Psychiatry Meets the Microbial World

Charles L. Raison, MDMary Sue and Mike Shannon Chair for Healthy Minds, Children & Families and Professor, School of Human EcologyProfessor, Department of Psychiatry, School of Medicine and Public HealthUniversity of Wisconsin-MadisonMadison, Wisconsin

Starting with the “Take-Home” Message of this Talk…

We’ve Gone Wrong Somewhere in the Modern World

DM1 = type 1 diabetes; MS = multiple sclerosis.Bach JF. N Engl J Med. 2002;347(12):911-920.

Crohn’s disease

400

MS

Inci

den

ce o

f Im

mu

ne

Dis

ord

ers

(%)

300

200

100 1960 1980 20001950 1970 1990

DM1

Asthma

Increased Prevalence of Immune-MediatedDisease in Modern World

Traditional Environments Appear to Protect Against Chronic Inflammation

CRP = C-reactive protein.McDade TW, et al. Am J Hum Biol. 2012;24(5):675-681.

CRP levels were measured repeatedly over 4 weeks in 52 individuals living a traditional lifestyle in the Amazon basin. Levels rose and fell with infectious status but were far lower overall than seen in the United States, and no cases of chronically-elevated CRP were observed, as is common in the developed world.

CR

P

THE “OLD FRIENDS”

Gut Flora

Saprophytic Mycobacteria

Helminths

Examples of the 3 Overlapping Categories of Organisms Implicated in the “Hygiene” or “Old Friends” Hypothesis

Rook GA, et al. Trends Immunol. 2008;29(4):150-158.

1) Organisms that form part of the co-evolved human microbiotathat are altered by modern diets, living conditions, and antibiotics

2) Infections commonly present in early man, usually harmless, transmitted by the fecal-oral route very early in life, that have been depleted since urbanization (eg, helminths, hepatitis A virus, Toxoplasma, Salmonella)

3) Harmless environmental organisms in mud, untreated water, and fermenting vegetable material (“pseudocommensals”: lactobacillus, environmental saprophytes) that are eliminated by the modern city lifestyle

Those that Needed to be Tolerated Became Teachers of Tolerance

Rook GA, et al. Cin Exp Immunol. 2014;177(1):1-12.

Those that Needed to be Tolerated Became Teachers of Tolerance

IL = interleukin; TGF = transforming growth factor.Rook GA, et al. Trends Immunol. 2008;29(4):150-158. Rook GA, et al. Microbiologist. 2008;12:32-36

The Stairway Down to Immune Dysregulation

SES = socioeconomic statusRook GA, et al. Clin Exp Immunol. 2014;177(1):1-12.

Modern Life has Changed the Microbiome as Much as It’s Changed Us

PC0 = plotted principal coordinates; UniFrac = a distance metric used for comparing biological communities.Schnorr SL, et al. Nat Commun 2014;5:3654.

Comparison of Microbiota from Italians vs Hunter-Gatherers

Modern Life has Changed the Microbiome as Much as It’s Changed Us

Schnorr SL, et al. Nat Commun. 2014;5:3654.

List of Diseases Associated with Microbiota Abnormalities (Partial and Idiosyncratic)

Gomez-Arango LF, et al. Hypertension. 2016;68(4):974-978. Senthong V, et al. J Am Heart Assoc. 2016;5(6):e002816. Huang R, et al. Nutrients. 2016;8(8):483. Hov JR, et al. Curr Opin Gastroenterol. 2017;33(2):85-92. Gong D, et al. Gastroenterol Res Pract. 2016;2016:6951091. Dinan TG, et al. Neurogastroenterol Motil. 2013;25(9):713-719. Petrof EO, et al. Benef Microbes. 2013;4(1):53-65. Cryan JF, et al. Nat Rev Neurosci. 2012;13(10):701-712. Evans SJ, et al. J Psychiatr Res. 2016;87:23-29. O’Mahony SM, et al. Pain. 2017;158 Suppl 1:S19-S28. Fond G, et al. Pathol Bio. 2015;63(1):35-42. Lin L, et al. BMC Immunol. 2017;18(1):2. Sampson TR, et al. Cell. 2016;167(6):1469-1480. Aguilar A. Nat Rev Nephrol. 2017;13:3.

