Update on the Role of Gut Microbiota Modulation for the Treatment & Prevention of Mood & Anxiety

Transcription

1 Update on the Role of Gut Microbiota Modulation for the Treatment & Prevention of Mood & Anxiety David J. Scheiderer, MD, MBA, DFAPA Director of Education, Integrative Psychiatry, Inc., Sarasota, Florida President, Tiberius Enterprises, Inc., Roanoke, Virginia Roger S. McIntyre, MD, FRCPC Professor 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 2018 Otsuka Pharmaceutical Development & Commercialization, Inc., Rockville, MD Lundbeck, LLC. March 2018 MRC2.CORP.D.00337

2 Today s Speakers David J. Scheiderer MD, MBA, DFAPA Integrative 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, FRCPC University of Toronto, University Health Network, and Brain and Cognition Discovery Foundation Dr. 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. 2

3 This program is paid for by Otsuka Pharmaceutical Development & Commercialization, Inc. and Lundbeck, LLC. Speakers are paid consultants for Otsuka Pharmaceutical Development & Commercialization, Inc.

4 PsychU Virtual Forum Rules of Engagement: Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) and Lundbeck, LLC. have entered into collaboration with OPEN MINDS, to explore new ways of bringing/increasing awareness around serious mental illness. OPDC/Lundbeck s interaction with OPEN MINDS is through PsychU, an online, non-branded portal dedicated to providing information and resources on important disease state and care delivery topics related to mental illness. One of the methods employed for the sharing of information will be the hosting of virtual fora. Virtual fora conducted by OPDC/Lundbeck are based on the following parameters: When conducting medical dialogue, whether by presentation or debate, OPDC/Lundbeck and/or its paid consultants aim to provide the viewer with information that is accurate, not misleading, scientifically rigorous, and does not promote OPDC/Lundbeck products. No continuing medical education (CME) credits are available for any PsychU program. OPDC/Lundbeck and/or their paid consultants do not expect to be able to answer every question or comment during a PsychU Virtual Forum; however, they will do their best to address important topics and themes that arise. OPDC/Lundbeck and/or their paid consultants are not able to provide clinical advice or answer questions relating to specific patient s condition. Otsuka and Lundbeck employees and contractors should not participate in this program (e.g., submit questions or comments) unless they have received express approval to do so from Otsuka Legal Affairs. OPDC/Lundbeck operate in a highly regulated and scrutinized industry. Therefore, we may not be able to discuss every issue or topic that you are interested in, but we will do our best to communicate openly and directly. The lack of response to certain questions or comments should not be taken as an agreement with the view posed or an admission of any kind. 4 The information The information provided provided by by PsychU is is intended for your educational benefit benefit only. only. It is not It is intended not intended as, nor as, is it nor a substitute is a substitute for medical for care medical or advice care or advice or or professional diagnosis. Users seeking medical advice should consult consult with their with physician their physician or other or healthcare other healthcare professional. professional.

5 Objectives Provide an overview of the origins and importance of the brain-gut connection Examine the relationship between the brain-gutmicrobiome 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 5

6 The Brain-Gut Connection: Origins and Importance

7 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 axis 1 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 disorders 1 The European Union launched a 5-year MyNewGut project ($10.1 million US dollars) for research on brain development and related disorders 1 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 disease 2 1. Wang HX, Wang YP. Chin Med J (Engl). 2016;129(19): Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):

8 Origins and Colonization of the Gut Microbiota The gut and brain originate from the same tissue during embryogenesis, the neural crest, and influence each other during development 1 Bacteria, mostly residing in the gut, outnumber the body s cells 10:1 and are referred to as a microbiome 1 3 A microbiome comprises the entirety of microscopic organisms and their genetic material that inhabit a particular environment Gut microbiota begin to colonize the GI tract at birth with a complex microbiome forming after the first year of age 4 Human brain Gut bacteria have been estimated to consist of >1000 species and >7,000 subspecies 3 ~1 kg The bacteria in our microbiome have 5 co-evolved with us and interact with our body in a bidirectional manner 2 Gut microbiota 1. Chen X, D'Souza R, Hong ST. Protein Cell. 2013;4(6): Verdino J. Health Psychol Open. 2017;4(2): Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3): Petra AI, et al. Clin Ther. 2015;37(5): Dinan TG, et al. Journal of Psychiatric Resarch. 2015;63:1-9. 8

9 Routes for, and Blockages of, Microbial Colonization of Westernized Humans Routes for microbial colonization Vaginal delivery Breastfeeding Environmental interaction Early life stages Gestation Newborn Infant Impediments to microbial colonization C-section delivery Mother treated with antibiotics Feeding by formula only Indoor living Excessive sanitation Food preservatives Toh MC & Allen-Vercoe E. Microb Ecol Health Dis. 2015;26:26309.

