Canadian Psychiatric Association
Association des psychiatres du Canada
Editorial
Stress and the Microbiota-Gut-Brain Axis: An Evolving Concept in Psychiatry
The Canadian Journal of Psychiatry / La Revue Canadienne de Psychiatrie 2016, Vol. 61(4) 201-203 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0706743716635538 TheCJP.ca | LaRCP.ca
John F. Cryan, PhD1,2
The concept of the gut influencing brain and behaviour has existed for almost 2 centuries. However, this gut-brain axis has been best appreciated and studied in the context of eating behaviour. Nonetheless, despite this concept being widely integrated into our everyday vernacular (gut feelings, gut instinct, gutted, gutsy, it takes guts, butterflies in one’s tummy), it was not until the advent of brain imaging that neuroscientists really began to appreciate the influence of this axis on modulating brain function and maintaining homeostasis, especially during stressful situations. A new player has emerged in the past decade: the gut microbiota, which is now seen as a key regulator of the gut-brain axis. The gut is home to a diverse array of trillions of microbes (mainly bacteria but also archaea, viruses, and protozoa), which is 1.3 to 10 times the number of human cells. Advances in sequencing technologies show that the microbiota influences almost all aspects of human biology. Evidence of a crucial role for the microbiota in regulating stress-related changes in physiology, behaviour, and brain function has emerged mostly from animal studies. In 2004, Sudo and colleagues discovered that mice that grow up devoid of a microbiome (in a germ-free environment) have an exaggerated hypothalamic-pituitary axis response to stress; importantly, these researchers also found that this effect could be reversed by colonization with a specific bifidobacteria species. Converse findings soon emerged showing that stress (either early in life or in adulthood) changed the microbiota composition or depended on it to induce its deleterious effects. 1-6 The concept that bacteria were required for normal brain development emerged soon afterward.7-12 Indeed, the microbiota is shown to regulate many key processes in the adult brain, such as neurogenesis13 and microglia activation.14 Thus, the ability to target the brain via the microbiome is viewed as a paradigm shift in neuroscience and psychiatry.15,16 Moreover, this research led to the concept of psychobiotics (bacteria with positive effects on mental health), coined by Dinan et al. in 2013.17 Animal studies again lead the way in showing that specific strains of bifidobacteria, lactobacilli, or bacteroides can have positive effects on the brain and behaviour.9,18-21 These studies are
slowly being translated into research with healthy human volunteers.22-26 One immediate research goal is to elucidate the mechanisms underpinning the beneficial effects of specific bacterial strains. The role of microbiota composition as a susceptibility factor for various stressful insults, especially at key neurodevelopmental windows, is also emerging.27 Two articles in this special issue focus on the latter concept. Leclercq et al. focus on post-traumatic stress disorder (PTSD). There are limited clinical data implicating the microbiome in the susceptibility or treatment of PTSD. The authors review the available evidence and plausibly argue that there are converging pathways that enable the microbiome to gate susceptibility or resilience to stress in early life. Although the authors focus primarily on childhood trauma, the same logic would also apply to combatassociated or other forms of adult PTSD. In addition to gating stress susceptibility, the microbiome is primed to modify aspects of fear learning and extinction, amygdala-dependent processes thought to underpin PTSD at a neurobiological level. The fact that certain strains of bacteria are shown to enhance cognitive processes and affect fear learning in animal models also supports this concept.18,20,28-30 Additional research is needed, but this is an exciting area of pursuit. McVey Neufeld et al. also examine stress susceptibility and resilience in adolescence, a particularly vulnerable period for environmental influences on brain function and development of psychopathology.31 The authors review evidence that the microbiota could be targeted to confer protection from insults to the brain and to ameliorate the negative effects of stressors at this vulnerable period. There is a
1 2
APC Microbiome Institute, University College Cork, Cork, Ireland Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Corresponding Author: John F. Cryan, PhD, Department of Anatomy and Neuroscience, APC Microbiome Institute, 2.33 Western Gateway Building, University College Cork, Western Rd., Cork, Ireland. Email: [email protected]
202
growing interest in understanding the effects of microbiota perturbations at this life stage on behaviours relevant to stress and cognitive-related disorders.32,33 The use of microbiota-based strategies is in the early stages in all aspects of medicine, especially in psychiatry. The articles by Leclercq et al. and McVey Neufeld et al. highlight the promise of such an approach in treating stress-related disorders, especially at vulnerable time windows across the lifespan. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. O’Mahony SM, Marchesi JR, Scully P, et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65(3):263-267. 2. Bailey MT, Dowd SE, Galley JD, et al. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011;25(3):397-407. 3. De Palma G, Blennerhassett P, Lu J, et al. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun. 2015;6:7735. 4. Jasˇarevic´ E, Howerton CL, Howard CD, et al. 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. 5. Bharwani A, Mian MF, Foster JA, et al. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology. 2016; 63:217-227. 6. Golubeva AV, Crampton S, Desbonnet L, et al. Prenatal stressinduced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrinology. 2015;60:58-74. 7. Clarke G, Grenham S, Scully P, et al. The microbiome-gutbrain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18(6):666-673. 8. Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047-3052. 9. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7): 1451-1463. 10. Neufeld KA, Kang N, Bienenstock J, et al. Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol. 2011;4(4):492-494.
