Abstract
Research on the microbiome and its interaction with various host organs, including the brain, is increasingly gaining momentum. With more evidence establishing a comprehensive microbiota-gut-brain axis, questions have been raised as to the extent to which microbes influence brain physiology and behaviour. In parallel, there is a growing literature showing active behavioural manipulation in favour of the microbe for certain parasites. However, it seems unclear where the hidden majority of microbes are localised on the parasitism-mutualism spectrum. A long evolutionary history intimately connects host and microbiota, which complicates this classification. In this conceptual minireview, we discuss current hypotheses on host-microbe interaction and argue that novel experimental approaches and theoretical concepts, such as the hologenome theory, are necessary to incorporate transgenerational epigenetic inheritance of the microbiome into evolutionary theories.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alcock J, Maley CC, Aktipis CA (2014) Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. BioEssays News Rev Mol Cell Dev Biol 36:940–949. doi:10.1002/bies.201400071
Bercik P, Verdu EF, Foster JA et al (2010) Chronic gastrointestinal inflammation induces anxiety-like behavior and alters central nervous system biochemistry in mice. Gastroenterology 139:2102–2112.e1. doi:10.1053/j.gastro.2010.06.063
Bercik P, Denou E, Collins J et al (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141:599–609:609.e1–3. doi:10.1053/j.gastro.2011.04.052
Bercik P, Collins SM, Verdu EF (2012) Microbes and the gut-brain axis. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc 24:405–413. doi:10.1111/j.1365-2982.2012.01906.x
Berer K, Mues M, Koutrolos M et al (2011) Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature 479:538–541. doi:10.1038/nature10554
Biron DG, Bonhomme L, Coulon M, Øverli Ø (2014) Microbiomes, plausible players or not in alteration of host behavior. Front Microbiol 5:775. doi:10.3389/fmicb.2014.00775
Borre YE, O’Keeffe GW, Clarke G et al (2014) Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med 20:509–518. doi:10.1016/j.molmed.2014.05.002
Braniste V, Al-Asmakh M, Kowal C et al (2014) The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med 6:263ra158. doi:10.1126/scitranslmed.3009759
Brew BJ, Chan P (2014) Update on HIV dementia and HIV-associated neurocognitive disorders. Curr Neurol Neurosci Rep 14:468. doi:10.1007/s11910-014-0468-2
Brucker RM, Bordenstein SR (2012) Speciation by symbiosis. Trends Ecol Evol 27:443–451. doi:10.1016/j.tree.2012.03.011
Brucker RM, Bordenstein SR (2013) The capacious hologenome. Zoology (Jena, Germany) 116:260–261. doi:10.1016/j.zool.2013.08.003
Cao X, Lin P, Jiang P, Li C (2013) Characteristics of the gastrointestinal microbiome in children with autism spectrum disorder: a systematic review. Shanghai Arch Psychiatry 25:342–353
Chung CY, Alden SL, Funderburg NT et al (2014) Progressive proximal-to-distal reduction in expression of the tight junction complex in colonic epithelium of virally-suppressed HIV+ individuals. PLoS Pathog 10:e1004198. doi:10.1371/journal.ppat.1004198
Claesson MJ, Jeffery IB, Conde S et al (2012) Gut microbiota composition correlates with diet and health in the elderly. Nature 488:178–184. doi:10.1038/nature11319
Clarke G, Grenham S, Scully P et al (2013a) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18:666–673. doi:10.1038/mp.2012.77
Clarke G, Grenham S, Scully P et al (2013b) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18:666–673. doi:10.1038/mp.2012.77
Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10:735–742. doi:10.1038/nrmicro2876
Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13:701–712. doi:10.1038/nrn3346
Decaestecker E, Gaba S, Raeymaekers JAM et al (2007) Host-parasite “Red Queen” dynamics archived in pond sediment. Nature 450:870–873. doi:10.1038/nature06291
Dheilly NM, Maure F, Ravallec M et al (2015) Who is the puppet master? Replication of a parasitic wasp-associated virus correlates with host behaviour manipulation. Proc R Soc Lond B Biol Sci 282:20142773. doi:10.1098/rspb.2014.2773
