Why does the microbiome affect behaviour?



Growing evidence indicates that the mammalian microbiome can affect behaviour, and several symbionts even produce neurotransmitters. One common explanation for these observations is that symbionts have evolved to manipulate host behaviour for their benefit. Here, we evaluate the manipulation hypothesis by applying evolutionary theory to recent work on the gut–brain axis. Although the theory predicts manipulation by symbionts under certain conditions, these appear rarely satisfied by the genetically diverse communities of the mammalian microbiome. Specifically, any symbiont investing its resources to manipulate host behaviour is expected to be outcompeted within the microbiome by strains that do not manipulate and redirect their resources into growth and survival. Moreover, current data provide no clear evidence for manipulation. Instead, we show how behavioural effects can readily arise as a by-product of natural selection on microorganisms to grow within the host and natural selection on hosts to depend upon their symbionts. We argue that understanding why the microbiome influences behaviour requires a focus on microbial ecology and local effects within the host.

  • Subscribe to Nature Reviews Microbiology for full access:



Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


  1. 1.

    Mayer, E. A. Gut feelings: the emerging biology of gut-brain communication. Nat. Rev. Neurosci. 12, 453–466 (2011).

  2. 2.

    Forsythe, P., Bienenstock, J. & Kunze, W. A. in Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease (eds Lyte, M. & Cryan, J. F.) 115–133 (Springer, 2014).

  3. 3.

    Fung, T. C., Olson, C. A. & Hsiao, E. Y. Interactions between the microbiota, immune and nervous systems in health and disease. Nat. Neurosci. 20, 145–155 (2017).

  4. 4.

    Neuman, H., Debelius, J. W., Knight, R. & Koren, O. Microbial endocrinology: the interplay between the microbiota and the endocrine system. FEMS Microbiol. Rev. 39, 509–521 (2015).

  5. 5.

    Lyte, M. Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog. 9, e1003726 (2013).

  6. 6.

    Cryan, J. F. & Dinan, T. G. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat. Rev. Neurosci. 13, 701–712 (2012).

  7. 7.

    Foster, J. A. & McVey Neufeld, K.-A. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 36, 305–312 (2013).

  8. 8.

    Sarkar, A. et al. Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends Neurosci. 39, 763–781 (2016).

  9. 9.

    Sharon, G., Sampson, T. R., Geschwind, D. H. & Mazmanian, S. K. The central nervous system and the gut microbiome. Cell 167, 915–932 (2016).

  10. 10.

    Rhee, S. H., Pothoulakis, C. & Mayer, E. A. Principles and clinical implications of the brain-gut-enteric microbiota axis. Nat. Rev. Gastroenterol. Hepatol. 6, 306–314 (2009).

  11. 11.

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

  12. 12.

    Desbonnet, L. et al. Effects of the probiotic Bifidobacterium infantis in the maternal separation model of depression. Neuroscience 170, 1179–1188 (2010).

  13. 13.

    Bercik, P. et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol. Motil. 23, 1132–1139 (2011).

  14. 14.

    Bravo, J. A. et al. Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve. Proc. Natl Acad. Sci. USA 108, 16050–16055 (2011).

  15. 15.

    Messaoudi, M. et al. Assessment of psychotropic-like properties of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in rats and human subjects. Br. J. Nutr. 105, 755–764 (2011).

  16. 16.

    Savignac, H. M., Kiely, B., Dinan, T. G. & Cryan, J. F. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol. Motil. 26, 1615–1627 (2014).

  17. 17.

    Davis, D. J. et al. Lactobacillus plantarum attenuates anxiety-related behavior and protects against stress-induced dysbiosis in adult zebrafish. Sci. Rep. 6, 33726 (2016).

  18. 18.

    Pinto-Sanchez, M. I. et al. Probiotic Bifidobacterium longum NCC3001 reduces depression scores and alters brain activity: a pilot study in patients with irritable bowel syndrome. Gastroenterology 153, 448–459 (2017).

  19. 19.

    Wallace, C. J. K. & Milev, R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann. Gen. Psychiatry 16, 14 (2017).

  20. 20.