The Canadian Journal of Psychiatry 61(4)
11. 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. 12. Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141(2):599-609, e1-e3. 13. Ogbonnaya ES, Clarke G, Shanahan F, et al. Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry. 2015;78(4):e7-e9. 14. Erny D, Hrabe de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965-977. 15. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-712. 16. Mayer EA, Knight R, Mazmanian SK, et al. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014; 34(46):15490-15496. 17. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013;74(10):720-726. 18. Bravo JA, Forsythe P, Chew MV, 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 U S A. 2011;108(38):16050-16055. 19. Savignac HM, Kiely B, Dinan TG, et al. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil. 2014;26(11): 1615-1627. 20. Savignac HM, Tramullas M, Kiely B, et al. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res. 2015;287:59-72. 21. Bercik P, Park AJ, Sinclair D, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23(12):1132-1139. 22. Kato-Kataoka A, Nishida K, Takada M, et al. Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress. Benef Microbes. 2015 Dec 21; Epub ahead of print. 23. Mohammadi AA, Jazayeri S, Khosravi-Darani K, et al. The effects of probiotics on mental health and hypothalamicpituitary-adrenal axis: a randomized, double-blind, placebocontrolled trial in petrochemical workers. Nutr Neurosci. 2015 Apr 16; Epub ahead of print. 24. Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2(4):256-261. 25. Steenbergen L, Sellaro R, van Hemert S, et al. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015; 48:258-264.
La Revue Canadienne de Psychiatrie 61(4)
26. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-1401, 1401.e1-1401.e4. 27. Borre YE, O’Keeffe GW, Clarke G, et al. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014;20(9):509-518. 28. Liang S, Wang T, Hu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience. 2015;310:561-577. 29. Distrutti E, O’Reilly JA, McDonald C, et al. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP. PLoS One. 2014;9(9):e106503.
203
30. Gareau MG. Microbiota-gut-brain axis and cognitive function. Adv Exp Med Biol. 2014;817:357-371. 31. O’Connor RM, Cryan JF. Adolescent brain vulnerability and psychopathology through the generations: role of diet and dopamine. Biol Psychiatry. 2014;75(1):4-6. 32. Desbonnet L, Clarke G, Traplin A, et al. Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav Immun. 2015;48: 165-173. 33. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-312.
