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
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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
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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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