• Gastrointestinal diseases (IBD) Ulcerative colitis (UC) Crohn’s disease Pouchitis Chronic intestinal inflammation Irritable bowel syndrome (IBS)

• Coronary artery disease (CAD)• Primary sclerosing cholangitis• Necrotizing enterocolitis (NEC)• Multiple sclerosis• Clostridium difficile infection (CDI)• Obesity• Visceral pain• Parkinson’s disease

• Types 1 and 2 diabetes• Autoimmune arthritis• Hypertension• Pregnancy-related conditions

Gestational hypertension Gestational diabetes (GDM)

• Psychiatric and Neurodevelopmental Disorders Depression Bipolar disorder Schizophrenia Anxiety (stress) Autism spectrum disorder

The Microbiota in Major Depression

Kelly JR, et al. J Psychiatr Res. 2016;82:109-118. (Similar findings in: Zheng P, et al. Mol Psychiatry. 2016;21(6):786-796.)

Early-Life Adversity May Impact Adult Microbiota

Labus JS, et al. Microbiome. 2017;5(1):49.

Microbiome, brain structure, and stress history assessed in 29 patients with IBS and healthy controls. Sub-group of IBS patients with altered microbiomes compared to controls had significantly higher rates of early-life adversity. Composition of microbiome associated with structure of brain regions involved in sensory processing.

So What?

Emerging Treatments Based on Human-Microbial Interactions

Association Does Not Prove Causality Needed for Treatment Relevance

Microbiota Disease

MicrobiotaDisease

Microbiota Disease

Microbiota Disease

Underlying Cause

Probiotics/PrebioticsSynbiotics

Fecal/MicrobiotaTransplant

“Old Friend”Micro-Organisms

POTENTIAL MICROBIAL TREATMENTS

• Probiotics

Usually a dairy food or a dietary supplement containing live bacteria that replace or add to the beneficial bacteria normally present in the gastrointestinal tract

• Prebiotics

A nondigestible food ingredient that promotes the growth of beneficial microorganisms in the gastrointestinal tract

• Synbiotics

A product containing both probiotics and prebiotics, with the prebiotic compound selectively favoring the probiotic compound

Meta-Analytic Data for Disease States that May Benefit from Probiotics, Prebiotics, or Synbiotics

GI = gastrointestinal. Fujiya M, et al. Clin J Gastroenterol. 2014;7(1):1-13. Chang YS, et al. JAMA Pediatr. 2016:170(3):236-242. Dong JY, et al. Br J Nutr. 2013;110(7):1188-1194. Khalesi S, et al. Hypertension. 2014;64(4):897-903. Shimizu M, et al. PLoS One. 2015;10(10):e0139795. Sun J, et al. Ann Med. 2015;47(6):430-440. Nikbakht E, et al. Eur J Nutr. 2016;[Epub ahead of print]. Zuccotti G, et al. Allergy.2015;70(11):1356-1371. Doege K, et al. Br J Nutr. 2012;107(1):1-6. He D, et al. Clin Res Hepatol Gastroenterol. 2013;37(4):406-415. Carter GM, et al. Open Forum Infect Dis. 2016;29;3(4):ofw164.

• Ulcerative colitis, not Crohn’s disease

• Hypertension

• Metabolic cardiovascular risk factors (hyperlipidemia, obesity, inflammatory markers, etc.)

• Diabetes and related parameters (eg, insulin sensitivity, blood glucose levels)

• Multiple GI-related clinical outcomes in context of colorectal cancer resection

• Possible benefits for CD4 count, recurrence or management of bacterial vaginosis, and diarrhea in HIV

• Atopic dermatitis in children ≥ 1 year and eczema in infants (but not asthma/wheezing) given to infants or pregnant mothers

Probiotics Impact Brain Responses to Depression-Relevant Social Cues

4 weeks of ingesting an FMPP in healthy women resulted in changes to activity- and resting-state brain function. Ingesting the FMPP reduced responses to emotional faces in a distributed functional network containing affective, viscerosensory, and somatosensory cortices. Changes in resting-state midbrain functional connectivity were also observed. FMPP = fermented milk product with multiple probiotic species.Tillisch K, et al. Gastroenterology. 2013;144(7):1394-1401.

