Stress and the Brain-Gut-Microbiota Axis (Prof. John F. Cryan)


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Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signaling. Regulation of the microbiota-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. Moreover, there is now expanding evidence for the view that commensal organisms within the gut play a role in early programming and later responsivity of the stress system. Research has focused on how the microbiota communicates with the central nervous system (CNS) and thereby influences brain function. The routes of this communication are not fully elucidated but include neural, humoral, immune and metabolic pathways. This view is underpinned by studies in germ-free animals and in animals exposed to pathogenic bacterial infections, probiotic agents or antibiotic agents which indicate a role for the gut microbiota in the regulation of mood, cognition, pain and obesity. Thus the concept of a microbiota-gut brain axis is emerging which suggests that modulation of the gut microflora may be a tractable strategy for developing novel therapeutics for complex stress-related CNS disorders where there is a huge unmet medical need.

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Stress and the Brain-Gut-Microbiota Axis (Prof. John F. Cryan)

  1. 1. apc.ucc.ieJohn F. Cryan Ph.D.Professor & ChairDepartment of Anatomy & Neuroscience&Principal Investigator,Alimentary Pharmabiotic CentreUniversity College CorkIrelandStress and the Brain-Gut-Microbiota Axis
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  3. 3. apc.ucc.ieNeuroAidsA U.S. Army Educational Commission Posterabout Neurosypilis, 1918Interfacing Microbiology and Neuroscience
  4. 4. apc.ucc.ieBrain & BodyClosely InteractTime, Jan 2003The Brain-Gut Axis
  5. 5. apc.ucc.ieStressors
  6. 6. apc.ucc.ieCryan et al., Trends in Pharmacol. Sci. 2002The Rodent Psychiatrist: Behavioural Neuroscientist??Gary Larson
  7. 7. apc.ucc.ieHuman vs. Mouse BrainCryan and Holmes, Nature Rev Drug Discov. Sept 2005
  8. 8. apc.ucc.ieAltered Stress Axis
  9. 9. apc.ucc.ieStress Alters Brain-Gut Axis
  10. 10. apc.ucc.ieLupien et al., Nat Rev NeuroscienceRomanian Orphans
  11. 11.“It’s not stress that kills us, it is our reaction to it”.Hans Selye
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  13. 13. apc.ucc.ieIrritable Bowel Syndrome (IBS) a disorder ofBrain-Gut Axis dysfunction Symptom complex including abdominal pain, altered bowelfunction, bloating, mucosal inflammation, exaggerated stressresponse, increases in plasma pro-inflammatory cytokines IBS affects approximately 10-20% of the general population It is the most common disease diagnosed by gastroenterologists Large co-morbidity with anxiety & depression Current therapies are frequently ineffective Visceral Pain is a key symptoms of IBS Stress (including early life stress) plays a major role in the onsetand exacerbation of symptoms in IBS Now viewed as a disorder of the Brain-Gut axisGastroenterologists: Gut disorderPsychiatrist: Stress-related disorderNeurobiologist-Neurologist: Chronic pain disorder
  14. 14. apc.ucc.ieMaternal Separation model of IBS Plotsky, Meaney and colleagues have long usedMS as an animal model of depression Neonatal psychosocial stress model where pupsare removed from the home cage for 3 hr/dayfrom pn day 2-12Results in: Enhanced stress response (O’Mahony et al,2006) Alterations in the serotonin system e.g.alterations in pain modulating system, increasein serotonin and its metabolite (O’Mahony et al.,2008) Increased colonic transit, intestinal permeability(Soderholm et al., 2002), mucosalinflammation, altered microfloraO’Mahony et al. Psychopharmacology (2011)
