update on the role of gut microbiota modulation for the … · 2020-03-31 · brain-gut connection...
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© 2018 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC.
Update on the Role of Gut Microbiota Modulation for the Treatment & Prevention of Mood & Anxiety
David J. Scheiderer, MD, MBA, DFAPADirector of Education, Integrative Psychiatry, Inc., Sarasota, Florida
President, Tiberius Enterprises, Inc., Roanoke, Virginia
Roger S. McIntyre, MD, FRCPCProfessor of Psychiatry and Pharmacology, University of Toronto
Head of the Mood Disorders Psychopharmacology Unit, University Health Network, and
Executive Director, Brain and Cognition Discovery Foundation, Toronto, Ontario, Canada
March 2018 MRC2.CORP.D.00337
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Today’s Speakers
2
David J. Scheiderer MD, MBA, DFAPAIntegrative Psychiatry, Inc. and Tiberius Enterprises, Inc.Dr. Scheiderer is a Medical Director and the Director of Education at Integrative Psychiatry, Inc. in Sarasota, Florida and is also the President of Tiberius Enterprises, Inc. in Roanoke, Virginia. He received his medical degree from The Ohio State University, completed his Behavioral Medicine and Psychiatry residency at the University of Virginia, and received his MBA from Averett College in Virginia. Dr. Scheiderer is certified by The American Board of Psychiatry and Neurology.
Roger S. McIntyre, MD, FRCPCUniversity of Toronto, University Health Network, and Brain and Cognition Discovery FoundationDr. McIntyre is a Professor of Psychiatry and Pharmacology at the University of Toronto, Head of the Mood Disorders Psychopharmacology Unit at the University Health Network, and the Executive Director of the Brain and Cognition Discovery Foundation in Toronto, Ontario, Canada. He received his medical degree at Dalhousie University, and his Psychiatry residency training at the University of Toronto in Canada.
This program is paid for by Otsuka Pharmaceutical Development &
Commercialization, Inc. and Lundbeck, LLC.
Speakers are paid consultants for Otsuka Pharmaceutical Development & Commercialization, Inc.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.4
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• Provide an overview of the origins and importance of the brain-gut connection
• Examine the relationship between the brain-gut-microbiome axis and chronic inflammation
• Consider current evidence of the brain-gut connection’s impact on mental health
• Discuss the impact of modern life on the microbiome • Consider potential implications of the gut-brain
connection for the treatment of mental illness
Objectives
5
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The Brain-Gut Connection: Origins and Importance
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1. Wang HX, Wang YP. Chin Med J (Engl). 2016;129(19):2373-80. 2. Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):239-44.
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The Gut-Brain Connection: A Topic of Much Interest
In 2014 and 2015, NIMH offered a fund of $1 million to study the gut microbiota-brain axis1
In 2015, the US Navy Institute announced a fund of $14.5 million over the next 6–7 years to research the role of the gut in cognitive and stress disorders1
The European Union launched a 5-year “MyNewGut” project ($10.1 million US dollars) for research on brain development and related disorders1
In 2014, >$1 million was transferred to the Human Microbiome Project, supported by the NIH, which aims to understand microbiome diversity and determine roles of microorganisms in health and disease2
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1. Chen X, D'Souza R, Hong ST. Protein Cell. 2013;4(6):403-14.2. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.3. Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):239-44.
4. Petra AI, et al. Clin Ther. 2015;37(5):984-95.5. Dinan TG, et al. Journal of Psychiatric Resarch. 2015;63:1-9.
• The gut and brain originate from the same tissue during embryogenesis, the neural crest, and influence each other during development1
• Bacteria, mostly residing in the gut, outnumber the body’s cells 10:1 and are referred to as a microbiome1–3
– A microbiome comprises the entirety of microscopic organisms and their genetic material that inhabit a particular environment
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Origins and Colonization of the Gut Microbiota
Gut microbiotaHuman brain
~1 kg5
• Gut microbiota begin to colonize the GI tract at birth with a complex microbiome forming after the first year of age4
• Gut bacteria have been estimated to consist of >1000 species and >7,000 subspecies3
• The bacteria in our microbiome have co-evolved with us and interact with our body in a bidirectional manner2
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Routes for, and Blockages of, Microbial Colonization of Westernized Humans
Toh MC & Allen-Vercoe E. Microb Ecol Health Dis. 2015;26:26309.