Probiotic Exposure and Depression in General Population

Cepeda MS, et al. J Neuropsychiatry Clin Neurosci. 2017;29(1):39-44.

Probiotics for Depression

McKean J, et al. J Altern Complement Med. 2017;23(4):249-258.

Meta-analysis of 5 studies examining impact of probiotic formulations for depression. Effects seen in non-clinically depressed and depressed participants, with effect size larger in major depression and in those under age 65 years.

What is the Best Probiotic or Probiotic Formulation(s)?

AKA FECALTRANSPLANT

Brave Mice and Timid Mice

Collins SM, et al. Curr Opin Microbiol. 2013;16(3):240-245.

NIH Swiss = “bold”

BALB/C = “anxious” Behavioral Differences betweenBALB/C and NIH Swiss Mice

If Men Were Mice, Fecal Transplant Would Change Everything: Part I

BDNF = brain derived neurotrophic factor.Bercik P, et al. Gastroenterology. 2011;141(2):599-609.

BALB/CNIH Swiss

NIH Swiss Fecal Transplant

Increased hippocampal BDNF

If Men Were Mice, Fecal Transplant Would Change Everything: Part II

Bercik P, et al. Gastroenterology. 2011;141(2):599-609.

NIH Swiss

BALB/C Fecal Transplant

Decreased hippocampal BDNF

Huge Microbiota Effect of Fecal Transplant in Patient with Clostridium difficile

Vázquez-Baeza Y, et al. Cell Host Microbe. 2017;21(1):7-10.

Fecal Matter Transplant Changes the Microbiome

Disease States that May Benefit from Fecal Transplant

Li YT, et al. Aliment Pharmacol Ther. 2016;43(4):445-457. Kassam Z, et al. Am J Gastroenterol. 2013;108(4):500-508. Colman RJ, et al. J Crohns Colitis. 2014;8(12):1569-1158. Rossen NG, et al. World J Gastroenterol. 2015;21(17):5359-5371. Shi Y, et al. PLOS One. 2016;11(6):e0157259. Philips CA, et al. Clin Gastroenterol Hepatol. 2017;15(4):600-602. Ren YD, et al. Hepatology. 2017;65(5):1765-1768. Vrieze A, et al. Gastroenterology. 2012;143(4):913-916. Wei Y, et al. Crit Care. 2016;18;20(1):332.

• Meta-analytic results

– Clostridium difficile infection (~90% cure rate)

– Ulcerative colitis, +/- Crohn’s disease

• Single studies

– Severe alcoholic hepatitis (improved liver indices and 1-year survival)

– Hepatitis B (e-antigen clearance)

– Metabolic syndrome (increased insulin sensitivity)

– Multiple organ dysfunction syndrome (in ICU)

Microbiota Transplant in Autism

ABC = Aberrant Behavior Checklist; CARS = Childhood Autism Rating Scale; GSRS = Gastrointestinal Symptom Rating Scale; PGI-III = Parent Global Impressions-III; SRS = Social Responsiveness Scale.Kang DW, et al. Microbiome. 2017;5(1):10.

• 18 patients with autism spectrum disorders, aged 7–16 years, underwent antibiotic cleansing of the gut followed by prolonged transplant of standardized human microbiota

• This treatment significantly improved both GI and behavioral symptoms

A Digression Relevant to Bodily Immune Processes in Autism

Sharma A, et al. Stem Cell Int. 2013;2013:623875.

Autologous bone marrow mononuclear cells intrathecal transplantation was conducted in 32 patients with autism. All patients were followed up for 26 months (mean 12.7). 29 (91%) patients improved on total Indian Scale for Assessment of Autism (ISAA) scores and 20 patients (62%) showed decreased severity on Clinical Global Impression Improvement subscale (CGI-I). Positron Emission Tomography 6 months after the intervention showed increased FDG uptake in frontal lobe, cerebellum, amygdala, hippocampus, parahippocampus, and mesial temporal lobe.

“Old Friend” Micro-Organisms:Mycobacterium vaccae

M vaccae and the Treatment of Cancer

Dlugovitzky D, et al. Respir Med. 2006;100(6):1079-1087. Stanford JL, et al. Eur J Cancer. 2008;44(2):224-227.