  15. 15. apc.ucc.ieOpen Field EndocrineGroup Mean Similarity%SEMNon Separated 75.2 16.8MaternallySeparated59.9 * 21.0Increased colonic transit, intestinalpermeability, mucosal inflammation,colonic morphology(O’Malley et al., 2010, Stress)Diversity of MicrobiotaImmune
  16. 16. apc.ucc.ieMaternal Separation results in visceralhypersensitivityO’Mahony et al., Biol. Psychiat 2008 In PressO’Mahoney et al., 2009Fasting CRDT=0 T=24hr080mmHg8 mins
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  18. 18. apc.ucc.iePhysiological Indicators of Chronic SocialDefeat and Overcrowding StressChronic intermittent psychosocial stress (social defeat/overcrowding) for 19 days (Reber et al., 2006)Tramullas et al., Stress 2012
  19. 19. apc.ucc.ieRepeated Social Interaction Stress Social stress can disrupt the brain-gut axis, inducing gut and psychiatric diseases; It is one of the first causes of stress in humans; Stronger immune reaction than other types of stress can be induced (Sheridan & al, 2000)Chronic:6 days++Back alone home cage2 Hours + 2 HoursKillingChronic:6 days++Back alone home cage2 Hours + 2 HoursKillingMale BALB/cHome cageMale C57BL/6AgressiveintruderOr acuteSampling
  20. 20. apc.ucc.ieRepeated Social Interaction Stress•Mice displayed 2 opposingbehavioural and physiologicalsubtypes after both stressexposure, vs controls:•Dominant/aggressive = lowercorticosterone and pro-inflammatory cytokines levels(IL-1β, IL-6 and mKC)•Submissive/defensive = highcorticosterone and cytokinelevels•Chronically stressed mice =weight loss and colonicmicroscopic damage increasedCorticosterone050000100000150000200000*Control Acute Dominant SubmissiveChronic+Concentrationpg/mlNumber of minor wounds apotential confoundSavignac et al., Behav Brain Res 2010
  21. 21. apc.ucc.ieThe Brain-Gut AxisSpinal CordGosselin et al. Trends Immunol,under review
  22. 22. apc.ucc.ieTargeting Spinal Glial Glutamate Transport Reverses Early-Life Stress-induced Visceral HypersensitivityIntrathecaladministrationof a glutamatetransportblocker TBOAproducesvisceralhypersensitivityGlutamate uptakeactivator riluzolereduces maternalseparation-inducedvisceralhypersensitivityGosselin et al Gastroenterology June 2010Maternal separation (MS) results in a selective reduction of theexpression of spinal glial glutamate transporter EAAT-1
  23. 23. apc.ucc.ieLPS-induced visceral hypersenitivityO’Mahony and Cryan unpublished
  24. 24. apc.ucc.ieToll-Like Receptors-A role in stress regulation of brain-gut axis
  25. 25. apc.ucc.ieTLR’s and IBSTLR4 (LPS Stimulation) TLR8 (ssRNA40 Stimulation)
  26. 26. apc.ucc.ieMcKernan et al., 2009 PLOS OneIncreased TLR mRNA Expression in Distal Colonof Two Models of Visceral HypersensitivityMaternally Separated RatWistar Kyoto Rat
  27. 27. apc.ucc.ieTLR4 is essential for chronic psychosocialstress-induced visceral hypersensitivityTramullas and Cryan unpublishedTLR4 antagonistattenuates basal andstress-inducedvisceral hyperalgesia
  28. 28. apc.ucc.ieGut Microbiome• The human intestinal microbiota is composed of 1013to 1014 microorganisms whose collective genome("microbiome") contains at least 100 times as manygenes as our own genome(Gill, S. R., et al(2006).Science 312, 1355-1359.)An individuals flora generally remains constant,however, the composition can fluctuate duringacute diarrhoeal illness, antibiotic treatments andby diet changes.
  29. 29., ...Malene et al., Early Human Development Volume 88, Supplement 1 2012 S41 - S49Bacterial Colonization and Gut Development in Neonates
  30. 30. apc.ucc.ieCryan and Dinan, Nat Rev Neurosci Oct 2012Signaling Along the Brain-Gut-Microbiota axisPain
  31. 31. apc.ucc.ieCryan and Dinan, Nat Rev Neurosci Oct 2012Strategies used to investigate the role of themicrobiota–gut–brain axis in health and disease.