Diaz Heijtz R, Wang S, Anuar F et al (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108:3047–3052. doi:10.1073/pnas.1010529108
Dinan TG, Stanton C, Cryan JF (2013) Psychobiotics: a novel class of psychotropic. Biol Psychiatry. doi:10.1016/j.biopsych.2013.05.001
Dinan TG, Stilling RM, Stanton C, Cryan JF (2015) Collective unconscious: how gut microbes shape human behavior. J Psychiatr Res 63:1–9. doi:10.1016/j.jpsychires.2015.02.021
El Aidy S, Dinan TG, Cryan JF (2014) Immune modulation of the brain-gut-microbe axis. Front Microbiol 5:146. doi:10.3389/fmicb.2014.00146
El Aidy S, Dinan TG, Cryan JF (2015) Gut microbiota: the conductor in the orchestra of immune-neuroendocrine communication. Clin Ther. doi:10.1016/j.clinthera.2015.03.002
Fitzpatrick BM (2014) Symbiote transmission and maintenance of extra-genomic associations. Front Microbiol 5:46. doi:10.3389/fmicb.2014.00046
Flegr J (2013) Influence of latent Toxoplasma infection on human personality, physiology and morphology: pros and cons of the Toxoplasma–human model in studying the manipulation hypothesis. J Exp Biol 216:127–133. doi:10.1242/jeb.073635
Foster JA, Neufeld K-AM (2013) Gut–brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36:305–312. doi:10.1016/j.tins.2013.01.005
Funkhouser LJ, Bordenstein SR (2013) Mom knows best: the universality of maternal microbial transmission. PLoS Biol 11:e1001631. doi:10.1371/journal.pbio.1001631
Gilbert SF (2014) A holobiont birth narrative: the epigenetic transmission of the human microbiome. Front Genet 5:282. doi:10.3389/fgene.2014.00282
Gilbert SF, McDonald E, Boyle N et al (2010) Symbiosis as a source of selectable epigenetic variation: taking the heat for the big guy. Philos Trans R Soc B Biol Sci 365:671–678. doi:10.1098/rstb.2009.0245
Hohorst W, Graefe G (1961) Ameisen—obligatorische Zwischenwirte des Lanzettegels (Dicrocoelium dendriticum). Naturwissenschaften 48:229–230. doi:10.1007/BF00597502
Hughes DP, Brodeur J, Thomas F (2012) Host manipulation by parasites. Oxford University Press
Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207–214. doi:10.1038/nature11234
Jackson AC (2015) Diabolical effects of rabies encephalitis. J Neurovirol. doi:10.1007/s13365-015-0351-1
Jašarević E, Rodgers AB, Bale TL (2015) A novel role for maternal stress and microbial transmission in early life programming and neurodevelopment. Neurobiol Stress 1:81–88. doi:10.1016/j.ynstr.2014.10.005
Jeffery IB, O’Toole PW, Öhman L et al (2012) An irritable bowel syndrome subtype defined by species-specific alterations in faecal microbiota. Gut 61:997–1006. doi:10.1136/gutjnl-2011-301501
Kennedy PJ, Clarke G, O’Neill A, et al (2013) Cognitive performance in irritable bowel syndrome: evidence of a stress-related impairment in visuospatial memory. Psychol Med 1–14. doi: 10.1017/S0033291713002171
Kjartansdóttir KR, Friis-Nielsen J, Asplund M et al (2015) Traces of ATCV-1 associated with laboratory component contamination. Proc Natl Acad Sci U S A 112:E925–926. doi:10.1073/pnas.1423756112
Kodaman N, Pazos A, Schneider BG et al (2014) Human and Helicobacter pylori coevolution shapes the risk of gastric disease. Proc Natl Acad Sci U S A 111:1455–1460. doi:10.1073/pnas.1318093111
Lee YK, Mazmanian SK (2014) Microbial learning lessons: SFB educate the immune system. Immunity 40:457–459. doi:10.1016/j.immuni.2014.04.002
Lee YK, Menezes JS, Umesaki Y, Mazmanian SK (2011) Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 108(Suppl 1):4615–4622. doi:10.1073/pnas.1000082107
Li J, Jia H, Cai X et al (2014) An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol 32:834–841. doi:10.1038/nbt.2942
Liow LH, Van Valen L, Stenseth NC (2011) Red Queen: from populations to taxa and communities. Trends Ecol Evol 26:349–358. doi:10.1016/j.tree.2011.03.016
Lizé A, McKay R, Lewis Z (2013) Gut microbiota and kin recognition. Trends Ecol Evol 28:325–326. doi:10.1016/j.tree.2012.10.013
Lyte M (2011) Probiotics function mechanistically as delivery vehicles for neuroactive compounds: microbial endocrinology in the design and use of probiotics. BioEssays News Rev Mol Cell Dev Biol 33:574–581. doi:10.1002/bies.201100024
