Mind Altering Microbes: Role of Microbiota-Gut-Brain Axis in Stress-Related Disorders

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1 Mind Altering Microbes: Role of Microbiota-Gut-Brain Axis in Stress-Related Disorders John F. Cryan Ph.D. Professor & Chair Department of Anatomy & Neuroscience & Principal Investigator, Alimentary Pharmabiotic Centre University College Cork Ireland

2 Brain & Body Closely Interact The Brain-Gut Axis Time, Jan 2003

3 Stressors

4 It s not stress that kills us, it is our reaction to it. Hans Selye

5 Romanian Orphans Lupien et al., Nat Rev Neuroscience

6 Stress Alters Brain-Gut Axis

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11 Human vs. Mouse Brain Cryan and Holmes, Nature Rev Drug Discov. Sept 2005

12 The Rodent Psychiatrist: Behavioural Neuroscientist?? Cryan et al., Trends in Pharmacol. Sci Gary Larson

13 Maternal Separation Model of Early Life Stress q Plotsky, Meaney and colleagues have long used MS as an animal model of depression q Psychosocial stress model where pups are removed from the home cage for 3 hr/day from pn day 2-12 Results in: ü Enhanced stress response (O Mahony et al, 2006) ü Alterations in the serotonin system e.g. alterations in pain modulating system, increase in serotonin and its metabolite (O Mahony et al., 2008) ü Increased colonic transit, intestinal permeability (Soderholm et al., 2002), mucosal inflammation, altered microflora O Mahony et al. Psychopharmacology (2011)

14 Endocrine Open Field Diversity of Microbiota Group Non Separated Maternally Separated Mean Similarity % SEM * 21.0 Immune Increased colonic transit, intestinal permeability, mucosal inflammation, colonic morphology (O Malley et al., 2010, Stress)

15 Maternal Separation results in visceral hypersensitivity 80mmHg Fasting O Mahoney et al., 2009 CRD 0 O Mahony et al., Biol. Psychiat 2008 In Press T=0 T=24hr 8 mins

16 Wistar Kyoto Model of Stress Wistar Kyoto (WKY) rats are genetically predisposed to high-anxiety behaviours Sensitive to induction of ulcers by stress (Pare, 1989) Model of depression (Will et al, 2003) Greenwood-van Meervald proposed to be a model of visceral hypersensitivity (Gunter et al., Physiol Behav 2000; 69: ).

17 Wistar Kyoto rats display spontaneous visceral hypersensitivity Cumulative Score Threshold 30 ** Number of pain behaviours Pressure of distension (mmhg) 20 Sprague Dawley Wistar Kyoto Sprague Dawley Wistar Kyoto Pressure of distension (m m Hg) O Mahony et al Neurogastroenterol & Motility, 2010

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20 Signaling Along the Brain-Gut-Microbiota axis Pain Cryan and Dinan, Nat Rev Neurosci Oct 2012

21 Strategies used to investigate the role of the microbiota gut brain axis in health and disease. Cryan and Dinan, Nat Rev Neurosci Oct 2012

22 Germ Free Mice: Understand impact of microbiota on brain function X

23 Germ Free Mice: Understand impact of microbiota on brain function

24 Decreased BDNF and Exaggerated Stress Response Ø BDNF is a neurotrophin supporting neuronal survival/growth Ø Decreased BDNF in germ free compared to control animals Corticosterone Germ Free 200,000 pg/ml Ø Altered stress response Control 250,000 ** 150, ,000 50,000 0 Baseline Clarke et al., Mol Psychiat 2012 Stress

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26 Could potential probiotic administration in adulthood affect stress-related anxiety and depression?

27 Probiotic Reduces Anxiety and Behavioural Despair Probiotic Reduces Stress-induced Corticosterone Levels Bravo et al., PNAS Sept 2011

28 Lactobacillus Increases Learning in Fear Conditioning

29 Lactobacillus Increases alter Cortical, Amygdalar and Hippocampal GABAA Receptor Subunits

30 Behavioural and Neurochemical effects of Probiotic are abolished in Vagotomised animals Bravo et al., PNAS Sept 2011

31 Gut Brain Axis: What Happens In Vagus Affects Emotion. Bravo et al. PNAS 2011;108: by National Academy of Sciences

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34 Can modulation of the gut microbiota affect cognitive performance in humans?

35 Summary Early life stress causes marked dysregulation in the Brain-Gut Axis and Behaviour Maternal separation is associated with visceral hypersensitivity Stress, especially early in life, alters composition of microbiota Microbiota in early life is critical for brain development, normal behaviour and visceral pain Probiotic administration has effects on stress, anxiety, depression and central GABA receptor levels Understanding the basis underlying the effects of gut microbiota on stress neural circuitry will be an important avenue to develop novel therapeutic targets for stress-related disorders

36 Does altered microbiota in early life prime for increased susceptibility to stress? or Does stress lead to altered microbiota?

37 Stress and the Microbiota-Gut Brain Axis in Health and Disease. Cryan and Dinan, Nat Rev Neurosci Oct 2012

38 The Daily Mail, London Sept 2011

39 Probiotics, Stress and the Brain: The next 10 Years Clinical validation required to fully investigate the translatability of animal studies to humans. a probiotic mixture (containing Bifidobacterium lactis CNCM I-2494, Lactobacillus bulgaricus and Streptococcus thermophilus, as well as Lactobacillus lactis) can substantially alter brain activity in the mid and posterior insula during an emotional reactivity test in healthy volunteers (Tillisch et al DDW 2012) Mechanisms underlying strain-specific effects will need to be elucidated Probiotics for stress-induced deficits in cognition Microbiota and autism???

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