10 Communication Along the Microbiota-Gut-Brain Axis 1-3 O OH CORTISOL H O H O H Systemic Communication: Immune Cytokines Bacterial metabolites Neural Communication Vagus nerve Sympathetic Nervous System Systemic Communication: Endocrine HPA axis Neurotransmitters Bacterial metabolites NH 2 SEROTONIN HO N H 1. Mayer EA et al., J Neurosci. 2014;34(46): Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9: Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:

11 Diseases Associated with Dysbiosis of Gut Microbiota Neurodegenerative disorders Multiple sclerosis 1 Parkinson s disease 2 Cardiovascular disease Coronary artery disease 3 Hypertension 4 Intestinal disorders Inflammatory Bowel Disease 5 Crohn s disease Ulcerative colitis Irritable Bowel Syndrome 5,6 Celiac disease 5 Psychiatric and mood disorders Anxiety 5,6 Depression 5,6 Autism spectrum disorder 5,6 Bipolar Disorder 6 Schizophrenia 6 Metabolic disorders Metabolic syndrome 5 Obesity 5,7 Types 1 and 2 diabetes 5,7 Pregnancy-related conditions Gestational hypertension 8 Gestational diabetes 8 1. Cekanaviciute E, et al. Proc Natl Acad Sci U S A. 2017;114(40): Sampson TR, et al Cell. 2016;167(6): e Senthong V, et al. J Am Heart Assoc Jun 10;5(6). 4. Li J, et al. Microbiome. 2017;5(1): Carding S, et al. Microb Ecol Health Dis. 2015; 26: Fond G, et al. Pathol Biol (Paris). 2015;63(1): Tai N, et al. Rev Endocr Metab Disord. 2015;16(1): Dunlop AL, et al. Adv Neonatal Care. 2015;15(6): The information The information provided provided by by PsychU is is intended for your educational benefit benefit only. only. It is not It is intended not intended as, nor as, is it nor a substitute is a substitute for medical for care medical or advice care or advice or or professional diagnosis. Users seeking medical advice should consult consult with their with physician their physician or other or healthcare other healthcare professional. professional.

12 Impact of Imbalance of Gut Microbiota on Mental Health An individual s gut microbiome composition is impacted by: 1,2 Vaginal birth Genetics Age Diet Physical activity Environment Stress Infections Other diseases Antibiotic use When an unhealthy imbalance of bacteria (dysbiosis) occurs, health problems may arise 3 Research suggests that chronic states of bacterial imbalance in the gut may play a role in psychiatric and behavioral problems 3 Evidence supports a link between the microbial state of the gut and overall health, emotional functioning, immune response, and mental health 1,3 1. Prinsloo S and Lyle RR. NeuroRegulation. 2015;2(4): Petra AI, et al. Clin Ther. 2015;37(5): Verdino J. Health Psychol Open. 2017;4(2):

13 Early Life Adversity and the Microbiome 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 axis 1 Altering immune system activity 2 Increasing intestinal permeability 2 Influencing epigenetic regulation 2 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 Th, T-helper; HPA, hypothalamo-pituitary-adrenal; Treg, regulatory T-cells. 1. Sudo N et al. J Physiol Jul 1;558(Pt 1): Gur TL, Worly BL, Bailey MT. Front Psychiatry. 2015;6:5. 13

14 Discussion

15 The Brain-Gut Connection and Inflammation 15

16 A Healthy Microbiome 1,2 Healthy Microbiome Normal gut microbiota Normal behavior and cognition Healthy levels of inflammatory cells/mediators Normal intestinal permeability 1. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9: Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:

17 Causes and Consequences of Dysbiosis 1,2 Dysbiosis Increased inflammation Altered behavior and cognition Increased gut permeability *Examples of potential causes of dysbiosis. Not an exhaustive list. 1. Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9: Cryan JF & Dinan TG. Nature Reviews Neuroscience. 2012;13:

18 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):

19 Classic vs Chronic Inflammation Classical Inflammation 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 Chronic inflammation ( Metaflammation ) 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 Egger G. Prev Chronic Dis. 2012;9:E95. The information The information provided provided by by PsychU is is intended for your educational benefit benefit only. only. It is not It is intended not intended as, nor as, is it nor a substitute is a substitute for medical for care medical or advice care or advice or or professional diagnosis. Users seeking medical advice should consult consult with their with physician their physician or other or healthcare other healthcare professional. professional.