Routes for microbial colonization
• Vaginal delivery
• Breastfeeding
• Environmental interaction
Impediments to microbial colonization
• C-section delivery
• Mother treated with antibiotics
• Feeding by formula only
• Indoor living
• Excessive sanitation
• Food preservatives
Early life stagesGestation
Newborn
Infant
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Communication Along the Microbiota-Gut-Brain Axis1-3
1. Mayer EA et al., J Neurosci. 2014;34(46):15490-96.2. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:3923. Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:701-12..
CORTISOLOH
H
O
O
OH
H
NH
NH2
HO
SEROTONIN
Neural CommunicationVagus nerve
Sympathetic Nervous System
Systemic Communication: EndocrineHPA axis
NeurotransmittersBacterial metabolites
Systemic Communication: ImmuneCytokines
Bacterial metabolites
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The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.11
Diseases Associated with Dysbiosis of Gut Microbiota
Psychiatric and mood disorders• Anxiety5,6
• Depression5,6
• Autism spectrum disorder5,6
• Bipolar Disorder6
• Schizophrenia6
Neurodegenerative disorders• Multiple sclerosis1
• Parkinson’s disease2
Cardiovascular disease• Coronary artery disease3
• Hypertension4
Metabolic disorders• Metabolic syndrome5
• Obesity5,7
• Types 1 and 2 diabetes5,7Intestinal disorders• Inflammatory Bowel Disease5
• Crohn’s disease• Ulcerative colitis
• Irritable Bowel Syndrome5,6
• Celiac disease5
Pregnancy-related conditions• Gestational hypertension8
• Gestational diabetes8
1. Cekanaviciute E, et al. Proc Natl Acad Sci U S A. 2017;114(40):10713-10718.2. Sampson TR, et al Cell. 2016;167(6):1469-1480.e12.3. Senthong V, et al. J Am Heart Assoc. 2016 Jun 10;5(6).4. Li J, et al. Microbiome. 2017;5(1):14.
5. Carding S, et al. Microb Ecol Health Dis. 2015; 26:26191.6. Fond G, et al. Pathol Biol (Paris). 2015;63(1):35-42.7. Tai N, et al. Rev Endocr Metab Disord. 2015;16(1):55-65.8. Dunlop AL, et al. Adv Neonatal Care. 2015;15(6):377-85.
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
1. Prinsloo S and Lyle RR. NeuroRegulation. 2015;2(4):158-161.2. Petra AI, et al. Clin Ther. 2015;37(5):984-95.3. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.
• An individual’s gut microbiome composition is impacted by:1,2
• When an unhealthy imbalance of bacteria (dysbiosis) occurs, health problems may arise3
• Research suggests that chronic states of bacterial imbalance in the gut may play a role in psychiatric and behavioral problems3
– Evidence supports a link between the microbial state of the gut and overall health, emotional functioning, immune response, and mental health1,3
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Impact of Imbalance of Gut Microbiota on Mental Health
Vaginal birth Genetics Age Diet Physical activity
Environment Stress Infections Other diseases Antibiotic use
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Th, T-helper; HPA, hypothalamo-pituitary-adrenal; Treg, regulatory T-cells.1. Sudo N et al. J Physiol. 2004 Jul 1;558(Pt 1):263-75. 2. Gur TL, Worly BL, Bailey MT. Front Psychiatry. 2015;6:5.
• Negative in-utero and early life experiences alter initial gut colonization, which predisposes an individual to stress-induced inflammation later in life by:1,2
• Establishing a hyperactive HPA axis1
• Altering immune system activity2
• Increasing intestinal permeability2
• Influencing epigenetic regulation2
• In essence, early life experiences, through modification of the gut ecology, magnify stressors, amplify the stress response, and inhibit corrective homeostatic mechanisms resulting in chronic sustained inflammation
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Early Life Adversity and the Microbiome
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Discussion
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The Brain-Gut Connection and Inflammation
15
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A Healthy Microbiome1,2
1. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:3922. Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:701-12.