    Bharwani, A., Mian, M. F., Surette, M. G., Bienenstock, J. & Forsythe, P. Oral treatment with Lactobacillus rhamnosus attenuates behavioural deficits and immune changes in chronic social stress. BMC Med. 15, 7 (2017).

  21. 21.

    Buffington, S. A. et al. Microbial reconstitution reverses maternal diet-induced social and synaptic deficits in offspring. Cell 165, 1762–1775 (2016).

  22. 22.

    Hsiao, E. Y. et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 155, 1451–1463 (2013).

  23. 23.

    Alcock, J., Maley, C. C. & Aktipis, C. A. Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. BioEssays 36, 940–949 (2014).

  24. 24.

    Wong, A. C.-N. et al. Behavioral microbiomics: a multi-dimensional approach to microbial influence on behavior. Front. Microbiol. 6, 1359 (2015).

  25. 25.

    Stilling, R. M., Dinan, T. G. & Cryan, J. F. The brain’s Geppetto — microbes as puppeteers of neural function and behaviour? J. Neurovirol. 22, 14–21 (2016).

  26. 26.

    Yuval, B. Symbiosis: gut bacteria manipulate host behaviour. Curr. Biol. 27, R746–R747 (2017).

  27. 27.

    Stilling, R. M., Bordenstein, S. R., Dinan, T. G. & Cryan, J. F. Friends with social benefits: host-microbe interactions as a driver of brain evolution and development? Front. Cell. Infect. Microbiol. 4, 147 (2014).

  28. 28.

    Lewin-Epstein, O., Aharonov, R. & Hadany, L. Microbes can help explain the evolution of host altruism. Nat. Commun. 8, 14040 (2017).

  29. 29.

    Brown, S. P. Do all parasites manipulate their hosts? Behav. Processes 68, 237–240 (2005).

  30. 30.

    Thomas, F., Adamo, S. A. & Moore, J. Parasitic manipulation: where are we and where should we go? Behav. Processes 68, 185–199 (2005).

  31. 31.

    Adamo, S. A. Modulating the modulators: parasites, neuromodulators and host behavioral change. Brain Behav. Evol. 60, 370–377 (2002).

  32. 32.

    Perrot-Minnot, M.-J. & Cézilly, F. Investigating candidate neuromodulatory systems underlying parasitic manipulation: concepts, limitations and prospects. J. Exp. Biol. 216, 134–141 (2013).

  33. 33.

    Andersen, S. B. et al. The life of a dead ant: the expression of an adaptive extended phenotype. Am. Nat. 174, 424–433 (2009).

  34. 34.

    Hughes, D. P. et al. Behavioral mechanisms and morphological symptoms of zombie ants dying from fungal infection. BMC Ecol. 11, 13 (2011).

  35. 35.

    Klein, S. L. Parasite manipulation of the proximate mechanisms that mediate social behavior in vertebrates. Physiol. Behav. 79, 441–449 (2003).

  36. 36.

    Berdoy, M., Webster, J. P. & Macdonald, D. W. Fatal attraction in rats infected with Toxoplasma gondii. Proc. Biol. Sci. 267, 1591–1594 (2000).

  37. 37.

    Vyas, A., Kim, S.-K., Giacomini, N., Boothroyd, J. C. & Sapolsky, R. M. Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc. Natl Acad. Sci. USA 104, 6442–6447 (2007).

  38. 38.

    Poulin, R. ‘Adaptive’ changes in the behaviour of parasitized animals: a critical review. Int. J. Parasitol. 25, 1371–1383 (1995).

  39. 39.

    Brown, S. P. Cooperation and conflict in host-manipulating parasites. Proc. Biol. Sci. 266, 1899–1904 (1999).

  40. 40.

    Vickery, W. L. & Poulin, R. The evolution of host manipulation by parasites: a game theory analysis. Evol. Ecol. 24, 773–788 (2010).

  41. 41.

    Schluter, J. & Foster, K. R. The evolution of mutualism in gut microbiota via host epithelial selection. PLoS Biol. 10, e1001424 (2012).

  42. 42.

    Xavier, J. B., Kim, W. & Foster, K. R. A molecular mechanism that stabilizes cooperative secretions in Pseudomonas aeruginosa. Mol. Microbiol. 79, 166–179 (2011).

  43. 43.