20 The Old Friends Hypothesis Hypothesis: The immune system evolved to require input from organisms collectively termed the old friends : i. Commensal microbiota ii. iii. Commonly encountered organisms from the natural environment Relatively harmless, subclinical old infections that could persist in small isolated huntergatherer 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 Rook GA, et al. Clin Exp Immunol. 2014;177(1):

21 Leaky Gut, Inflammation and the Brain Stress Infection Antibiotics Poor Diet Immune activation HPA activation Disrupted intestinal barrier Leaky Gut Bacteria translocation Proinflammatory cytokines Neuroinflammation Prebiotics Probiotics Good Diet Intact intestinal barrier Cognitive Dysfunction Depression Anxiety Decreased Social Function Kelly JR et al., Frontiers in Cellular Neuroscience. 2015;9:

22 Selected Pro- and Anti-inflammatory Inducers of Metaflammation Strength of Evidence: Strong Moderate Limited Pro-inflammatory Anti-inflammatory or neutral Inactivity Obesity Fast food/westernstyle diet High omega 6:omega 3 ratio Exercise Weight loss Capsaicin 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.

23 Discussion

24 The Role of the Brain-Gut Connection in Mental Health

25 Clinical Observations Suggestive of Brain-Gut Connection 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 worse 3 Experiencing emotion, such as excitement or nervousness, may impact the digestive system, causing the butterflies in the stomach feeling 3 1. Prinsloo S and Lyle RR. NeuroRegulation. 2015;2(4): Schnorr SL, Bachner HA. Yale J Biol Med. 2016;89(3): The Cleveland Clinic. The Gut-Brain Connection. November 27, Available at: Accessed February 27,

26 The Microbiota in Major Depression Kelly et al., demonstrated a connection between depressive behavior and the microbiome: Depressed patients microbiota richness and diversity inflammatory markers cortisol levels Healthy controls FMT Microbiota-depleted rats FMT Compared to healthy controls: Anhedonia like behavior Anxiety like behaviors Intestinal transit time Trend toward increased levels of plasma CRP CRP, C-reactive protein; FMT, fecal matter transplant. Kelly JR, et al. J Psychiatr Res. 2016;82:

27 Evidence of the Brain Gut Connection 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 studies 1,2 1. Stress in rats has been reported to lead to a reduction in diversity of the GI microbiome 1 2. The naturally exaggerated physiological response to stress in germ-free mice was reversed when they were colonized with a particular strain of bacteria 1 3. Rats given a strain of bacteria for 28 days showed a decline in both anxiety and depression scores 2 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 group 1 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 processing 1 1. Verdino J. Health Psychol Open. 2017;4(2): Evrensel A, Ceylan ME. Clin Psychopharmacol Neurosci. 2015;13(3):

28 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:

29 Probiotics for Depression 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 Huang R et al., Nutrients. 2016;8:483.

30 Discussion

31 Future Considerations for the Brain-Gut Connection in the Treatment of Mental Illness Mental health disorders are unlikely to be treated with probiotics and prebiotics alone 1 While mental health requires specialized care provided by mental health professionals, complimentary therapeutic strategies should also be utilized 2 Sufficient rest, digestion, exercise, mindful relaxation, and eating a nutritionally rich and varied diet may be considered 2 Additional studies are required to identify strains of bacteria which may confer mental health benefits, as well as those associated with specific symptoms 1 It is the hope that additional research can lead to nutritionally based and psychobiotic treatments that can be combined with traditional psychological and psychotropic approaches Areas of Focus in Treatment of Psychiatric Illness 1 Therapy: Focus on behavioral and psychological variables Psychotropic intervention: Focus on biology and neurochemistry Nutritional therapy: Focus on the impact of the microbial environment of the gut on mental health 1. Verdino J. Health Psychol Open. 2017;4(2): Schnorr SL, Bachner HA. Yale J Biol Med. 2016;89(3):

32 Discussion

33 QUESTIONS

34 CLOSING