Probiota Americas, San Diego, June 3-5, 2015
Microbiota and its Impact on the GutBrain Axis – How Much Do We Know?
Emeran A. Mayer, MD, PhD
Professor of Medicine, Physiology & Psychiatry
UCLA Division of Digestive Diseases, David Geffen School of Medicine at UCLA
Overview
•
•
•
•
•
Historical perspective
Preclinical behavioral evidence
Preclinical mechanistic evidence
Clinical evidence
Future perspectives
Illustration by Benjamin Arthur for NPR
The 20th Century View
Treatment of “Intestinal Putrefaction” by Colonic
Irrigation
In the 5th century B.C., Herodotus wrote: "The Egyptians clear themselves on
three consecutive days, every month, seeking after health by emetics and
enemas for they think that all disease comes to man from his food."
Colonic irrigation as a
treatment for “auto
intoxication”
• became popular in the
late 1800s and early
1900s.
• An early English version
was known as the
“Harrogate System of
Intestinal Lavage”.
• 15,000 patients annually
were receiving irrigations
at the “Harrogate Spa”
(Whorton, 2000)
Treatment of Depression by Probiotics
The 21th Century View
Putative Communication Channels and
Molecules between Gut Microbiome and Brain
Sampson & Mazmanian, 2015; Mayer et al. JNS 2015; Mayer et al. JCI, 2015
Experimental Paradigms and Readouts of the
Brain Gut Microbiome Axis
Mayer et al., JCI 2015
Preclinical Studies
Modulation of Gut Microbiota by the Brain
• Pre and Postnatal Stress Affects Intestinal Microbiota in Animals
Bailey and Coe, 2004; Bailey and Coe 1999; Santos et al, 2001; O’Mahonney et al 2009;
Manipulation of Gut Microbiota Can Affect Behavior
and Brain Biochemistry in Animals
Behavioral Readouts
• Nociceptive reflexes1-3
• Emotional behavior4-5
• Social behavior8-10
• Ingestive behavior11
Biological Readouts
• Brain neurochemistry4,5
• HPA axis6-7
Mayer et al, JCI (2015); 1 Kamiya T et al (2006); 2 Rousseaux C et al (2007); 3 Verdu EF et
al (2006); 4. Bravo JA et al (2011); 5. Bercik P et al (2011); 6. Gareau MG et al (2007); 7
Sudo N et al (2004); 8 Hsiao et al (2014); 9 Desbonnet et al. 2013; 10 De Theije et al. 2014;
11 Vijay-Kumar et al. 2010
A Mouse is not a Monkey, is not a Human –
Neither are their Brains the same…
adapted from AD Craig, Nature Reviews Neuroscience 2009
Mechanistic evidence
Sampson & Mazmanian, 2015
Sampson & Mazmanian, 2015
Human Studies
The Fancy: Translational Speculations Based on Preclinical Data
The Oppenheimer Center
The Effect of Probiotics on Mood & Affect
55 healthy human subjects were treated with probiotic
mixture and placebo for 30 days:
• Reduction in in global psychological symptoms
(SCL-90)
• Reduction of combined anxiety and depression
score compared to placebo
• No effect on individual anxiety and depression
• Changes were small, unclear if they are clinically
significant
Messaoudi et al Brit J Nutrition, 2011
Effects of Probiotics on Mood and Memory
• Double blind placebo controlled trial of a probiotic milk
drink in 124 healthy subjects for 3 weeks
– No change in daily ratings on Profiles of Mood
States
– When lowest tertile of mood examined, depression
was improved in the treatment group
• Memory testing (details of a story at 20 days) was
worse in the probiotic group
Benton et al, Eur J Nutrition, 2007
A Randomized Controlled Trial to Test the Effect of
Multispecies Probiotics on Cognitive Reactivity to Sad Mood
• Methods: 40 healthy controls (20 received 4 week
probiotic mix, 20 received placebo)
• Results: Compared to placebo group, participants who
received the 4-week multispecies probiotics
intervention showed a significantly reduced overall
cognitive reactivity to sad mood
• Conclusion: … first evidence that the intake of
probiotics may help reduce negative thoughts
associated with sad mood. Probiotics supplementation
warrants further research as a potential preventive
strategy for depression.
Steenbergen et al. 2015
Fermented Foods, Neuroticism, and Social
Anxiety: An Interaction Model
• Methods: Asample of young adults (n=710,445
female) completed self report measures of fermented
food consumption, neuroticism, and social anxiety.
• Results:
– Exercise frequency, neuroticism,and fermented food
consumption significantly and independently predicted social
anxiety.