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  35. 35. apc.ucc.ieXGerm Free Mice:Understand impact of microbiota on brain function
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  37. 37. apc.ucc.ieGerm Free Mice:Understand impact of microbiota on brain function
  38. 38. apc.ucc.ieDecreased BDNF and Exaggerated StressResponse BDNF is a neurotrophinsupporting neuronalsurvival/growth Decreased BDNF in germfree compared to controlanimals Altered stress responseCorticosterone050,000100,000150,000200,000250,000ControlGerm FreeBaseline Stress**pg/mlClarke et al., Mol Psychiat 2012
  39. 39. apc.ucc.ieMicrobiota controls visceral hypersensitivityTramullas et al., unpublished
  40. 40. apc.ucc.ieDoes early-life antibiotic administrationaffect behaviour in adulthoodO’Mahony et al., SubmittedVancomycin 10-100 mg/kgadministered from postnatalday 4 for 10 days in ratsNo change in• Cognition• Anxiety• Stress Response• Immune Response
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  46. 46. apc.ucc.ieCould potential probiotic administration in adulthoodaffect stress-related anxiety and depression?“PSYCHOBIOTICS”Biol Psychiat 2013 In Press
  47. 47. apc.ucc.ieProbiotic Reduces Anxiety and Behavioural DespairProbiotic ReducesStress-inducedCorticosterone LevelsBravo et al., PNAS Sept 2011
  48. 48. apc.ucc.ieLactobacillus Increases alter Cortical, Amygdalarand Hippocampal GABAA Receptor Subunits
  49. 49. apc.ucc.ieBehavioural and Neurochemical effects of Probiotic areabolished in Vagotomised animalsBravo et al.,PNAS Sept 2011
  50. 50. apc.ucc.ieGut–Brain Axis:What Happens In Vagus Affects Emotion.Bravo et al. PNAS 2011;108:15661-15662©2011 by National Academy of Sciences
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  52. 52. apc.ucc.ieA distributed network of brain regionsshowing decreases during an emotionalfaces attention taskA resting state midbrain centered is negativelycorrelated with midbrain activity after FMPP
  53. 53. apc.ucc.ieAndrea Levy, The Plain Dealer
  54. 54. apc.ucc.ieBercik et al., Gastroenterology, 2011Microbiota Transplantation Modifies Host Behaviour
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  56. 56. apc.ucc.ieAutism spectrum disorders (ASD)Neurodevelopmental disorder with highheritability1.1% general population4:1 male/female ratio3 symptom domains (DSM-IV)Abnormal social interactionImpaired communicationRepetitive behavioursOther associated symptoms:Cognitive impairmentSeizuresAnxietyHyperactivitySensory deficitsGI distress (<90% of patients)
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  59. 59. apc.ucc.ieCanmodulation ofthe gutmicrobiotaaffectcognitiveperformance inhumans?
  60. 60. apc.ucc.ieCognitive Assessment• Intra/Extradimensional SetShift (IED)• Paired Associate Learning(PAL)• Spatial Working Memory(SWM)• Additional Tests:• Classic Stroop
  61. 61. apc.ucc.ieCognitive TestsIntra/Extradimensional Set Shift (IED)Executive Function: Reversal learning &cognitive flexibilityPaired Associate Learning (PAL)Visuspatial Episodic MemorySpatial Working Memory (SWM)StroopAttention/ Response Inhibition1) 2)3) 4)
  62. 62. apc.ucc.ieAm J Gastroenterol 2010; 105:1994–2002
  63. 63. apc.ucc.ieVisuospatial MemoryDeficit in IBSAttentional Deficit inCrohns DiseasePaul J Kennedy, Gerard Clarke, Ann O’Neill, John A Groeger, Eamonn MMQuigley, Fergus Shanahan, John F Cryan, Timothy G Dinan Paper In Preparation
  64. 64. apc.ucc.ieStress and the Microbiota-Gut–Brain Axis inHealth and DiseaseCryan and Dinan, Nat Rev Neurosci Oct 2012
  65. 65. apc.ucc.ieThe Daily Mail, London Sept 2011
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