    Adamo, S. A. Parasites: evolution’s neurobiologists. J. Exp. Biol. 216, 3–10 (2013).

  44. 44.

    Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A. & Gordon, J. I. Host-bacterial mutualism in the human intestine. Science 307, 1915–1920 (2005).

  45. 45.

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

  46. 46.

    Coyte, K. Z., Schluter, J. & Foster, K. R. The ecology of the microbiome: networks, competition, and stability. Science 350, 663–666 (2015).

  47. 47.

    Stein, R. R. et al. Ecological modeling from time-series inference: insight into dynamics and stability of intestinal microbiota. PLoS Comput. Biol. 9, e1003388 (2013).

  48. 48.

    Marino, S., Baxter, N. T., Huffnagle, G. B., Petrosino, J. F. & Schloss, P. D. Mathematical modeling of primary succession of murine intestinal microbiota. Proc. Natl Acad. Sci. USA 111, 439–444 (2014).

  49. 49.

    Kommineni, S. et al. Bacteriocin production augments niche competition by enterococci in the mammalian gastrointestinal tract. Nature 526, 719–722 (2015).

  50. 50.

    Chatzidaki-Livanis, M., Geva-Zatorsky, N. & Comstock, L. E. Bacteroides fragilis type VI secretion systems use novel effector and immunity proteins to antagonize human gut Bacteroidales species. Proc. Natl Acad. Sci. USA 113, 3627–3632 (2016).

  51. 51.

    Wexler, A. G. et al. Human symbionts inject and neutralize antibacterial toxins to persist in the gut. Proc. Natl Acad. Sci. USA 113, 3639–3644 (2016).

  52. 52.

    Rao, S. et al. Pathogen-mediated inhibition of anorexia promotes host survival and transmission. Cell 168, 503–516 (2017).

  53. 53.

    Murray, M. J. & Murray, A. B. Anorexia of infection of host defense as a mechanism. Am. J. Clin. Nutr. 32, 593–596 (1979).

  54. 54.

    Wickham, M. E., Brown, N. F., Provias, J., Finlay, B. B. & Coombes, B. K. Oral infection of mice with Salmonella enterica serovar Typhimurium causes meningitis and infection of the brain. BMC Infect. Dis. 7, 65 (2007).

  55. 55.

    David, L. A. et al. Host lifestyle affects human microbiota on daily timescales. Genome Biol. 15, R89 (2014).

  56. 56.

    Rivera-Chávez, F. & Bäumler, A. J. The pyromaniac inside you: Salmonella metabolism in the host gut. Annu. Rev. Microbiol. 69, 31–48 (2015).

  57. 57.

    Balmer, O. & Tanner, M. Prevalence and implications of multiple-strain infections. Lancet Infect. Dis. 11, 868–878 (2011).

  58. 58.

    Rao, M. & Gershon, M. D. The bowel and beyond: the enteric nervous system in neurological disorders. Nat. Rev. Gastroenterol. Hepatol. 13, 517–528 (2016).

  59. 59.

    Quigley, E. M. M. Microflora modulation of motility. J. Neurogastroenterol. Motil. 17, 140–147 (2011).

  60. 60.

    Fukumoto, S. et al. Short-chain fatty acids stimulate colonic transit via intraluminal 5-HT release in rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1269–R1276 (2003).

  61. 61.

    Reigstad, C. S. et al. Gut microbes promote colonic serotonin production through an effect of short-chain fatty acids on enterochromaffin cells. FASEB J. 29, 1395–1403 (2015).

  62. 62.

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

  63. 63.

    Dey, N. et al. Regulators of gut motility revealed by a gnotobiotic model of diet-microbiome interactions related to travel. Cell 163, 95–107 (2015).

  64. 64.

    Wiles, T. J. et al. Host gut motility promotes competitive exclusion within a model intestinal microbiota. PLoS Biol. 14, e1002517 (2016).

  65. 65.

    Logan, S. L. et. al. The Vibrio cholerae type VI secretion system can modulate host intestinal mechanics to displace gut bacterial symbionts. Proc Natl Acad. Sci. USA (2018).

  66. 66.

    Sansonetti, P. J. & Di Santo, J. P. Debugging how bacteria manipulate the immune response. Immunity 26, 149–161 (2007).

  67. 67.

