Skip to main content
View expanded cover

Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease pp 357–371Cite as

Microbiota-Gut-Brain Axis and Cognitive Function

Part of the Advances in Experimental Medicine and Biology book series (MICENDO,volume 817)

Abstract

Recent studies have demonstrated a clear association between changes in the microbiota and cognitive behavior. Intestinal dysbiosis, as modeled using GF mice (containing no microbiota), bacterial infection with an enteric pathogen, and administration of probiotics, can modulate cognitive behavior including learning and memory. This chapter will highlight recent findings in both human and animal studies indicating how changes in the composition and diversity of the microbiota can impact behavior and brain physiology in both disease states and in health. Cognitive behavior can not only be affected in cases of intestinal disease, but also manifests changes in extra-intestinal disease conditions.

Keywords

  • Inflammatory Bowel Disease
  • Irritable Bowel Syndrome
  • Hepatic Encephalopathy
  • Intestinal Microbiota
  • Maternal Separation

These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

This is a preview of subscription content, access via your institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • DOI: 10.1007/978-1-4939-0897-4_16
  • Chapter length: 15 pages
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
eBook
USD   219.00
Price excludes VAT (USA)
  • ISBN: 978-1-4939-0897-4
  • Instant PDF download
  • Readable on all devices
  • Own it forever
  • Exclusive offer for individuals only
  • Tax calculation will be finalised during checkout
Softcover Book
USD   279.99
Price excludes VAT (USA)
Hardcover Book
USD   279.99
Price excludes VAT (USA)
Learn about institutional subscriptions
Fig. 16.1

Abbreviations

5-HT:

Serotonin

ANS:

Autonomic nervous system

BDNF:

Brain derived neurotropic factor

CD:

Crohn’s disease

CREB:

cAMP response element binding protein

CRF:

Corticotrophin-releasing factor

DA:

Dopamine

DLPFC:

Dorsolateral pre-frontal cortex

EPSP:

Excitatory postsynaptic potential

GF:

Germ-free

GI:

gastrointestinal

HE:

Hepatic encephalopathy

HPA:

Hypothalamus-pituitary-adrenal

IBD:

Inflammatory bowel disease

IBS:

Irritable bowel syndrome

LPS:

Lipopolysaccharide

MS:

Maternal separation

NGF:

Nerve growth factor

PAMPs:

pathogen associated molecular patterns

PGN:

Peptidoglycan

SPF:

Specific pathogen free

UC:

Ulcerative colitis

References

  1. Cryan JF, Dinan TG (2012) Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13(10):701–712

    CAS  PubMed  CrossRef  Google Scholar 

  2. Gareau MG, Sherman PM, Walker WA (2010) Probiotics and the gut microbiota in intestinal health and disease. Nat Rev Gastroenterol Hepatol 7(9):503–514

    PubMed  CrossRef  Google Scholar 

  3. Collins SM, Surette M, Bercik P (2012) The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol 10(11):735–742

    CAS  PubMed  CrossRef  Google Scholar 

  4. Sudo N, Chida Y, Aiba Y, Sonoda J, Oyama N, Yu XN et al (2004) Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 558(Pt 1):263–275

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  5. Gareau MG, Wine E, Rodrigues DM, Cho JH, Whary MT, Philpott DJ et al (2011) Bacterial infection causes stress-induced memory dysfunction in mice. Gut 60(3):307–317

    PubMed  CrossRef  Google Scholar 

  6. Cowansage KK, LeDoux JE, Monfils MH (2010) Brain-derived neurotrophic factor: a dynamic gatekeeper of neural plasticity. Curr Mol Pharmacol 3(1):12–29

    CAS  PubMed  CrossRef  Google Scholar 

  7. Mizuno K, Giese KP (2005) Hippocampus-dependent memory formation: do memory type-specific mechanisms exist? J Pharmacol Sci 98(3):191–197

    CAS  PubMed  CrossRef  Google Scholar 

  8. Heijtz RD, Wang S, Anuar F, Qian Y, Bjorkholm B, Samuelsson A et al (2011) Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci U S A 108(7):3047–3052

    CAS  PubMed Central  CrossRef  Google Scholar 

  9. Clarke G, Grenham S, Scully P, Fitzgerald P, Moloney RD, Shanahan F et al (2013) The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 18(6):666–673