Association des psychiatres du Canada
Editorial
Stress and the Microbiota-Gut-Brain Axis: An Evolving Concept in Psychiatry
The Canadian Journal of Psychiatry / La Revue Canadienne de Psychiatrie 2016, Vol. 61(4) 201-203 ª The Author(s) 2016 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0706743716635538 TheCJP.ca | LaRCP.ca
John F. Cryan, PhD1,2
The concept of the gut influencing brain and behaviour has existed for almost 2 centuries. However, this gut-brain axis has been best appreciated and studied in the context of eating behaviour. Nonetheless, despite this concept being widely integrated into our everyday vernacular (gut feelings, gut instinct, gutted, gutsy, it takes guts, butterflies in one’s tummy), it was not until the advent of brain imaging that neuroscientists really began to appreciate the influence of this axis on modulating brain function and maintaining homeostasis, especially during stressful situations. A new player has emerged in the past decade: the gut microbiota, which is now seen as a key regulator of the gut-brain axis. The gut is home to a diverse array of trillions of microbes (mainly bacteria but also archaea, viruses, and protozoa), which is 1.3 to 10 times the number of human cells. Advances in sequencing technologies show that the microbiota influences almost all aspects of human biology. Evidence of a crucial role for the microbiota in regulating stress-related changes in physiology, behaviour, and brain function has emerged mostly from animal studies. In 2004, Sudo and colleagues discovered that mice that grow up devoid of a microbiome (in a germ-free environment) have an exaggerated hypothalamic-pituitary axis response to stress; importantly, these researchers also found that this effect could be reversed by colonization with a specific bifidobacteria species. Converse findings soon emerged showing that stress (either early in life or in adulthood) changed the microbiota composition or depended on it to induce its deleterious effects. 1-6 The concept that bacteria were required for normal brain development emerged soon afterward.7-12 Indeed, the microbiota is shown to regulate many key processes in the adult brain, such as neurogenesis13 and microglia activation.14 Thus, the ability to target the brain via the microbiome is viewed as a paradigm shift in neuroscience and psychiatry.15,16 Moreover, this research led to the concept of psychobiotics (bacteria with positive effects on mental health), coined by Dinan et al. in 2013.17 Animal studies again lead the way in showing that specific strains of bifidobacteria, lactobacilli, or bacteroides can have positive effects on the brain and behaviour.9,18-21 These studies are
slowly being translated into research with healthy human volunteers.22-26 One immediate research goal is to elucidate the mechanisms underpinning the beneficial effects of specific bacterial strains. The role of microbiota composition as a susceptibility factor for various stressful insults, especially at key neurodevelopmental windows, is also emerging.27 Two articles in this special issue focus on the latter concept. Leclercq et al. focus on post-traumatic stress disorder (PTSD). There are limited clinical data implicating the microbiome in the susceptibility or treatment of PTSD. The authors review the available evidence and plausibly argue that there are converging pathways that enable the microbiome to gate susceptibility or resilience to stress in early life. Although the authors focus primarily on childhood trauma, the same logic would also apply to combatassociated or other forms of adult PTSD. In addition to gating stress susceptibility, the microbiome is primed to modify aspects of fear learning and extinction, amygdala-dependent processes thought to underpin PTSD at a neurobiological level. The fact that certain strains of bacteria are shown to enhance cognitive processes and affect fear learning in animal models also supports this concept.18,20,28-30 Additional research is needed, but this is an exciting area of pursuit. McVey Neufeld et al. also examine stress susceptibility and resilience in adolescence, a particularly vulnerable period for environmental influences on brain function and development of psychopathology.31 The authors review evidence that the microbiota could be targeted to confer protection from insults to the brain and to ameliorate the negative effects of stressors at this vulnerable period. There is a
1 2
APC Microbiome Institute, University College Cork, Cork, Ireland Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
Corresponding Author: John F. Cryan, PhD, Department of Anatomy and Neuroscience, APC Microbiome Institute, 2.33 Western Gateway Building, University College Cork, Western Rd., Cork, Ireland. Email: [email protected]
202
growing interest in understanding the effects of microbiota perturbations at this life stage on behaviours relevant to stress and cognitive-related disorders.32,33 The use of microbiota-based strategies is in the early stages in all aspects of medicine, especially in psychiatry. The articles by Leclercq et al. and McVey Neufeld et al. highlight the promise of such an approach in treating stress-related disorders, especially at vulnerable time windows across the lifespan. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. O’Mahony SM, Marchesi JR, Scully P, et al. Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry. 2009;65(3):263-267. 2. Bailey MT, Dowd SE, Galley JD, et al. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011;25(3):397-407. 3. De Palma G, Blennerhassett P, Lu J, et al. Microbiota and host determinants of behavioural phenotype in maternally separated mice. Nat Commun. 2015;6:7735. 4. Jasˇarevic´ E, Howerton CL, Howard CD, et al. 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. 5. Bharwani A, Mian MF, Foster JA, et al. Structural & functional consequences of chronic psychosocial stress on the microbiome & host. Psychoneuroendocrinology. 2016; 63:217-227. 6. Golubeva AV, Crampton S, Desbonnet L, et al. Prenatal stressinduced alterations in major physiological systems correlate with gut microbiota composition in adulthood. Psychoneuroendocrinology. 2015;60:58-74. 7. Clarke G, Grenham S, Scully P, et al. The microbiome-gutbrain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry. 2013;18(6):666-673. 8. Diaz Heijtz R, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A. 2011;108(7):3047-3052. 9. Hsiao EY, McBride SW, Hsien S, et al. Microbiota modulate behavioral and physiological abnormalities associated with neurodevelopmental disorders. Cell. 2013;155(7): 1451-1463. 10. Neufeld KA, Kang N, Bienenstock J, et al. Effects of intestinal microbiota on anxiety-like behavior. Commun Integr Biol. 2011;4(4):492-494.
