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
Let food be thy medicine
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?
Brain-Gut-Microbiome Axis Grenham, Clarke et al., Frontiers in Physiology 2011
Signalling Along the Brain-Gut-Microbiota axis Cryan and Dinan, Nat Rev Neurosci Oct 2012
Where do we get our microbiota from? Grenham et al., 2011
What Shapes our Gut Microbiota?
Germ-Free Living? Kirk, R, Bulletin of the History of Medicine, 2012
Microbiota, Brain and Behaviour Clarke et al., Encyclopedia Metagenomics 2013
Stressors It s not stress that kills us, it is our reaction to Hans Selye
Microbiota Controls Stress Response Germ-free animals have an exaggerated stress response Probiotic Reduces Stress-induced Corticosterone Levels Bravo et al., PNAS Sept 2011
Microbiota Determines Amygdala Volume & Dendritic Morphology Dendritic Hypertrophy of Basolateral Amygdala Neurons CC GF = Conventionally Colonised = Germ Free
Anatomical correlates of abnormal fear and anxiety can be localised to the amygdala in germ-free animals using cued fear conditioning
Signalling Along the Brain-Gut-Microbiota axis Cryan and Dinan, Nat Rev Neurosci Oct 2012
The Kynurenine Pathway O Mahony et al, Behavioural Brain Research 2015
Microbiota Regulates Tryptophan Metabolism
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
Restoring intestinal Lactobacillus levels normalized stressinduced behavior and suppressed kynurenine production
Summary
Behind the Curve! For example, if they detected high levels of amino acid Tryptophan," he explained, "they concluded that person was calm and approachable.
Translational Research Cryan et al., Trends in Pharmacol. Sci. 2002 Gary Larson
Altered Microbiota in Depression Obs e r ve d Spe c ie s Rich ness 600 ** Cha o1 400 200 600 200 0 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 ** 400 0 40 Richn es s 20 10 0 *0.07 5.5 5.0 4.5 4.0 ControlsDepression Controls Depression Genus Level Differences Controls Turicibacter Depression Gelria Mogibacterium Dialister Prevotella Paraprevotella Holdemania Eggerthella 0.00 0.02 0.04 Reduced microbial diversity in depression 0.2 0.4 1.0 1.2 1.4 1.6 % Relative Abundance Kelly et al., J Psych Res 2016 Prevotella, a genus of Gramnegative bacteria, is reduced in depression
Transfer of Depressive Phenotype S u cr ose p r efer en ce (% ) Sucrose preference (1% sucrose) 100 80 * 60 40 20 0 Controls Anhedonia-like behaviours transferred via gut microbiota Depression % visits to the open arms Ele vate d Plus M aze 40 * 30 20 10 0 Controls Depression Kynurenine/Tryptophan ** 0.06 Ratio 0.04 0.02 0.00 Controls Anxiety-like behaviours transferred via gut microbiota Depression Kelly et al., J Psych Res 2016 Tryptophan metabolism Profile transferred via gut microbiota
B. longum reduces stress response in healthy human volunteers Stress * Perceived stress 40 30 20 10 Area under the curve * 400 * 300 200 100 0 Memory: total errors Brain activity 3 2 1 0 Allen et al., 2016, Trans Psych * P AL: T otal errors F z M o b ilit y ( H z ) * 4 8 6 4 2 0 * ot ic Cortisol output Ps yc ho bi Pl ac eb o 0
Prebiotic reverses consequences of chronic stress Social behaviour and cognition Anxiety
Let food be thy medicine
Let food be thy medicine
Andrea Levy, The Plain Dealer
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
Acknowledgements Laboratory of NeuroGastroenterology
Summary Serotonin on the Wild Atlantic Way University College Cork July 15-19 2018
7th International Human Microbiome Consortium (IHMC) meeting 26th-28th June, Killarney, Ireland For registration & further details go to: /ihmc-2018/ @IHMC2018 #IHMC2018
Thank you g.clarke@ucc.ie The Daily Mail, London Sept 2011