    CAS  PubMed  CrossRef  Google Scholar 

  10. Bercik P, Denou E, Collins J, Jackson W, Lu J, Jury J et al (2011) The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141(2):599–609, e1–e3

    Google Scholar 

  11. Neufeld KM, Kang N, Bienenstock J, Foster JA (2011) Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol Motil 23(3):255–264, e119

    Google Scholar 

  12. Matsumoto M, Kibe R, Ooga T, Aiba Y, Sawaki E, Koga Y et al (2013) Cerebral low-molecular metabolites influenced by intestinal microbiota: a pilot study. Front Syst Neurosci 7:9

    PubMed Central  PubMed  CrossRef  Google Scholar 

  13. Schmitt JA, Wingen M, Ramaekers JG, Evers EA, Riedel WJ (2006) Serotonin and human cognitive performance. Curr Pharm Des 12(20):2473–2486

    CAS  PubMed  CrossRef  Google Scholar 

  14. O’Brien ME, Anderson H, Kaukel E, O’Byrne K, Pawlicki M, Von Pawel J et al (2004) SRL172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer: phase III results. Ann Oncol 15(6):906–914

    PubMed  CrossRef  Google Scholar 

  15. Matthews DM, Jenks SM (2013) Ingestion of Mycobacterium vaccae decreases anxiety-related behavior and improves learning in mice. Behav Processes 96:27–35

    PubMed  CrossRef  Google Scholar 

  16. Lowry CA, Hollis JH, de Vries A, Pan B, Brunet LR, Hunt JR et al (2007) Identification of an immune-responsive mesolimbocortical serotonergic system: potential role in regulation of emotional behavior. Neuroscience 146(2):756–772

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  17. Bonaz BL, Bernstein CN (2013) Brain-gut interactions in inflammatory bowel disease. Gastroenterology 144(1):36–49

    PubMed  CrossRef  Google Scholar 

  18. Soderholm JD, Yang PC, Ceponis P, Vohra A, Riddell R, Sherman PM et al (2002) Chronic stress induces mast cell-dependent bacterial adherence and initiates mucosal inflammation in rat intestine. Gastroenterology 123(4):1099–1108

    PubMed  CrossRef  Google Scholar 

  19. Sun Y, Zhang M, Chen CC, Gillilland M, 3rd, Sun X, El-Zaatari M et al (2013) Stress-induced corticotropin-releasing hormone-mediated NLRP6 inflammasome inhibition and transmissible enteritis in mice. Gastroenterology 144(7):1478–1487 e8

    Google Scholar 

  20. Cameron HL, Perdue MH (2005) Stress impairs murine intestinal barrier function: improvement by glucagon-like peptide-2. J Pharmacol Exp Ther 314(1):214–220

    CAS  PubMed  CrossRef  Google Scholar 

  21. Sweis BM, Veverka KK, Dhillon ES, Urban JH, Lucas LR (2013) Individual differences in the effects of chronic stress on memory: behavioral and neurochemical correlates of resiliency. Neuroscience 246C:142–159

    CrossRef  Google Scholar 

  22. Bailey MT, Dowd SE, Parry NM, Galley JD, Schauer DB, Lyte M (2010) Stressor exposure disrupts commensal microbial populations in the intestines and leads to increased colonization by Citrobacter rodentium. Infect Immun 78(4):1509–1519

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  23. Zareie M, Johnson-Henry K, Jury J, Yang PC, Ngan BY, McKay DM et al (2006) Probiotics prevent bacterial translocation and improve intestinal barrier function in rats following chronic psychological stress. Gut 55(11):1553–1560

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  24. Wagner KV, Hartmann J, Mangold K, Wang XD, Labermaier C, Liebl C et al (2013) Homer1 mediates acute stress-induced cognitive deficits in the dorsal hippocampus. J Neurosci 33(9):3857–3864

    CAS  PubMed  CrossRef  Google Scholar 

  25. Soderholm JD, Yates DA, Gareau MG, Yang PC, MacQueen G, Perdue MH (2002) Neonatal maternal separation predisposes adult rats to colonic barrier dysfunction in response to mild stress. Am J Physiol Gastrointest Liver Physiol 283(6):G1257–G1263