The Canadian Journal of Psychiatry 61(4)
11. 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. 12. Bercik P, Denou E, Collins J, et al. The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology. 2011;141(2):599-609, e1-e3. 13. Ogbonnaya ES, Clarke G, Shanahan F, et al. Adult hippocampal neurogenesis is regulated by the microbiome. Biol Psychiatry. 2015;78(4):e7-e9. 14. Erny D, Hrabe de Angelis AL, Jaitin D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18(7):965-977. 15. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701-712. 16. Mayer EA, Knight R, Mazmanian SK, et al. Gut microbes and the brain: paradigm shift in neuroscience. J Neurosci. 2014; 34(46):15490-15496. 17. Dinan TG, Stanton C, Cryan JF. Psychobiotics: a novel class of psychotropic. Biol Psychiatry. 2013;74(10):720-726. 18. Bravo JA, Forsythe P, Chew MV, 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 U S A. 2011;108(38):16050-16055. 19. Savignac HM, Kiely B, Dinan TG, et al. Bifidobacteria exert strain-specific effects on stress-related behavior and physiology in BALB/c mice. Neurogastroenterol Motil. 2014;26(11): 1615-1627. 20. Savignac HM, Tramullas M, Kiely B, et al. Bifidobacteria modulate cognitive processes in an anxious mouse strain. Behav Brain Res. 2015;287:59-72. 21. Bercik P, Park AJ, Sinclair D, et al. The anxiolytic effect of Bifidobacterium longum NCC3001 involves vagal pathways for gut-brain communication. Neurogastroenterol Motil. 2011;23(12):1132-1139. 22. Kato-Kataoka A, Nishida K, Takada M, et al. Fermented milk containing Lactobacillus casei strain Shirota prevents the onset of physical symptoms in medical students under academic examination stress. Benef Microbes. 2015 Dec 21; Epub ahead of print. 23. Mohammadi AA, Jazayeri S, Khosravi-Darani K, et al. The effects of probiotics on mental health and hypothalamicpituitary-adrenal axis: a randomized, double-blind, placebocontrolled trial in petrochemical workers. Nutr Neurosci. 2015 Apr 16; Epub ahead of print. 24. Messaoudi M, Violle N, Bisson JF, et al. Beneficial psychological effects of a probiotic formulation (Lactobacillus helveticus R0052 and Bifidobacterium longum R0175) in healthy human volunteers. Gut Microbes. 2011;2(4):256-261. 25. Steenbergen L, Sellaro R, van Hemert S, et al. A randomized controlled trial to test the effect of multispecies probiotics on cognitive reactivity to sad mood. Brain Behav Immun. 2015; 48:258-264.
La Revue Canadienne de Psychiatrie 61(4)
26. Tillisch K, Labus J, Kilpatrick L, et al. Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology. 2013;144(7):1394-1401, 1401.e1-1401.e4. 27. Borre YE, O’Keeffe GW, Clarke G, et al. Microbiota and neurodevelopmental windows: implications for brain disorders. Trends Mol Med. 2014;20(9):509-518. 28. Liang S, Wang T, Hu X, et al. Administration of Lactobacillus helveticus NS8 improves behavioral, cognitive, and biochemical aberrations caused by chronic restraint stress. Neuroscience. 2015;310:561-577. 29. Distrutti E, O’Reilly JA, McDonald C, et al. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP. PLoS One. 2014;9(9):e106503.
203
30. Gareau MG. Microbiota-gut-brain axis and cognitive function. Adv Exp Med Biol. 2014;817:357-371. 31. O’Connor RM, Cryan JF. Adolescent brain vulnerability and psychopathology through the generations: role of diet and dopamine. Biol Psychiatry. 2014;75(1):4-6. 32. Desbonnet L, Clarke G, Traplin A, et al. Gut microbiota depletion from early adolescence in mice: implications for brain and behaviour. Brain Behav Immun. 2015;48: 165-173. 33. Foster JA, McVey Neufeld KA. Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci. 2013;36(5):305-312.