    Ayres, J. S. Cooperative microbial tolerance behaviors in host-microbiota mutualism. Cell 165, 1323–1331 (2016).

  68. 68.

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

  69. 69.

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

  70. 70.

    Hooper, L. V. Do symbiotic bacteria subvert host immunity? Nat. Rev. Microbiol. 7, 367–374 (2009).

  71. 71.

    Steinman, L. Elaborate interactions between the immune and nervous systems. Nat. Immunol. 5, 575–581 (2004).

  72. 72.

    Baganz, N. L. & Blakely, R. D. A dialogue between the immune system and brain, spoken in the language of serotonin. ACS Chem. Neurosci. 4, 48–63 (2013).

  73. 73.

    Wohleb, E. S., Franklin, T., Iwata, M. & Duman, R. S. Integrating neuroimmune systems in the neurobiology of depression. Nat. Rev. Neurosci. 17, 497–511 (2016).

  74. 74.

    Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337–341 (2015).

  75. 75.

    De Palma, G. et al. Transplantation of fecal microbiota from patients with irritable bowel syndrome alters gut function and behavior in recipient mice. Sci. Transl Med. 9, eaaf6397 (2017).

  76. 76.

    Foster, K. R., Schluter, J., Coyte, K. Z. & Rakoff-Nahoum, S. The evolution of the host microbiome as an ecosystem on a leash. Nature 548, 43–51 (2017).

  77. 77.

    Rooks, M. G. & Garrett, W. S. Gut microbiota, metabolites and host immunity. Nat. Rev. Immunol. 16, 341–352 (2016).

  78. 78.

    Koh, A., De Vadder, F., Kovatcheva-Datchary, P. & Bäckhed, F. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 165, 1332–1345 (2016).

  79. 79.

    Mao, Y.-K. et al. Bacteroides fragilis polysaccharide A is necessary and sufficient for acute activation of intestinal sensory neurons. Nat. Commun. 4, 1465 (2013).

  80. 80.

    Mazmanian, S. K. & Kasper, D. L. The love–hate relationship between bacterial polysaccharides and the host immune system. Nat. Rev. Immunol. 6, 849–858 (2006).

  81. 81.

    Braniste, V. et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl Med. 6, 263ra158 (2014).

  82. 82.

    Abbott, N. J., Rönnbäck, L. & Hansson, E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat. Rev. Neurosci. 7, 41–53 (2006).

  83. 83.

    Frost, G. et al. The short-chain fatty acid acetate reduces appetite via a central homeostatic mechanism. Nat. Commun. 5, 3611 (2014).

  84. 84.

    Barrett, E., Ross, R. P., O’Toole, P. W., Fitzgerald, G. F. & Stanton, C. γ-Aminobutyric acid production by culturable bacteria from the human intestine. J. Appl. Microbiol. 113, 411–417 (2012).

  85. 85.

    Pokusaeva, K. et al. GABA-producing Bifidobacterium dentium modulates visceral sensitivity in the intestine. Neurogastroenterol. Motil. 29, e12904 (2017).

  86. 86.

    Guthrie, G. D. & Nicholson-Guthrie, C. S. γ-Aminobutyric acid uptake by a bacterial system with neurotransmitter binding characteristics. Proc. Natl Acad. Sci. USA 86, 7378–7381 (1989).

  87. 87.

    Strandwitz, P. et al. GABA modulating bacteria of the human gut microbiome at ASM Microbe Conference (Poster) American Society for Microbiology!/4060/presentation/18619 (2016).

  88. 88.

    Asano, Y. et al. Critical role of gut microbiota in the production of biologically active, free catecholamines in the gut lumen of mice. Am. J. Physiol. Gastrointest. Liver Physiol. 303, G1288–G1295 (2012).

  89. 89.

    Wall, R. et al. in Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease (eds Lyte, M. & Cryan, J. F.) 221–239 (Springer, 2014).

  90. 90.

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

  91. 91.

    Roshchina, V. V. in Mic robial En do crino logy: Interkingdom Signaling in Infectious Disease and Health (eds Lyte, M. & Freestone, P. E.) 17–52 (Springer, 2010).

  92. 92.

