Science 349, aab1253 (2015)

    ADS  PubMed  PubMed Central  Google Scholar 

  116. 116

    Nam, Y.-D. et al. Bacterial, archaeal, and eukaryal diversity in the intestines of Korean people. J. Microbiol. 46, 491–501 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Scanlan, P. D. & Marchesi, J. R. Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces. ISME J. 2, 1183–1193 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118

    Elliott, D. E. & Weinstock, J. V. Helminth–host immunological interactions: prevention and control of immune-mediated diseases. Ann. NY Acad. Sci. 1247, 83–96 (2012)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  119. 119

    Hoffmann, C. et al. Archaea and fungi of the human gut microbiome: correlations with diet and bacterial residents. PLoS One 8, e66019 (2013)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120

    Kilkenny, C., Browne, W. J., Cuthill, I. C., Emerson, M. & Altman, D. G. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. J. Pharmacol. Pharmacother. 1, 94–99 (2010)

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

Both authors contributed equally to planning and writing the manuscript.

Corresponding authors

Correspondence to Thaddeus S. Stappenbeck or Herbert W. Virgin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stappenbeck, T., Virgin, H. Accounting for reciprocal host–microbiome interactions in experimental science. Nature 534, 191–199 (2016). https://doi.org/10.1038/nature18285

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.