    CAS  PubMed  Google Scholar 

  26. Uchida S, Hara K, Kobayashi A, Funato H, Hobara T, Otsuki K et al (2010) Early life stress enhances behavioral vulnerability to stress through the activation of REST4-mediated gene transcription in the medial prefrontal cortex of rodents. J Neurosci 30(45):15007–15018

    CAS  PubMed  CrossRef  Google Scholar 

  27. Gareau MG, Jury J, Yang PC, MacQueen G, Perdue MH (2006) Neonatal maternal separation causes colonic dysfunction in rat pups including impaired host resistance. Pediatr Res 59(1):83–88

    PubMed  CrossRef  Google Scholar 

  28. Gareau MG, Jury J, MacQueen G, Sherman PM, Perdue MH (2007) Probiotic treatment of rat pups normalises corticosterone release and ameliorates colonic dysfunction induced by maternal separation. Gut 56(11):1522–1528

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  29. O’Mahony SM, Marchesi JR, Scully P, Codling C, Ceolho AM, Quigley EM et al (2009) Early life stress alters behavior, immunity, and microbiota in rats: implications for irritable bowel syndrome and psychiatric illnesses. Biol Psychiatry 65(3):263–267

    PubMed  CrossRef  Google Scholar 

  30. Barreau F, Ferrier L, Fioramonti J, Bueno L (2004) Neonatal maternal deprivation triggers long term alterations in colonic epithelial barrier and mucosal immunity in rats. Gut 53(4):501–506

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  31. Barreau F, de Lahitte JD, Ferrier L, Frexinos J, Bueno L, Fioramonti J (2006) Neonatal maternal deprivation promotes Nippostrongylus brasiliensis infection in adult rats. Brain Behav Immun 20(3):254–260

    PubMed  CrossRef  Google Scholar 

  32. Suri D, Veenit V, Sarkar A, Thiagarajan D, Kumar A, Nestler EJ et al (2013) Early stress evokes age-dependent biphasic changes in hippocampal neurogenesis, BDNF expression, and cognition. Biol Psychiatry 73(7):658–666

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  33. Couto FS, Batalha VL, Valadas JS, Data-Franca J, Ribeiro JA, Lopes LV (2012) Escitalopram improves memory deficits induced by maternal separation in the rat. Eur J Pharmacol 695(1–3):71–75

    CAS  PubMed  CrossRef  Google Scholar 

  34. Aisa B, Gil-Bea FJ, Marcos B, Tordera R, Lasheras B, Del Rio J et al (2009) Neonatal stress affects vulnerability of cholinergic neurons and cognition in the rat: involvement of the HPA axis. Psychoneuroendocrinology 34(10):1495–1505

    CAS  PubMed  CrossRef  Google Scholar 

  35. Baudin A, Blot K, Verney C, Estevez L, Santamaria J, Gressens P et al (2012) Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex. Neurobiol Learn Mem 98(3):207–214

    CAS  PubMed  CrossRef  Google Scholar 

  36. Meyer U, Feldon J, Fatemi SH (2009) In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev 33(7):1061–1079

    CAS  PubMed  CrossRef  Google Scholar 

  37. Jiang PF, Zhu T, Gao JD, Gao F, Mao SS, Zhao WT et al (2013) The effect of maternal infection on cognitive development and hippocampus neuronal apoptosis, proliferation and differentiation in the neonatal rats. Neuroscience 246:422–434

    Google Scholar 

  38. Wang KC, Fan LW, Kaizaki A, Pang Y, Cai Z, Tien LT (2013) Neonatal lipopolysaccharide exposure induces long-lasting learning impairment, less anxiety-like response and hippocampal injury in adult rats. Neuroscience 234:146–157

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  39. Bilbo SD, Newsum NJ, Sprunger DB, Watkins LR, Rudy JW, Maier SF (2007) Differential effects of neonatal handling on early life infection-induced alterations in cognition in adulthood. Brain Behav Immun 21(3):332–342

    PubMed  CrossRef  Google Scholar 

  40. Ratnayake U, Quinn TA, Castillo-Melendez M, Dickinson H, Walker DW (2012) Behaviour and hippocampus-specific changes in spiny mouse neonates after treatment of the mother with the viral-mimetic Poly I:C at mid-pregnancy. Brain Behav Immun 26(8):1288–1299