– For those high in neuroticism,higher frequency of fermented
food consumption was associated with fewer symptoms of
social anxiety.
• Conclusions: Fermented foods that contain probiotics
may have a protective effect against social anxiety
symptoms for those at higher genetic risk,
Hilimire et al, 2015
Mechanistic/causal Studies on Human Gut
Microbiota Brain Interactions
 In order to identify possible causal relationships
between gut microbes and the brain, interventions
to manipulate gut microbiota composition and
metabolic function, while simultaneously monitoring
behavioral and brain parameters are required.
 In humans, such interventions/perturbations are
limited to:
 short term antibiotic treatment1
 dietary manipulations
 psychosocial stressors
 probiotic treatment2,3
1 Ahluwalia et al 2014; 2 Messaoudi BJN 2011; 3 Benton et al. Europ J Clin Nutrition 2007
Can Probiotics Modulate the Gut-Microbiota-Brain axis?
Tillisch et al. Gastroenterology 2013
Perturbation of gut microbial composition and function
by ingestion affect brain function in humans?
•
45 Healthy women
–
–
–
–
–
Study Design:
Age 18-50 (mean age 29 years)
No gastrointestinal symptoms
No chronic pain
No psychiatric illness
No probiotic or antibiotic use in the last month
Double blind,
randomized, controlled
•
•
•
Test product (n= 15)
• Commercially available fermented milk
product (FMPP)
• 125 grams twice/day for 4 weeks
Non-fermented dairy product (n= 12)
• 125 grams twice/day for 4 weeks
No treatment (n=14)
Tillisch, et al, Gastroenterology 2013
Probiotic Intake was Associated with Blunted
Reactivity of Interoceptive and Somatosensory
Regions
Regions with less
activation in probiotic
vs no treatment
Insula
No Tx > PFM
Somatosensory
Regions with less
activation in probiotic
vs control
Tillisch, et al, Gastroenterology 2013
Probiotic Intake was Associated with Decreased
Connectivity within an Extensive Task Dependent
Brain Network, Including Sensory and Pain
Modulatory Regions
 Across visits the network
becomes:
• stronger with no treatment
• stays the same with control
• decreased in the probiotic
Test Product.
Treatment related change in
network (design score)
Network crossblock covariance 49%, P <.005
Tillisch, et al, Gastroenterology 2013
Probiotic Associated Brain Effects were not
Accompanied by Changes in Mood or Gastrointestinal
Function
• No effect on:
– Anxiety or depression scores
– Positive or negative affect after the Emotional Faces
Attention Task
– Daily diary measures of bowel function
• Bloating
• Pain
• Bowel movement frequency
The Future
What Role do Alterations in Brain Gut Microbiome
Interactions Play in GI and non-GI Disorders?
Brain Gut disorders1-3:
Obesity, food addiction, metabolic syndrome
IBS
Inflammatory bowel diseases
Non-GI disorders4-5
Anxiety and depression
Multiple sclerosis
Alzheimers disease
Parkinson’s disease
Autism
Alcoholism
1. Mayer& Tillisch. Ann Rev Med 2011; 2. Agostini et al. NGM 2012; 3. Yau et al. Pediatrics 2012;130:e85664; 4. Gonzalez et al. Dialogues Clin Neurosci 2011; 5. Mayer Nature Reviews Neurosci 2011; Cryan & Dinan
Nature Reviews Neurosci 2012; 6. Howitt & Garrett, Nature Med 2012
Do manipulations of the gut microbiome (diet,
probiotics, antibiotics, chronic infections) influence brain
development during pre and postnatal period
Are Structural Brain Differences Related to Pre and
Postnatal Influences on Gut Microbiome?
Mayer et al., JCI 2015
Are there any relevant influences of the gut microbiota
on the development and clinical course of brain
diseases (IBS, Autism, Alzheimers, Parkinsons disease,
anxiety and depression)?
Can gut microbial signatures predict disease risk and
response to therapy?
Gail and Gerald Oppenheimer Family Center for Neurobiology of Stress at UCLA
Neuroimaging
Investigators
Neuroimaging
Core
Emeran Mayer
Bruce Naliboff
Jennifer Labus
Lisa Kilpatrick
Claudia San Miguel
Cody Ashe-McNalley
Mher Alaverdyan
Cathy Liu
Annie Gupta
Gilbert Hong
Kristin Coveleskie
Zafar Gill
Michelle Chen
Aubrey Love
Research nurses
Jean Stains
Suzanne Smith
The CNS Neuroimaging core is funded by NIDDK, NIDA,
NCCAM, NICHD, and the ORWH