the role of microbiota in mental health

8/11/2019 The Role of Microbiota in Mental Health

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CNP

Oct.10,

2014.

Sinaia

Ede Frecska, Department of Psychiatry

University of Debrecen


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Thatshouldbeyourgutflora


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Yourmicrobiota


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Question #3:

What are the two dumbestspecies on Earth?

AmonkeywhichcallsitselfHomosapienssapiensanditsbestfriend Canisfamiliaris.Theydontknowwhatisthebestforthemtoeat.


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Our gut flora consists of10-times more cells and

100-times more genes

than our body.

We are Petri dishes

on foot.

The forgotten organism

Meet Joe S#!t


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The human

superorganism

Human

cells

Microbiota

organisms

(virus, bacteria, fungi)

The human genome is in close relationship with

the microbiome

The microbiota is part of our phenotype

Microbiota

genom

(microbiome)

The total genome

of humans

Human

genome


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The gut flora is part of the human microbiota

300-1000 species of

microorganisms in commensal and symbiotic

relationship with us

with million years of

coevolution in behind

influence almost every vital

processes inside us


8/27Bourlioux P et al 2003, Am J Clin Nutr

Our cohabitants for life

Enteroecology or

biofascism?


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In mutual codependence

The gut flora fulfills numerous functions: burns unused calories

keeps the pH low

suppresses pathogens trains the immune system

regulates the development of gut and brain

synthetizes vitamins (e.g., biotin and Vit. K)

controls fat metabolism

is the main source of kinurenic acid and SCFAs

(for gut mucosa, immune cells and neurons)

repairs gut via Toll-like receptors


10/27Goa'uld, the symbiote in the Stargate TV seriesStargate SG-1, 1997


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The Tau'rissymbiote also kills cancer

Its immune function involves:

cytokine activation, lymphatic stimulation

tolerance against oral allergens immune-discrimination

T-helper 17 cell differentiation which elicits

pTH17 response for antitumor environment

Chemotherapeutic agents like cyclophosphamide

and platinum work through the microbiota!1,2

1. Viaud S et al 2013, Science; 2. Iida N et al 2013, Science


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The gut flora modulates the expression of numerous

critical genes: e.g., for BDNF, NMDA, and 5-HT

receptors. It communicates chemically with the striatum,

hippocampus, amygdala, hypothalamus, and cingulum.

The effects of gut flora on the CNS


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Rodents with sterile intestines are anxious, more

sensitive to stress, and exhibit less exploratory activity.

The gut flora influences stress-reaction


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The microbiota-gut-brain axis


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The brain-immune-gut triangle (BIG-T)

with microbiota in the center

gut-immune interaction

Szabo A et al 2013, Curr Immun Rev


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Leaky gut: the source of

degenerative and immune illnesses?

Increased permeability is a characteristic of the civilized gut,with loose connections between gut cells.

Caused by:

proteotoxic effects of gluten and casein,dysbiotic gut flora, grilling-frying,stress,

low fiber in food, too much physical exercise (No sport! saidSir Winston Churchill)

Aggravated by:NSAID, aspirin, steroids, antacids (PPIs), antibiotics

Leading to:

chronic low-grade inflammation


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1. leaky gut chronic low-grade inflammation:

A leaky gut lets some gut contents (endotoxins, LPSs) to enter

circulation and shifts the anti-inflammatory pro-inflammatory

cytokine balance to pro-inflammatory.

2. chronic low-grade inflammation universal membrane

deficiency illnesses of civilization:

The long-lasting pro-inflammatory condition can change the

permeability of other membranes in the body (e.g., blood-brain

barrier, synovial stratum, endothel, bronchial mucosa and

alveolar wall). This way the permeability problem of the gut

extends to other barriers, and a universal membrane deficiency

may be the common ground of many illnesses of civilization.

The gut and the GUT

(Grand Unification Theory) in medicine


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The 3 degrees of gluten sensitivity


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Comorbid conditions of leaky gut


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According to the clearance hypothesis:

The BBB is not just a barrier but a dynamic, two-way interface

between the blood and the CNS1

The in-and-out transport of the soluble form of amyloid--peptid

(sABP) is regulated by receptors for advanced glycation end

products (RAGE) and low-density receptor-related protein-1 (LRP1)complexes2

Deficit in the outward transport of the sABP has a role in the

accumulation of amyloid plaques

LPS induced inflammation facilitates theretention of sABP within the CNS3

BBB permeability is also increased by deficits of endothelial cells4

The blood-brain barrier inAlzheimersdisease

1. Sharma HS et al 2012, Int Rev Neurobiol; 2. Deane R et al 2009, CNS

Neurol Disord Drug Targets; 3. Erickson ME et al 2012 J Neuroinflammation;4. Bowman GL and Quinn JF 2012, Aging Health


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The leaky gut and exorphins in ASD

A controversial study by the Royal Free Hospital

of London found more gastrointestinal problems in

autistic children (N=60) than in healthy controls.

90% of autistic children had chronic enteritis.1

Gliadomorphins and casomorphins originating

from poorly digested gluten and casein may enter

circulation, pass the BBB and exert endorphin-like

effects.2

Autistic children have dysbiotic gut flora.3

1. Wakefield AJ 2000, Am J Gastroenterol;

2. Shattock P 2002, Expert Opin Ther Targets;

3. Paraccho HM 2005, J Med Microbiol.


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Curr Opin Psychiatry 2011, 24(6):519-525

I nf lammatory mechanisms in major depressive disorder.

inflammation depression

BMC Medicine 2013, 11(200):1-16

So depression is an inf lammatory disease,

but where does the inf lammation come from?

poor diet

leaky gut

stressobesity

atopy

Vit. D

deficiency


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Cytokine activation by endotoxin infusion elicits typicalmajor depression (sickness behavior) in healthy subjects1

Parenteral administration of cytokines may result in

affective, vegetative, behavioral, and cognitive symptoms

of depression (e.g., treatment of hepatitis C by interferon-

alpha causes depression in 25% of subjects)2,3

Antidepressants (especially SSRIs), decrease plasma

level of pro-inflammatory cytokines (e.g., TNF-, IL-1) and

increase anti-inflammatory cytokines (e.g., IL-10)4,5

SSRIs also change the gene expression of the above

cytokines in the expected direction

Depression and inflammation

1. Reichenberg A et al 2001, Arch Gen Psychiatry; 2. Udina M et al 2012,

J Clin Psychiatry; 3. Connor TJ et al 1998, Life Sci; 4. Xia Z et al 1996,Immunopharmacology; 5. Maes M et al 1999, Neuropsychopharmacology


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depression

Th2 (humoral)

IL-4, IL-5, IL-9,IL-13

depression

Th1 (cellular)

IL-2, IL-12, IFN-,TNF-

Cytokines in depression

A dysbiotic gut flora shifts the balance to Th1


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Stress

Depression

Leaky gut

Lysosomal

overload

LPS influx andendotoxemia

Chronic, low-

grade

inf lammat ion

Gut floraPro-

inflammatoriccytokine balance


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the role of microbiota in mental health

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