Lyte M (2013) Microbial endocrinology in the microbiome-gut-brain axis: how bacterial production and utilization of neurochemicals influence behavior. PLoS Pathog 9:e1003726. doi:10.1371/journal.ppat.1003726
Lyte M (2014) Microbial endocrinology and the microbiota-gut-brain axis. Adv Exp Med Biol 817:3–24. doi:10.1007/978-1-4939-0897-4_1
Mayer EA, Tillisch K, Gupta A (2015) Gut/brain axis and the microbiota. J Clin Invest 125:926–938. doi:10.1172/JCI76304
McFall-Ngai M, Hadfield MG, Bosch TCG et al (2013) Animals in a bacterial world, a new imperative for the life sciences. Proc Natl Acad Sci 110:3229–3236. doi:10.1073/pnas.1218525110
Messaoudi M, Lalonde R, Violle N et al (2011a) 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. doi:10.1017/S0007114510004319
Messaoudi M, Violle N, Bisson J-F et al (2011b) Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes 2:256–261. doi:10.4161/gmic.2.4.16108
Mielcarz DW, Kasper LH (2015) The gut microbiome in multiple sclerosis. Curr Treat Options Neurol 17:344. doi:10.1007/s11940-015-0344-7
Montiel-Castro, Augusto J, Baez-Yanez et al (2014) Social neuroeconomics: the influence of microbiota in partner-choice and sociality. Curr Pharm Des 20:4774–4783
Montiel-Castro AJ, González-Cervantes RM, Bravo-Ruiseco G, Pacheco-López G (2013) The microbiota–gut–brain axis: neurobehavioral correlates, health and sociality. Front Integr Neurosci 7:70. doi:10.3389/fnint.2013.00070
Moon C, Baldridge MT, Wallace MA et al (2015) Vertically transmitted faecal IgA levels determine extra-chromosomal phenotypic variation. Nature. doi:10.1038/nature14139
Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23:255–e119. doi:10.1111/j.1365-2982.2010.01620.x
O’Mahony SM, Marchesi JR, Scully P et al (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 65:263–267. doi:10.1016/j.biopsych.2008.06.026
Ochoa-Repáraz J, Kasper LH (2014) Gut microbiome and the risk factors in central nervous system autoimmunity. FEBS Lett 588:4214–4222. doi:10.1016/j.febslet.2014.09.024
Ochoa-Repáraz J, Mielcarz DW, Ditrio LE et al (2009) Role of gut commensal microflora in the development of experimental autoimmune encephalomyelitis. J Immunol (Baltimore Md) 183:6041–6050. doi:10.4049/jimmunol.0900747
Ochoa-Repáraz J, Mielcarz DW, Begum-Haque S, Kasper LH (2011) Gut, bugs, and brain: role of commensal bacteria in the control of central nervous system disease. Ann Neurol 69:240–247. doi:10.1002/ana.22344
Ogbonnaya ES, Clarke G, Shanahan F et al (2015) Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry. doi:10.1016/j.biopsych.2014.12.023
Öhman L, Törnblom H, Simrén M (2015) Crosstalk at the mucosal border: importance of the gut microenvironment in IBS. Nat Rev Gastroenterol Hepatol 12:36–49. doi:10.1038/nrgastro.2014.200
Phillips AC, Carroll D, Khan N, Moss P (2008) Cytomegalovirus is associated with depression and anxiety in older adults. Brain Behav Immun 22:52–55. doi:10.1016/j.bbi.2007.06.012
Ponton F, Lebarbenchon C, Lef|[egrave]|vre T et al (2006) Parasitology: parasite survives predation on its host. Nature 440:756–756. doi:10.1038/440756a
Romig T, Lucius R, Frank W (1980) Cerebral larvae in the second intermediate host of Dicrocoelium dendriticum (Rudolphi, 1819) and Dicrocoelium hospes Looss, 1907 (Trematodes, Dicrocoeliidae). Z Parasitenkd (Berlin, Germany) 63:277–286
Rook GA (2013) Regulation of the immune system by biodiversity from the natural environment: an ecosystem service essential to health. Proc Natl Acad Sci U S A 110:18360–18367. doi:10.1073/pnas.1313731110
Rook GAW, Lowry CA, Raison CL (2013) Microbial “Old Friends”, immunoregulation and stress resilience. Evol Med Public Health 2013:46–64. doi:10.1093/emph/eot004
Rook GAW, Raison CL, Lowry CA (2014) Microbiota, immunoregulatory old friends and psychiatric disorders. Adv Exp Med Biol 817:319–356. doi:10.1007/978-1-4939-0897-4_15
Rosenberg E, Koren O, Reshef L et al (2007) The role of microorganisms in coral health, disease and evolution. Nat Rev Microbiol 5:355–362. doi:10.1038/nrmicro1635