Healthy Microbiome
• Normal gut microbiota• Normal behavior and cognition• Healthy levels of inflammatory
cells/mediators• Normal intestinal permeability
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Causes and Consequences of Dysbiosis1,2
*Examples of potential causes of dysbiosis. Not an exhaustive list.1. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:392.2. Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:701-12.
Dysbiosis
• Increased inflammation• Altered behavior and cognition• Increased gut permeability
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We’ve Gone Wrong Somewhere in the Modern World
DM1, type 1 diabetes; MS, multiple sclerosis. Bach JF. N Engl J Med. 2002;247(12):911-920
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The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
“Classic” vs Chronic Inflammation
Egger G. Prev Chronic Dis. 2012;9:E95.
Cla
ssic
al In
flam
mat
ion • Described ~2000 years ago
• Pain (dolor)• Redness (rubor)• Heat (calor)• Swelling (tumor)
• Short-term response to infection and injury
• Aims to remove infective stimulus and allow repair of damaged tissue
Chr
onic
infla
mm
atio
n (“
Met
afla
mm
atio
n”)
• Described in 1993• Low-grade, causing only a small
rise in immune system markers• Persistent, resulting in chronic,
rather than acute, allostasis• Has systemic, rather than local
effects• Has antigens that are less apparent
as foreign (“inducers”)• Appears to perpetuate, rather than
resolve disease• Is associated with reduced, rather
than increased metabolism
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Rook GA, et al. Clin Exp Immunol. 2014;177(1):1-12.
Hypothesis: The immune system evolved to require input from organisms collectively termed the “old friends”:
i. Commensal microbiota ii. Commonly encountered organisms from the natural environmentiii. Relatively harmless, subclinical ‘old’ infections that could persist in small isolated hunter-
gatherer groups Loss of contact with “old friends” leads to immune dysregulation, which, in turn, contributes to the development of immunoregulatory disorders (e.g. allergic and autoimmune conditions)
Supporting Evidence• Some “old friends” are known to specifically expand regulatory T cell populations• Chronic inflammatory disorders tend to increase when populations immigrate from low-income to
developed high-income countries• Within any given country, chronic inflammatory disorders are more common in urban than in rural
communities• This is equally true for psychiatric disorders, including autism, schizophrenia, and depression
• Contact with animals (e.g., farm animals, dogs) has a protective effect from allergic disorders and correlates with a better ability to control background inflammation in humans
• Cesarean birth has been linked with an increased risk of type I diabetes, asthma and celiac disease
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The “Old Friends” Hypothesis
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Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:392.
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Leaky Gut, Inflammation and the Brain
PrebioticsProbioticsGood Diet
Neuroinflammation
HPA activation
Immune activation
Disrupted intestinal barrier
“Leaky Gut”
Stress
Bacteria translocation
Cognitive DysfunctionDepression
AnxietyDecreased Social Function
Intact intestinal barrier
InfectionAntibioticsPoor Diet
Proinflammatory cytokines
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Pro-inflammatory Anti-inflammatory or neutral
Inactivity Fast food/Western-style diet
Exercise Capsaicin
Obesity High omega 6:omega 3 ratio
Weight loss Cocoa/chocolate
Excessive energy intake Low fiber intake Restricted energy intake High fiber intake
Smoking Fructose/glucose Smoking cessation Garlic
Sleep deprivation High glycemic load Fish/fish oils Grapes/raisins
Stress/anxiety/depression Air pollution Fruits/vegetables Mediterranean diet
High fat diet/Saturated and trans fats
Inequality/economic insecurity
Nuts Moderate alcohol
Secondhand smoke Domesticated meat Monounsaturated fats Tea/green tea
Excessive exercise Excessive alcohol Lean game meat Eggs
Egger G. Prev Chronic Dis. 2012;9:E95.
Selected Pro- and Anti-inflammatory “Inducers” of Metaflammation
Strength of Evidence:Strong Moderate Limited
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Discussion
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
The Role of the Brain-Gut Connection in Mental Health
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
1. Prinsloo S and Lyle RR. NeuroRegulation. 2015;2(4):158-161.2. Schnorr SL, Bachner HA. Yale J Biol Med. 2016;89(3):397-422.3. The Cleveland Clinic. The Gut-Brain Connection. November 27, 2017. Available at: https://my.clevelandclinic.org/health/treatments/16358-gut-brain-connection. Accessed February
27, 2018.