    CAS  PubMed  CrossRef  Google Scholar 

  41. Katan M, Moon YP, Paik MC, Sacco RL, Wright CB, Elkind MS (2013) Infectious burden and cognitive function: the Northern Manhattan Study. Neurology 80(13):1209–1215

    PubMed Central  PubMed  CrossRef  Google Scholar 

  42. Strandberg TE, Pitkala KH, Linnavuori KH, Tilvis RS (2003) Impact of viral and bacterial burden on cognitive impairment in elderly persons with cardiovascular diseases. Stroke 34(9):2126–2131

    PubMed  CrossRef  Google Scholar 

  43. Ringel Y, Maharshak N (2013) The intestinal microbiota and immune function in the pathogenesis of irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol 305:G529–G541

    Google Scholar 

  44. Stasi C, Rosselli M, Bellini M, Laffi G, Milani S (2012) Altered neuro-endocrine-immune pathways in the irritable bowel syndrome: the top-down and the bottom-up model. J Gastroenterol 47(11):1177–1185

    CAS  PubMed  CrossRef  Google Scholar 

  45. Ghoshal UC, Ranjan P (2011) Post-infectious irritable bowel syndrome: the past, the present and the future. J Gastroenterol Hepatol 26(Suppl 3):94–101

    PubMed  CrossRef  Google Scholar 

  46. Gomborone JE, Dewsnap PA, Libby GW, Farthing MJ (1993) Selective affective biasing in recognition memory in the irritable bowel syndrome. Gut 34(9):1230–1233

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  47. Gibbs-Gallagher N, Palsson OS, Levy RL, Meyer K, Drossman DA, Whitehead WE (2001) Selective recall of gastrointestinal-sensation words: evidence for a cognitive-behavioral contribution to irritable bowel syndrome. Am J Gastroenterol 96(4):1133–1138

    CAS  PubMed  CrossRef  Google Scholar 

  48. Kilkens TO, Honig A, van Nieuwenhoven MA, Riedel WJ, Brummer RJ (2004) Acute tryptophan depletion affects brain-gut responses in irritable bowel syndrome patients and controls. Gut 53(12):1794–1800

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  49. Aizawa E, Sato Y, Kochiyama T, Saito N, Izumiyama M, Morishita J et al (2012) Altered cognitive function of prefrontal cortex during error feedback in patients with irritable bowel syndrome, based on FMRI and dynamic causal modeling. Gastroenterology 143(5):1188–1198

    PubMed  CrossRef  Google Scholar 

  50. Faust AH, Halpern LF, Danoff-Burg S, Cross RK (2012) Psychosocial factors contributing to inflammatory bowel disease activity and health-related quality of life. Gastroenterol Hepatol (N Y) 8(3):173–181

    Google Scholar 

  51. Goodhand JR, Wahed M, Mawdsley JE, Farmer AD, Aziz Q, Rampton DS (2012) Mood disorders in inflammatory bowel disease: relation to diagnosis, disease activity, perceived stress, and other factors. Inflamm Bowel Dis 18:2301–2309

    Google Scholar 

  52. Goodhand JR, Greig FI, Koodun Y, McDermott A, Wahed M, Langmead L et al (2012) Do antidepressants influence the disease course in inflammatory bowel disease? A retrospective case-matched observational study. Inflamm Bowel Dis 18:1232–1239

    Google Scholar 

  53. Dancey CP, Attree EA, Stuart G, Wilson C, Sonnet A (2009) Words fail me: the verbal IQ deficit in inflammatory bowel disease and irritable bowel syndrome. Inflamm Bowel Dis 15(6):852–857

    PubMed  CrossRef  Google Scholar 

  54. Attree EA, Dancey CP, Keeling D, Wilson C (2003) Cognitive function in people with chronic illness: inflammatory bowel disease and irritable bowel syndrome. Appl Neuropsychol 10(2):96–104

    PubMed  CrossRef  Google Scholar 

  55. Castaneda AE, Tuulio-Henriksson A, Aronen ET, Marttunen M, Kolho KL (2013) Cognitive functioning and depressive symptoms in adolescents with inflammatory bowel disease. World J Gastroenterol 19(10):1611–1617

