, Volume 15, Issue 1, pp 31–35 | Cite as

The Microbiome–Gut–Behavior Axis: Crosstalk Between the Gut Microbiome and Oligodendrocytes Modulates Behavioral Responses

  • Achilles Ntranos
  • Patrizia Casaccia


Environmental and dietary stimuli have always been implicated in brain development and behavioral responses. The gut, being the major portal of communication with the external environment, has recently been brought to the forefront of this interaction with the establishment of a gut–brain axis in health and disease. Moreover, recent breakthroughs in germ-free and antibiotic-treated mice have demonstrated the significant impact of the microbiome in modulating behavioral responses in mice and have established a more specific microbiome–gut–behavior axis. One of the mechanisms by which this axis affects social behavior is by regulating myelination at the prefrontal cortex, an important site for complex cognitive behavior planning and decision-making. The prefrontal cortex exhibits late myelination of its axonal projections that could extend into the third decade of life in humans, which make it susceptible to external influences, such as microbial metabolites. Changes in the gut microbiome were shown to alter the composition of the microbial metabolome affecting highly permeable bioactive compounds, such as p-cresol, which could impair oligodendrocyte differentiation. Dysregulated myelination in the prefrontal cortex is then able to affect behavioral responses in mice, shifting them towards social isolation. The reduced social interactions could then limit microbial exchange, which could otherwise pose a threat to the survival of the existing microbial community in the host and, thus, provide an evolutionary advantage to the specific microbial community. In this review, we will analyze the microbiome–gut–behavior axis, describe the interactions between the gut microbiome and oligodendrocytes and highlight their role in the modulation of social behavior.

Key Words

Gut microbiome • myelin plasticity • social behavior • metabolites • oligodendrocytes • prefrontal cortex 


Required Author Forms

Disclosure forms provided by the authors are available with the online version of this article.

Supplementary material

13311_2017_597_MOESM1_ESM.pdf (1.2 mb)
ESM 1 (PDF 1224 kb)