• Common co-occurrence of GI-related comorbidities with a variety of psychiatric conditions (anxiety, depression, schizophrenia)1,2
• GI problems can create stress and anxiety; conversely, stress and anxiety can make GI problems worse3
• Experiencing emotion, such as excitement or nervousness, may impact the digestive system, causing the “butterflies in the stomach” feeling3
25
Clinical Observations Suggestive of Brain-Gut Connection
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CRP, C-reactive protein; FMT, fecal matter transplant.Kelly JR, et al. J Psychiatr Res. 2016;82:109-118.
• Kelly et al., demonstrated a connection between depressive behavior and the microbiome:
The Microbiota in Major Depression
Depressed patients• ↓ microbiota richness and diversity• ↑ inflammatory markers• ↑ cortisol levels
Healthy controls
Microbiota-depleted rats FMTFMT
Compared to healthy controls:↑ Anhedonia like behavior ↑ Anxiety like behaviors ↑ Intestinal transit timeTrend toward increased levels of plasma CRP
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
1. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.2. Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):239-44.
Preclinical• Most research in this area is based on preclinical studies. Connections between
microbiome and anxiety-related behaviors in animals have been shown in many studies1,2
1. Stress in rats has been reported to lead to a reduction in diversity of the GI microbiome1
2. The naturally exaggerated physiological response to stress in germ-free mice was reversed when they were colonized with a particular strain of bacteria1
3. Rats given a strain of bacteria for 28 days showed a decline in both anxiety and depression scores2
Clinical (limited)• A double-blind, placebo-controlled trial of 66 subjects who ingested a fruit bar
containing a probiotic formula for 30 days reported significantly lower levels of anxiety, anger, depression, and somatization as well as lower cortisol levels in the probiotic group1
• A placebo-controlled study assessing the effect of a fermented milk product containing probiotics on the brain activity of healthy women reported significant impact on the regions controlling emotional and sensory processing1
27
Evidence of the Brain–Gut Connection
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Effect of Gut Microbiota on Mood-Related Behavior
GF, germ free; MDD, major depressive disorder; SPF, specific pathogen free.Zheng et al. Mol Psychiatry. 2016;21:786-796.
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Huang R et al., Nutrients. 2016;8:483.
• In a systematic review and meta-analysis of 5 randomized controlled trials of the anti-depressant effects of probiotics:
– One study examined anti-depressant effects in depressed patients, and reported that probiotics significantly improved depression scores in subjects vs placebo
– The remaining four studies examined the effect of probiotics in non-depressed individuals and the analysis suggested a role for probiotics in reducing the risk of depression
Probiotics for Depression
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Discussion
The information provided by PsychU is intended for your educational benefit only. It is not intended as, nor is it a substitute for medical care or advice or professional diagnosis. Users seeking medical advice should consult with their physician or other healthcare professional.
1. Verdino J. Health Psychol Open. 2017;4(2):2055102917724335.2. Schnorr SL, Bachner HA. Yale J Biol Med. 2016;89(3):397-422.
• Mental health disorders are unlikely to be treated with probiotics and prebiotics alone1
• While mental health requires specialized care provided by mental health professionals, complimentary therapeutic strategies should also be utilized2
– Sufficient rest, digestion, exercise, mindful relaxation, and eating a nutritionally rich and varied diet may be considered2
• Additional studies are required to identify strains of bacteria which may confer mental health benefits, as well as those associated with specific symptoms1
– It is the hope that additional research can lead to nutritionally based and psychobiotictreatments that can be combined with traditional psychological and psychotropic approaches
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Future Considerations for the Brain-Gut Connection in the Treatment of Mental Illness
Psychotropic intervention:
Focus on biology and
neurochemistry
Nutritional therapy:Focus on the impact of the microbial environment of the gut on mental health
Therapy:Focus on
behavioral and psychological
variables
Areas of Focus in Treatment of Psychiatric Illness1
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Discussion
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QUESTIONS
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