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Friends with Benefits: The Gut Microbiota as a Key Regulator of
Physiology & Behaviour Across the Lifespan
Prof. John. F. CryanDept. Anatomy & Neuroscience and
APC Microbiome Institute University College Cork
Ireland@jfcryan
www.NPR.org Nov 2013
Stressors
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Lupien et al., Nat Rev Neuroscience, 2009
Stress across the Lifespan
“It’s not stress that kills us, it is our reaction to it”Hans Selye
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Stress Alters Brain-Gut Axis
Group Mean Similarity % SEM
Non Separated 75.2 16.8
Maternally Separated
59.9 * 21.0
Increased colonic transit, intestinal permeability, mucosal inflammation, colonic
morphology (O’Malley et al., 2010, Stress)
Diversity of Microbiota
Immune
O’Mahony et al. Psychopharmacology (201 1 )
EndocrineVisceral Pain
Open Field
Genus Control PNS p
Lactobacillus 3.48(2.16;4.99) 1.42(0.11;2.82) 0.054
Oscillibacter 0.34(0.32;0.64) 0.82(0.07;1.14) 0.029
Anaerotruncus 0.27(0.25;0.42) 0.70(0.04;0.85) 0.024
Peptococcus 0.06(0.03;0.15) 0.19(0.01;0.23) 0.014
Relative abundance of bacterial phyla, %
Relative abundance of bacterial genera, %
Prenatal stress induces lasting changes in certain bacterial
genera of the Lactobacillales and Clostridiales orders
Science News Magazine
Gut MicrobiomeThe human intestinal microbiota is composed of 1013 to 1014 microorganisms whose collective genome ("microbiome") contains at least 100 times as many genes 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 during
acute diarrhoeal illness, antibiotic treatments and by diet changes.
~500x more genes
~2-10x more cells
~1.5 kg
The human holobiont
Bacteria & Archaea Viruses & Phages
Protists
Nematodes
Fungi
Time, Jan 2003
The Brain-Gut Axis
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Programming infant gut microbiota: influence of dietary and environmental factors
Borre et al. Trends Mol Med 2014
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Behavioural impairment in Aged mice: Cognition, Anxiety & Social
Test mouse
Familiar Novel
Phase 3: Social recognition (10 min)Scott et al Unpublished
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Increased gut permeability in Ageing
Oral GavageFITC-dextran FD4 (600mg.kg-1)
2 h
Plasma
Restraint stress
1 h
Plasma
Intestinal Permeability (FITC) S tre s s
Y o u n g Ag e d0
1 0
2 0
3 0
4 0
Pla
sma
FIT
C-d
ext
ran
(ug
/ml)
* * * P v a lu e : P < 0 .0 0 1
* * *
B a s a l
Y o u n g Ag e d0
1 0
2 0
3 0
4 0
Pla
sma
FIT
C-d
ext
ran
(ug
/ml)
* P va lu e : P < 0 .0 5
*
Scott et al Unpublished
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Increased pro-inflammatory profile in ageing
Scott et al Unpublished
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Ageing Affects Caecal Microbiota Combosition
Scott et al Unpublished
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Brad Perkins, Human Longevity Wired Health Talk April 2015
Microbiome & Metabolome Play key role in Longevity ProjectsElie Metchnikoff (1845-1916)Nobel Prize 1908
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Signalling Along the Brain-Gut-Microbiota axis
Cryan and Dinan, Nat Rev Neurosci Oct 2012
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(A) Bacterial-derived signals NO and ncRNAs regulate C. elegans longevity
(B) Metformin increases C. elegans lifespan via effects on bacterial folate metabolism
(C) L. plantarum drive Drosophila growth under low-nutrient conditions via the longevity modulator TOR.
(D) Different bacterial species elicit specific transcriptional responses in C. elegans.
Microbe Modulation of Invertebrate Aging and Physiology
Heintz & Mair, Cell 2014, 156; Pages 408–411
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Strategies used to investigate the role of the microbiota–gut–brain axis in health and disease
Cryan and Dinan, Nat Rev Neurosci Oct 2012
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Germ Free Animals as a Tool to Study Microbiome-Gut-Brain axis
J Gerontol (1966) 21 (3): 380-387.
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Fontana & Partridge 2015 Cell 161, 106-118
The Effectors of Dietary Restriction: A role for Gut Microbiome?