    Iyer, L. M., Aravind, L., Coon, S. L., Klein, D. C. & Koonin, E. V. Evolution of cell-cell signaling in animals: did late horizontal gene transfer from bacteria have a role? Trends Genet. 20, 292–299 (2004).

  93. 93.

    Mountfort, D. O. & Pybus, V. Regulatory influences on the production of gamma-aminobutyric acid by a marine pseudomonad. Appl. Environ. Microbiol. 58, 237–242 (1992).

  94. 94.

    de Mazancourt, C., Loreau, M. & Dieckmann, U. Understanding mutualism when there is adaptation to the partner. J. Ecol. 93, 305–314 (2005).

  95. 95.

    Weinersmith, K. L. & Earley, R. L. Better with your parasites? Lessons for behavioural ecology from evolved dependence and conditionally helpful parasites. Anim. Behav. 118, 123–133 (2016).

  96. 96.

    Pannebakker, B. A., Loppin, B., Elemans, C. P. H., Humblot, L. & Vavre, F. Parasitic inhibition of cell death facilitates symbiosis. Proc. Natl Acad. Sci. USA 104, 213–215 (2007).

  97. 97.

    Moya, A. & Ferrer, M. Functional redundancy-induced stability of gut microbiota subjected to disturbance. Trends Microbiol. 24, 402–413 (2016).

  98. 98.

    Diaz Heijtz, R. et al. Normal gut microbiota modulates brain development and behavior. Proc. Natl Acad. Sci. USA 108, 3047–3052 (2011).

  99. 99.

    Desbonnet, L., Clarke, G., Shanahan, F., Dinan, T. G. & Cryan, J. F. Microbiota is essential for social development in the mouse. Mol. Psychiatry 19, 146–148 (2014).

  100. 100.

    Desbonnet, L. et al. Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain. Behav. Immun. 48, 165–173 (2015).

  101. 101.

    Hoban, A. E. et al. Behavioural and neurochemical consequences of chronic gut microbiota depletion during adulthood in the rat. Neuroscience 339, 463–477 (2016).

  102. 102.

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

  103. 103.

    Hill, D. A. & Artis, D. Intestinal bacteria and the regulation of immune cell homeostasis. Annu. Rev. Immunol. 28, 623–667 (2010).

  104. 104.

    Furusawa, Y. et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504, 446–450 (2013).

  105. 105.

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

  106. 106.

    Brestoff, J. R. & Artis, D. Commensal bacteria at the interface of host metabolism and the immune system. Nat. Immunol. 14, 676–684 (2013).

  107. 107.

    Strachan, D. P. Hay fever, hygiene, and household size. Br. Med. J. 299, 1259–1260 (1989).

  108. 108.

    Rook, G. A. W. & Lowry, C. A. The hygiene hypothesis and psychiatric disorders. Trends Immunol. 29, 150–158 (2008).

  109. 109.

    Wells, J. M. Immunomodulatory mechanisms of lactobacilli. Microb. Cell Fact. 10, S17 (2011).

  110. 110.

    Fanning, S. et al. Bifidobacterial surface-exopolysaccharide facilitates commensal-host interaction through immune modulation and pathogen protection. Proc. Natl Acad. Sci. USA 109, 2108–2113 (2012).

  111. 111.

    Fetissov, S. O. Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour. Nat. Rev. Endocrinol. 13, 11–25 (2016).

  112. 112.

    Rosenbaum, M., Knight, R. & Leibel, R. L. The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol. Metab. 26, 493–501 (2015).

  113. 113.

    McLoughlin, K., Schluter, J., Rakoff-Nahoum, S., Smith, A. L. & Foster, K. R. Host selection of microbiota via differential adhesion. Cell Host Microbe 19, 550–559 (2016).

  114. 114.

    Franzosa, E. A. et al. Sequencing and beyond: integrating molecular ‘omics’ for microbial community profiling. Nat. Rev. Microbiol. 13, 360–372 (2015).

  115. 115.

    Mitri, S. & Foster, K. R. The genotypic view of social interactions in microbial communities. Annu. Rev. Genet. 47, 247–273 (2013).

  116. 116.

    Nadell, C. D., Drescher, K. & Foster, K. R. Spatial structure, cooperation and competition in biofilms. Nat. Rev. Microbiol. 14, 589–600 (2016).

