Can the Gut Microbiome Control the Brain? Dr Gerard Clarke Department of Psychiatry and Neurobehavioural Science and APC Microbiome Ireland

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1 Can the Gut Microbiome Control the Brain? Dr Gerard Clarke Department of Psychiatry and Neurobehavioural Science and APC Microbiome Ireland University College Cork Ostrava January 31st 2018

2 Let food be thy medicine

3 Gut Feelings Brain-Gut-Microbiome Axis Health and Disease Mind altering microbes Anxiety, Depression, Stress and Cognition Tryptophan availability and metabolism Translational implications and opportunities for intervention?

4 Brain-Gut-Microbiome Axis Grenham, Clarke et al., Frontiers in Physiology 2011

5 Signalling Along the Brain-Gut-Microbiota axis Cryan and Dinan, Nat Rev Neurosci Oct 2012

6 Where do we get our microbiota from? Grenham et al., 2011

7 What Shapes our Gut Microbiota?

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10 Germ-Free Living? Kirk, R, Bulletin of the History of Medicine, 2012

11 Microbiota, Brain and Behaviour Clarke et al., Encyclopedia Metagenomics 2013

12 Stressors It s not stress that kills us, it is our reaction to Hans Selye

13 Microbiota Controls Stress Response Germ-free animals have an exaggerated stress response Probiotic Reduces Stress-induced Corticosterone Levels Bravo et al., PNAS Sept 2011

14 Microbiota Determines Amygdala Volume & Dendritic Morphology Dendritic Hypertrophy of Basolateral Amygdala Neurons CC GF = Conventionally Colonised = Germ Free

15 Anatomical correlates of abnormal fear and anxiety can be localised to the amygdala in germ-free animals using cued fear conditioning

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17 Signalling Along the Brain-Gut-Microbiota axis Cryan and Dinan, Nat Rev Neurosci Oct 2012

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19 The Kynurenine Pathway O Mahony et al, Behavioural Brain Research 2015

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21 Microbiota Regulates Tryptophan Metabolism

22 Transcriptional Regulation of Kynurenine Pathway Metabolism in Hippocampus CON Hippocampus Dissection GF Total RNA Extraction mircury LNA microrna Array exgf Female Male Male Female mirna qpcr Validation TDO KAT1 CON CON GF exgf CON GF GF exgf CON GF exgf exgf Moloney et al., Behavioural Brain Research 2017 Target Validation

23 Restoring intestinal Lactobacillus levels normalized stressinduced behavior and suppressed kynurenine production

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25 Summary

26 Behind the Curve! For example, if they detected high levels of amino acid Tryptophan," he explained, "they concluded that person was calm and approachable.

27 Translational Research Cryan et al., Trends in Pharmacol. Sci Gary Larson

28 Altered Microbiota in Depression Obs e r ve d Spe c ie s Rich ness 600 ** Cha o ControlsDepression Controls Depression Diver s ity Dive rsity 6.0 ** 30 Sh an n on Ind e x Ph ylo ge ne tic Dive r s ity ** Richn es s * ControlsDepression Controls Depression Genus Level Differences Controls Turicibacter Depression Gelria Mogibacterium Dialister Prevotella Paraprevotella Holdemania Eggerthella Reduced microbial diversity in depression % Relative Abundance Kelly et al., J Psych Res 2016 Prevotella, a genus of Gramnegative bacteria, is reduced in depression

29 Transfer of Depressive Phenotype S u cr ose p r efer en ce (% ) Sucrose preference (1% sucrose) * Controls Anhedonia-like behaviours transferred via gut microbiota Depression % visits to the open arms Ele vate d Plus M aze 40 * Controls Depression Kynurenine/Tryptophan ** 0.06 Ratio Controls Anxiety-like behaviours transferred via gut microbiota Depression Kelly et al., J Psych Res 2016 Tryptophan metabolism Profile transferred via gut microbiota

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32 B. longum reduces stress response in healthy human volunteers Stress * Perceived stress Area under the curve * 400 * Memory: total errors Brain activity Allen et al., 2016, Trans Psych * P AL: T otal errors F z M o b ilit y ( H z ) * * ot ic Cortisol output Ps yc ho bi Pl ac eb o 0

33 Prebiotic reverses consequences of chronic stress Social behaviour and cognition Anxiety

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35 Let food be thy medicine

36 Let food be thy medicine

37 Andrea Levy, The Plain Dealer

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40 Summary & Conclusions Gut microbiota is both stress-susceptable and can regulate stress response Regulates behaviours and physiology relevant to neuropsychiatric disorders Tryptophan availability/kynurenine metabolism Translation to clinic? Microbial-based strategies for the treatment of stress-related disorders? Kelly et al., Frontiers Neuroscience 2017

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42 Acknowledgements Laboratory of NeuroGastroenterology

43 Summary Serotonin on the Wild Atlantic Way University College Cork July

44 7th International Human Microbiome Consortium (IHMC) meeting 26th-28th June, Killarney, Ireland For registration & further details go to: #IHMC2018

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46 Thank you The Daily Mail, London Sept 2011