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Germ Free Mice: Understanding the impact of microbiota on brain function
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Enhanced Stress Response & Abnormal Brain Development in Male Mice Lacking Microbiota
X
Clarke et al., Mol Psychiat 2013
Corticosterone
0
50,000
100,000
150,000
200,000
250,000Control
Germ Free
Baseline Stress
**
pg/
ml
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Adult Hippocampal Neurogenesis is Regulated by the MicrobiomeO’Leary & Cryan, TiPS Dec 2014
Ogbonnaya et al., Biol Psychiat 2015
http://apc.ucc.ieIncreased Volume Dendritic hypertrophy of BLA aspiny stellate neurons
Increased spine density
Microbiota Determines Amygdala Volume & Dendritic Morphology
Luczynski et al unpublished
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Regulation of Myelination by the Microbiome
Hoban et al., Unpublished
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Lacking a strong blood-brain barrier, germ-free mice (left) can't prevent a radioactive tracer (yellow) from entering the brain the way that mice with microbes (middle) can. But adding microbes to germ-free mice (right) restores the blood-brain barrier.
Desbonnet et al. Mol Psychiatry 2014
Social Deficits in Mice lacking MicrobesSociability
Social Cognition
Mouse Empty
Novel Familiar
“NOTHING IN BIOLOGY MAKES SENSE EXCEPT IN THE LIGHT OF EVOLUTION”(Theodosius Dobzhansky, 1973)
Microbiota, Neurodevelopment & Mental Illness
Borre et al. Trends Mol 2014
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Breaking Down the Barriers: Brain-Gut-Microbiota Axis and intestinal barrier function
Kelly et al., Frontiers in Cellular Neuroscience In Press
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Probiotic Reduces Anxiety and Behavioural Despair
Probiotic Alters GABA Receptors in various
Brain areas
Bravo et al., PNAS Sept 2011
http://apc.ucc.ieDefensive Marble Burying
Probe Trial Errors
Veh Esc B lgm B bre0
2
4
6
8
*
C
Erro
rs (n
)
Savignac et al., Behav Brain Res 2015
Barnes Maze
Bifidobacteria modulate anxiety and cognitive processes in the mouse
Savignac et al., Neurogastroenterol Motil. 2014 26:1615-27
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How do Bacteria Signal to the Brain?- Role of Vagus Nerve
Bravo et al., PNAS Sept 2011
Gut–brain Axis: What Happens In Vagus Affects Emotion.
Bravo et al. PNAS 2011;108:15661-15662
©2011 by National Academy of Sciences
Andrea Levy, The Plain Dealer
Microbiota Transplantation Modifies Host Behaviour NIH Swiss BALB/c
Collins et al., Curr Opin Microbiol. 2013
Sunday 28th June 2015
In Press 2015
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Stress and the Microbiota-Gut–Brain Axis in Health and Disease
Cryan and Dinan, Nat Rev Neurosci Oct 2012
“A state of gut” will markedly affect your “state of mind”.
• 20th century- kill microbes via antibiotics• 21st century- bacteria have beneficial effects on
health
Dr. Hamdy ShabanDr. Karen-Anne McVey NeufeldDr. Sahar El AidyDr. Cristina TorresDr. Anna GolubevaDr. Karen ScottDr. Cara HeustonDr. Yuliya BorreDr. Roman StillingDr. Gerry MoloneyDr. Aurelijus Burokas
Dr. Andrew AllenDr. Paul KennedyDr. Rachel MoloneyDr. Angela MoyaDr. Meena MalhotraDr. Masa IdaPatrick Fitzgerald Matteo PusceddoMaria O’DonovanDavid McCarthyJames O’LearyCiaran O’Leime
Wesley van OeffelenLivia MoraisAlan HobanClara Seira OriachDr. John KellyDr. Patrick KirwanDr. Jahangir SajjadBrunno Rocha LevoneAna Paula Veronica PetersonRory O’Connor
Anna ConnollySurabi TheratikeDalia KandilEilleen CurranPauline Luczynski,Ruairi Robertson
Prof. Ted DinanProf. CaitrionaO’DriscollProf. Fergus ShanahanDr. Yvonne NolanDr. Ken NallyDr. Silvia Melgar, Dr. Niall P. HylandDr. Siobhain O'MahonyDr. Brendan GriffinDr. Gerard McGlackanDr. Olivia O’LearyProf Louise Kenny
Dr. Gerard O’KeeffeDr. Ger ClarkeDr. Harriet SchellekensProf Catherine StantonProf Paul RossDr. Paul CotteProf Paul O’TooleProf Colin HillrJohn Bienenstock/Paul Forsythe, McMaster UniversityDr. Andrew Holmes, NIH, USA
Current Lab Collaborators