Rosenberg E, Sharon G, Zilber-Rosenberg I (2009) The hologenome theory of evolution contains Lamarckian aspects within a Darwinian framework. Environ Microbiol 11:2959–2962. doi:10.1111/j.1462-2920.2009.01995.x
Scheperjans F, Aho V, Pereira PAB et al (2014) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord Off J Mov Disord Soc. doi:10.1002/mds.26069
Sommer F, Bäckhed F (2013) The gut microbiota—masters of host development and physiology. Nat Rev Microbiol 11:227–238. doi:10.1038/nrmicro2974
Stilling RM, Bordenstein SR, Dinan TG, Cryan JF (2014a) Friends with social benefits: host-microbe interactions as a driver of brain evolution and development? Front Cell Infect Microbiol 4:147. doi:10.3389/fcimb.2014.00147
Stilling RM, Dinan TG, Cryan JF (2014b) Microbial genes, brain & behaviour—epigenetic regulation of the gut-brain axis. Genes Brain Behav 13:69–86. doi:10.1111/gbb.12109
Sweatt JD (2013) The emerging field of neuroepigenetics. Neuron 80:624–632. doi:10.1016/j.neuron.2013.10.023
Tillisch K, Labus J, Kilpatrick L et al (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144:1394–1401.e4. doi:10.1053/j.gastro.2013.02.043
Toh MC, Allen-Vercoe E (2015) The human gut microbiota with reference to autism spectrum disorder: considering the whole as more than a sum of its parts. Microb Ecol Health Dis 26:26309
Tung J, Barreiro LB, Burns MB et al (2015) Social networks predict gut microbiome composition in wild baboons. eLife 4:e05224. doi:10.7554/eLife.05224
Van Valen L (1973) An evolutionary law. Evol Theory 1:1–30
Vyboh K, Jenabian M-A, Mehraj V, Routy J-P (2015) HIV and the gut microbiota, partners in crime: breaking the vicious cycle to unearth new therapeutic targets. J Immunol Res 2015:614127. doi:10.1155/2015/614127
Wang Y, Kasper LH (2014) The role of microbiome in central nervous system disorders. Brain Behav Immun 38:1–12. doi:10.1016/j.bbi.2013.12.015
Yolken RH, Torrey EF (2008) Are some cases of psychosis caused by microbial agents? A review of the evidence. Mol Psychiatry 13:470–479. doi:10.1038/mp.2008.5
Yolken RH, Jones-Brando L, Dunigan DD et al (2014) Chlorovirus ATCV-1 is part of the human oropharyngeal virome and is associated with changes in cognitive functions in humans and mice. Proc Natl Acad Sci 111:16106–16111. doi:10.1073/pnas.1418895111
Yolken RH, Jones-Brando L, Dunigan DD et al (2015) Reply to Kjartansdóttir et al.: chlorovirus ATCV-1 findings not explained by contamination. Proc Natl Acad Sci U S A 112:E927. doi:10.1073/pnas.1424665112
Zilber-Rosenberg I, Rosenberg E (2008) Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution. FEMS Microbiol Rev 32:723–735. doi:10.1111/j.1574-6976.2008.00123.x
Acknowledgments
The Alimentary Pharmabiotic Centre is a research centre funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan (Grant Numbers 07/CE/B1368 and 12/RC/2273). R.M.S. is supported by the Irish Research Council (IRC) through a Government of Ireland Postdoctoral Fellowship (Grant Number GOIPD/2014/355). T. G. D. and J. F. C. are supported by SFI (Grant Number 07/CE/B1368 and 12/RC/2273). T. G. D. and J. F. C. are also supported by the Irish Health Research Board, the Department of Agriculture, Food and Fisheries and Forestry and Enterprise Ireland.
Conflict of interest
R.M.S. reports no conflict of interest. T.G.D. and J.F.C. are principal investigators in the Alimentary Pharmabiotic Centre, University College Cork. The Alimentary Pharmabiotic Centre has conducted research funded by Pfizer, GlaxoSmithKline, Proctor & Gamble, Mead Johnson, Suntory Wellness and Cremo. T.G.D. has been an invited speaker at meetings organised by Servier, Lundbeck, Janssen and AstraZeneca. J.F.C. has been an invited speaker at meetings organised by Mead Johnson, Yakult, Alkermes and Janssen.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Invited contribution to minireview series on “Mind-altering Microbes”
Guest editor: Alan C. Jackson
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1007/s13365-015-0355-x
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13365-015-0355-x