  117. 117.

    Markel, T. A. et al. The struggle for iron: gastrointestinal microbes modulate the host immune response during infection. J. Leukoc. Biol. 81, 393–400 (2007).

  118. 118.

    Choi, E.-Y. et al. Iron chelator triggers inflammatory signals in human intestinal epithelial cells: involvement of p38 and extracellular signal-regulated kinase signaling pathways. J. Immunol. 172, 7069–7077 (2004).

  119. 119.

    Weimer, P. J. Redundancy, resilience, and host specificity of the ruminal microbiota: implications for engineering improved ruminal fermentations. Front. Microbiol. 6, 296 (2015).

  120. 120.

    Caballero, S. et al. Cooperating commensals restore colonization resistance to vancomycin-resistant Enterococcus faecium. Cell Host Microbe 21, 592–602 (2017).

  121. 121.

    Thompson, J. N. Interaction and Coevolution (Univ. of Chicago Press, 1982).

  122. 122.

    Marchesi, J. R. & Ravel, J. The vocabulary of microbiome research: a proposal. Microbiome 3, 31 (2015).

  123. 123.

    Méthot, P.-O. & Alizon, S. What is a pathogen? Toward a process view of host-parasite interactions. Virulence 5, 775–785 (2014).

  124. 124.

    May, G. & Nelson, P. Defensive mutualisms: do microbial interactions within hosts drive the evolution of defensive traits? Funct. Ecol. 28, 356–363 (2014).

  125. 125.

    Hamilton, W. D. The genetical evolution of social behaviour I. J. Theor. Biol. 7, 1–16 (1964).

  126. 126.

    Hamilton, W. D. The genetical evolution of social behaviour II. J. Theor. Biol. 7, 17–52 (1964).

  127. 127.

    Bourke, A. F. G. Principles of Social Evolution (Oxford Univ. Press, 2011).

  128. 128.

    Wilson, E. O. Sociobiology: The New Synthesis (Harvard Univ. Press, 1975).

  129. 129.

    Sana, T. G., Lugo, K. A. & Monack, D. M. T6SS: the bacterial ‘fight club’ in the host gut. PLoS Pathog. 13, e1006325 (2017).

  130. 130.

    Mitri, S. & Foster, K. R. Pleiotropy and the low cost of individual traits promote cooperation. Evolution 70, 488–494 (2016).

  131. 131.

    Laterra, J., Keep, R., Betz, L. A. & Goldstein, G. W. in Basic Neurochemistry: Molecular, Cellular and Medical Aspects (eds Siegel, G. J., Agranoff, B. W., Albers, R. W., Fisher, S. K. & Uhler, M. D.) (Lippincott-Raven, 1999).

  132. 132.

    Forsythe, P. & Kunze, W. A. Voices from within: gut microbes and the CNS. Cell. Mol. Life Sci. 70, 55–69 (2013).

  133. 133.

    Fernstrom, J. D. Role of precursor availability in control of monoamine biosynthesis in brain. Physiol. Rev. 63, 484–546 (1983).

  134. 134.

    Banks, W. A. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 9, S3 (2009).

  135. 135.

    O’Mahony, S. M., Clarke, G., Borre, Y. E., Dinan, T. G. & Cryan, J. F. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav. Brain Res. 277, 32–48 (2015).

  136. 136.

    Fernstrom, J. D. & Wurtman, R. J. Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173, 149–152 (1971).

  137. 137.

    Biron, D. G. et al. Behavioural manipulation in a grasshopper harbouring hairworm: a proteomics approach. Proc. Biol. Sci. 272, 2117–2126 (2005).

Download references


The authors thank S. Knowles, S. Rakoff-Nahoum, E. Hsiao, J. Webster and three anonymous reviewers for helpful comments on the manuscript.

Author information


  1. Department of Experimental Psychology, University of Oxford, Oxford, UK

    • Katerina V.-A. Johnson
  2. Department of Zoology, University of Oxford, Oxford, UK

    • Kevin R. Foster


  1. Search for Katerina V.-A. Johnson in:

  2. Search for Kevin R. Foster in:


Both authors researched data for the article, substantially contributed to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Katerina V.-A. Johnson or Kevin R. Foster.