Dlugovitzky et al. Respiratory Medicine 2006; 100: 1079‐87

M Vaccae and Survivalin Patients with LungAdenocarcinoma

CHEMO+

M VACCAE

CHEMOALONE

O’Brien ME, et al. Ann Oncol. 2004;15(6):906-914.

TreatmentSample

Size

Raw Mean

Change from

Baseline

Adjusted Mean

Change from

Baselinea

Raw SD

P Value unadjusted

P Value adjusteda

1. Global Health Status

Chemo only 172 -14.2087 -14.3462 25.9887 .007 .002

Chemo + SRL172 179 -6.7368 -6.6271 25.0216

2. Physical functioning

Chemo only 169 -24.5853 -27.7450 26.5044 .010 .002

Chemo + SRL172 178 -16.8608 -18.9749 24.6951

3. Role limited due to physical problems

Chemo only 170 -16.5159 -21.1727 35.8395 .579 .120

Chemo + SRL172 178 -14.1684 -14.6474 34.5462

4. Social functioning

Chemo only 172 -15.0322 -17.5890 36.5165 .413 .120

Chemo + SRL172 180 -11.8696 -12.2119 30.4944

5. Role limited due to emotional problems

Chemo only 172 -8.9916 -12.5583 32.7143 .008 .001

Chemo + SRL172 180 0.5039 -1.4788 27.6059

6. Cognitive functioning

Chemo only 172 -17.7260 -21.6305 32.1991 .006 .001

Chemo + SRL172 180 -6.1101 -8.6470 28.3704

7. Bodily pain

Chemo only 172 12.4058 13.4189 34.5525 .008 .001

Chemo + SRL172 180 0.8010 -0.7503 33.7000

8. Vitality

Chemo only 172 19.3619 21.0849 28.1991 .237 .021

Chemo + SRL172 180 14.5830 14.2318 27.3624

9. Nausea and vomiting

Chemo only 172 24.9984 24.9445 32.5458 .008 .011

Chemo + SRL172 180 14.4041 15.2163 29.5638aMean change and P values adjusted for age, sex, current smoking status, cancer stage, weight loss and country. Mean change also adjusted for baseline.Note: for Global Health Status and the functioning parameters (parameters 1-6 above), a decrease from baseline indicates worsening. For the symptom parameters (parameters 7-9 above), a decrease from baseline indicates improvement.For all parameters except Global Health Status, the P values presented are the Hochberg-Benjamini P values.

Mycobacterium vaccae

M vaccae as a “Stress Vaccine”?

CSC = chronic subordinate colony.Reber SO, et al. Proc Natl Acad Sci USA. 2016;113(22):E3130-E3139.

Chronic Subordinate Colony HousingSingle Housed Controls

Pre-Immunization with M vaccae Protects Against Physical and Behavioral Stress Pathology

Reber SO, et al. Proc Natl Acad Sci USA. 2016;113(22):E3130-E3139.

• Blocked the development of intestinal inflammation

• Prevented stress-induced increases in peripheral inflammatory cytokines

• Increased proactive behavior; ie, they fought back more and because of this were left alone more by the “bully mouse”

• Prevented all measures of stress-induced increases in anxiety-like behavior

• Anti-anxiety and anti-inflammatory effects of M vaccaewere erased when regulatory T cells were blocked

Sociality before Sickness: Who (or What) Benefits Most from Positive Social Connections?

Reiber C, et al. Ann Epidemiol. 2010;20(10):729-733.

In individuals receiving an influenza vaccine, social contacts were significantlyincreased in the 48 hours after the injection when compared to either pre-injection or follow-up periods. Importantly, the period when sociality was maximally increased following vaccine coincides with the period of greatestvirus shedding, and hence infectivity, during naturalistic influenza infection.

Conclusions: I

• 21st century medicine will increasingly see human individuals as pan-species communities

• Changes in the modern world have disrupted our relationship with the microbial world in ways that promote medical and psychiatric disorders

• Data increasingly suggest that manipulating the microbiome may hold promise for the treatment of a wide array of disease states, but much remains to be learned

• Our relationships with the microbial world mirror our relations with other humans: cooperation, conflict, and deception

Conclusions: II

Don’t overestimate

the brain…..