Microbiota and its Impact on the Gut- Brain Axis How Much Do We Know?

Transcription

1 Probiota Americas, San Diego, June 3-5, 2015 Microbiota and its Impact on the Gut- Brain 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

2 Overview Historical perspective Preclinical behavioral evidence Preclinical mechanistic evidence Clinical evidence Future perspectives Illustration by Benjamin Arthur for NPR

3 The 20 th Century View

4 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)

5

6

7 Treatment of Depression by Probiotics

8 The 21 th Century View

9 Putative Communication Channels and Molecules between Gut Microbiome and Brain Sampson & Mazmanian, 2015; Mayer et al. JNS 2015; Mayer et al. JCI, 2015

10 Experimental Paradigms and Readouts of the Brain Gut Microbiome Axis Mayer et al., JCI 2015

11 Preclinical Studies

12 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;

13 Manipulation of Gut Microbiota Can Affect Behavior and Brain Biochemistry in Animals Behavioral Readouts Nociceptive reflexes 1-3 Emotional behavior 4-5 Social behavior 8-10 Ingestive behavior 11 Biological Readouts Brain neurochemistry 4,5 HPA axis 6-7 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

14 A Mouse is not a Monkey, is not a Human Neither are their Brains the same adapted from AD Craig, Nature Reviews Neuroscience 2009

15 Mechanistic evidence

16 Sampson & Mazmanian, 2015

17 Sampson & Mazmanian, 2015

18 Human Studies

19 The Fancy: Translational Speculations Based on Preclinical Data The Oppenheimer Center

20 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

21 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

22 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

23 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

24 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 treatment 1 dietary manipulations psychosocial stressors probiotic treatment 2,3 1 Ahluwalia et al 2014; 2 Messaoudi BJN 2011; 3 Benton et al. Europ J Clin Nutrition 2007

25 Can Probiotics Modulate the Gut-Microbiota-Brain axis? Tillisch et al. Gastroenterology 2013

26 Perturbation of gut microbial composition and function by ingestion affect brain function in humans? Study Design: 45 Healthy women Age (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

27 Probiotic Intake was Associated with Blunted Reactivity of Interoceptive and Somatosensory Regions Regions with less activation in probiotic vs no treatment No Tx > PFM Insula Somatosensory Regions with less activation in probiotic vs control Tillisch, et al, Gastroenterology 2013

28 Probiotic Intake was Associated with Decreased Connectivity within an Extensive Task Dependent Brain Network, Including Sensory and Pain Modulatory Regions Treatment related change in network (design score) Network crossblock covariance 49%, P <.005 Across visits the network becomes: stronger with no treatment stays the same with control decreased in the probiotic Test Product. Tillisch, et al, Gastroenterology 2013

29 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

30 The Future

31 What Role do Alterations in Brain Gut Microbiome Interactions Play in GI and non-gi Disorders? Brain Gut disorders 1-3 : Obesity, food addiction, metabolic syndrome IBS Inflammatory bowel diseases Non-GI disorders 4-5 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:e856-64; 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

32 Do manipulations of the gut microbiome (diet, probiotics, antibiotics, chronic infections) influence brain development during pre and postnatal period

33 Are Structural Brain Differences Related to Pre and Postnatal Influences on Gut Microbiome? Mayer et al., JCI 2015

34 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

35 Neuroimaging Investigators Emeran Mayer Bruce Naliboff Jennifer Labus Lisa Kilpatrick Claudia San Miguel Research nurses Jean Stains Suzanne Smith Neuroimaging Core Cody Ashe-McNalley Mher Alaverdyan Cathy Liu Annie Gupta Gilbert Hong Kristin Coveleskie Zafar Gill Michelle Chen Aubrey Love The CNS Neuroimaging core is funded by NIDDK, NIDA, NCCAM, NICHD, and the ORWH