  1. 1.
    Fuster JM. Frontal lobe and cognitive development. J Neurocytol. 2003;31(3–5):373–385.Google Scholar
  2. 2.
    Kanji S, Fonseka TM, Marshe VS, Sriretnakumar V, Hahn MK, Müller DJ. The microbiome-gut-brain axis: implications for schizophrenia and antipsychotic induced weight gain. Eur Arch Psychiatry Clin Neurosci 2017.Google Scholar
  3. 3.
    Sharon G, Sampson TR, Geschwind DH, Mazmanian SK. The central nervous system and the gut microbiome. Cell 2016; 167: 915–932.CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell 2013;155(7):1451–1463.CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    Tanji J, Hoshi E. Behavioral planning in the prefrontal cortex. Curr Opin Neurobiol. 2001;11(2):164–170.CrossRefPubMedGoogle Scholar
  6. 6.
    Franklin TB, Silva BA, Perova Z, et al. Prefrontal cortical control of a brainstem social behavior circuit. Nat Neurosci. 2017;20(2):260–270.CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Kikusui T, Kiyokawa Y, Mori Y. Deprivation of mother-pup interaction by early weaning alters myelin formation in male, but not female, ICR mice. Brain Res. 2007;1133(1):115–122.CrossRefPubMedGoogle Scholar
  8. 8.
    Makinodan M, Rosen KM, Ito S, Corfas G. A critical period for social experience–dependent oligodendrocyte maturation and myelination. Science 2012;337(September):1357–1360.CrossRefPubMedCentralPubMedGoogle Scholar
  9. 9.
    Wallace DL, Han M-H, Graham DL, et al. CREB regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits. Nat Neurosci. 2009;12(2):200–209.CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Regenold WT, D’Agostino CA, Ramesh N, Hasnain M, Roys S, Gullapalli RP. Diffusion-weighted magnetic resonance imaging of white matter in bipolar disorder: a pilot study. Bipolar Disord. 2006;8(2):188–195.CrossRefPubMedGoogle Scholar
  11. 11.
    Liu J, Dietz K, DeLoyht JM, et al. Impaired adult myelination in the prefrontal cortex of socially isolated mice. Nat Neurosci. 2012;15(12):1621–1623.CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Mehta MA, Golembo NI, Nosarti C, et al. Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: the English and Romanian Adoptees study pilot. J Child Psychol Psychiatry. 2009;50(8):943–951.CrossRefPubMedGoogle Scholar
  13. 13.
    Rutter M, Colvert E, Kreppner J, et al. Early adolescent outcomes for institutionally-deprived and non-deprived adoptees. I: Disinhibited attachment. J Child Psychol Psychiatry Allied Discip. 2007;48(1):17–30.CrossRefGoogle Scholar
  14. 14.
    Nelson CA, Bos K, Gunnar MR, Sonuga-Barke, EJS. The neurobiological toll of early human deprivation. Monogr Soc Res Child Dev 2011;76(4):127–146.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Sonuga-Barke EJ, Schlotz W, Kreppner J. Differentiating developmental trajectories for conduct, emotion, and peer problems following early deprivation. Monogr Soc Res Child Dev. 2010;75(1):102–124.CrossRefPubMedGoogle Scholar
  16. 16.
    Scholz J, Klein MC, Behrens TE, Johansen-Berg H. Training induces changes in white-matter architecture. Nat Neurosci 2009;12(11):1370–1371.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Liu J, Dupree JL, Gacias M, et al. Clemastine enhances myelination in the prefrontal cortex and rescues behavioral changes in socially isolated mice. J Neurosci. 2016;36(3):957–962.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Yano JM, Yu K, Donaldson GP, et al. Indigenous bacteria from the gut microbiota regulate host serotonin biosynthesis. Cell 2015;161(2):264–276.CrossRefPubMedCentralPubMedGoogle Scholar
  19. 19.
    Jašarević E, Howerton CL, Howard CD, Bale TL. Alterations in the vaginal microbiome by maternal stress are associated with metabolic reprogramming of the offspring gut and brain. Endocrinology 2015;156(9):3265–3276.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Hoban AE, Stilling RM, Ryan FJ, et al. Regulation of prefrontal cortex myelination by the microbiota. Transl Psychiatry 2016;6(4):e774.CrossRefPubMedCentralPubMedGoogle Scholar
  21. 21.
    Gacias M, Gaspari S, Santos PMG, et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife 2016;5.Google Scholar
  22. 22.
    Flight MH. Neurodevelopmental disorders: The gut–microbiome–brain connection. Nat Rev Neurosci. 2013;15(2):65.Google Scholar
  23. 23.
    Han Y, Li Q, Dy ABC, Hagerman RJ. The gut microbiota and autism spectrum disorders. Front Cell Neurosci 2017;11:120.CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Westfall S, Lomis N, Kahouli I, Dia SY, Singh SP, Prakash S. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell Mol Life Sci 2017;74:3769-3787.CrossRefPubMedGoogle Scholar
  25. 25.
    O’Mahony SM, Clarke G, Borre YE, Dinan TG, Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 2015;227: 32–48.CrossRefGoogle Scholar
  26. 26.
    Ochoa-Reparaz J, Mielcarz DW, Begum-Haque S, Kasper LH. Gut, bugs, and brain: Role of commensal bacteria in the control of central nervous system disease. Ann Neurol 2011;69(2):240–247.CrossRefPubMedGoogle Scholar
  27. 27.
    Burokas A, Moloney RD, Dinan TG, Cryan JF. Microbiota regulation of the mammalian gut-brain axis. Adv Appl Microbiol. 2015;91:1–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Wikoff WR, Anfora AT, Liu J, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009;106(10):3698–3703.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Mosher KI, Wyss-Coray T. Go with your gut: microbiota meet microglia. Nat Neurosci. 2015;18(7):930–931.CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Michel L, Prat A. One more role for the gut: microbiota and blood brain barrier. Ann Transl Med 2016;4(1):15.PubMedCentralPubMedGoogle Scholar
  31. 31.
    Ogbonnaya ES, Clarke G, Shanahan F, Dinan TG, Cryan JF, O’Leary OF. Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry 2015; 78: e7–39.CrossRefPubMedGoogle Scholar
  32. 32.
    Luczynski P, Neufeld KAMV, Oriach CS, Clarke G, Dinan TG, Cryan JF. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 2016;19(8):1–17.CrossRefGoogle Scholar
  33. 33.
    Desbonnet L, Clarke G, Shanahan F, Dinan TG, Cryan JF. Microbiota is essential for social development in the mouse. Mol Psychiatry 2014;19(2):146–148.CrossRefPubMedGoogle Scholar
  34. 34.
    Neufeld KM, Kang N, Bienenstock J, Foster JA. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 2011;23(3):255-e119.CrossRefPubMedGoogle Scholar
  35. 35.
    Hoban AE, Stilling RM, Moloney G, et al. The microbiome regulates amygdala-dependent fear recall. Mol Psychiatry 2017.Google Scholar
  36. 36.
    Strati F, Cavalieri D, Albanese D, et al. New evidences on the altered gut microbiota in autism spectrum disorders. Microbiome. 2017;5(1):24.CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Huuskonen J, Suuronen T, Nuutinen T, Kyrylenko S, Salminen A. Regulation of microglial inflammatory response by sodium butyrate and short-chain fatty acids. Br J Pharmacol. 2004;141(5):874–880.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Shen S, Sandoval J, Swiss VA, et al. Age-dependent epigenetic control of differentiation inhibitors is critical for remyelination efficiency. Nat Neurosci. 2008;11(9):1024–1034.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Stilling RM, Ryan FJ, Hoban AE, et al. Microbes & neurodevelopment—Absence of microbiota during early life increases activity-related transcriptional pathways in the amygdala. Brain Behav Immun 2015;50:209–220.CrossRefPubMedGoogle Scholar
  40. 40.
    Tomassy GS, Dershowitz LB, Arlotta P. Diversity matters: a revised guide to myelination. Trends Cell Biol 2016;26:135–147.CrossRefPubMedGoogle Scholar
  41. 41.
    Wake H, Lee PR, Fields RD. Control of local protein synthesis and initial events in myelination by action potentials. Science 2011;333(6049):1647–1651.CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Wallace CJK, Milev R. The effects of probiotics on depressive symptoms in humans: a systematic review. Ann Gen Psychiatry 2017;16:14.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Dominguez-Bello MG, De Jesus-Laboy KM, Shen N, et al. Partial restoration of the microbiota of cesarean-born infants via vaginal microbial transfer. Nat Med 2016;22(3):250–253.CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2017

Authors and Affiliations

  1. 1.The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of NeurologyIcahn School of Medicine at Mount SinaiNew YorkUSA
  2. 2.Neuroscience InitiativeCUNY Advanced Science Research CenterNew YorkUSA
  3. 3.Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA

Personalised recommendations