    PubMed Central  PubMed  CrossRef  Google Scholar 

  56. Mrakotsky C, Forbes PW, Bernstein JH, Grand RJ, Bousvaros A, Szigethy E et al (2013) Acute cognitive and behavioral effects of systemic corticosteroids in children treated for inflammatory bowel disease. J Int Neuropsychol Soc 19(1):96–109

    PubMed Central  PubMed  CrossRef  Google Scholar 

  57. Jeffery IB, O’Toole PW (2013) Diet-microbiota interactions and their implications for healthy living. Nutrients 5(1):234–252

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  58. Hold GL (2014) Western lifestyle: a ‘master’ manipulator of the intestinal microbiota? Gut 63:5–6

    Google Scholar 

  59. Li W, Dowd SE, Scurlock B, Acosta-Martinez V, Lyte M (2009) Memory and learning behavior in mice is temporally associated with diet-induced alterations in gut bacteria. Physiol Behav 96(4–5):557–567

    CAS  PubMed  CrossRef  Google Scholar 

  60. Ohland CL, Kish L, Bell H, Thiesen A, Hotte N, Pankiv E et al (2013) Effects of Lactobacillus helveticus on murine behavior are dependent on diet and genotype and correlate with alterations in the gut microbiome. Psychoneuroendocrinology 38:1738–1747

    Google Scholar 

  61. Tillisch K, Labus J, Kilpatrick L, Jiang Z, Stains J, Ebrat B et al (2013) Consumption of fermented milk product with probiotic modulates brain activity. Gastroenterology 144(7):1394–1401 e4

    Google Scholar 

  62. Lien do TK, Nhung BT, Khan NC, Hop le T, Nga NT, Hung NT et al (2009) Impact of milk consumption on performance and health of primary school children in rural Vietnam. Asia Pac J Clin Nutr 18(3):326–334

    Google Scholar 

  63. Benton D, Williams C, Brown A (2007) Impact of consuming a milk drink containing a probiotic on mood and cognition. Eur J Clin Nutr 61(3):355–361

    CAS  PubMed  CrossRef  Google Scholar 

  64. Davari S, Talaei SA, Alaei H, Salami M (2013) Probiotics treatment improves diabetes-induced impairment of synaptic activity and cognitive function: behavioral and electrophysiological proofs for microbiome-gut-brain axis. Neuroscience 240:287–296

    CAS  PubMed  CrossRef  Google Scholar 

  65. Benjamin J, Singla V, Arora I, Sood S, Joshi YK (2013) Intestinal permeability and complications in liver cirrhosis: a prospective cohort study. Hepatol Res 43(2):200–207

    CAS  PubMed  CrossRef  Google Scholar 

  66. Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S et al (2012) Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J Physiol Gastrointest Liver Physiol 302(1):G168–G175

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  67. Patidar KR, Bajaj JS (2013) Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis 28(2):307–312

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  68. Bajaj JS, Heuman DM, Sanyal AJ, Hylemon PB, Sterling RK, Stravitz RT et al (2013) Modulation of the metabiome by rifaximin in patients with cirrhosis and minimal hepatic encephalopathy. PLoS One 8(4):e60042

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  69. Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG et al (2011) 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 108(38):16050–16055

    CAS  PubMed Central  PubMed  CrossRef  Google Scholar 

  70. Messaoudi M, Lalonde R, Violle N, Javelot H, Desor D, Nejdi A et al (2011) 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(5):755–764

    CAS  PubMed  CrossRef  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, 9500 Gilman Dr #0063, La Jolla, CA, 92093, USA

    Mélanie G. Gareau

Authors
  1. Mélanie G. Gareau
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mélanie G. Gareau .

Editor information

Editors and Affiliations

  1. Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, Abilene, Texas, USA

    Mark Lyte

  2. Department of Anatomy and Neuroscience, University College, Cork, Cork, Ireland

    John F. Cryan

Rights and permissions

Reprints and Permissions

Copyright information

© 2014 Springer New York

About this chapter

Cite this chapter

Gareau, M.G. (2014). Microbiota-Gut-Brain Axis and Cognitive Function. In: Lyte, M., Cryan, J. (eds) Microbial Endocrinology: The Microbiota-Gut-Brain Axis in Health and Disease. Advances in Experimental Medicine and Biology(), vol 817. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0897-4_16

Download citation