CNP

Oct.10,
2014.


Sinaia
Ede Frecska, Department of Psychiatry
University of Debrecen
T h a t s h o u l d b e y o u r g u t f l o r a
Y o u r m i c r o b i o t a
Question #3:
What are the two dumbest
species on Earth?
A m o n k e y w h i c h c a l l s i t s e l f H o m o s a p i e n s s a p i e n s a n d i t s b e s t f r i e n d
C a n i s f a m i l i a r i s . T h e y d o n t k n o w w h a t i s t h e b e s t f o r t h e m t o e a t .

Our gut flora consists of
10-times more cells and
100-times more genes
than our body.

We are Petri dishes
on foot.
The forgotten organism
Meet Joe S#!t
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
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
Bourlioux P et al 2003, Am J Clin Nutr
Our cohabitants for life
Enteroecology or
biofascism?
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
Goa'uld, the symbiote in the Stargate TV series
Stargate SG-1, 1997
The Tau'ris symbiote also kills cancer
Its immune function involves:
cytokine activation, lymphatic stimulation
tolerance against oral allergens
immune-discrimination
T-helper 17 cell differentiation which elicits
pT
H
17 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
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
Rodents with sterile intestines are anxious, more
sensitive to stress, and exhibit less exploratory activity.
The gut flora influences stress-reaction
The microbiota-gut-brain axis
The brain-immune-gut triangle (BIG-T)
with microbiota in the center
gut-immune interaction
Szabo A et al 2013, Curr Immun Rev
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! said
Sir Winston Churchill)
Aggravated by:
NSAID, aspirin, steroids, antacids (PPIs), antibiotics
Leading to:
chronic low-grade inflammation
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
The 3 degrees of gluten sensitivity
Comorbid conditions of leaky gut
According to the clearance hypothesis:
The BBB is not just a barrier but a dynamic, two-way interface
between the blood and the CNS
1
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)
complexes
2
Deficit in the outward transport of the sABP has a role in the
accumulation of amyloid plaques
LPS induced inflammation facilitates the
retention of sABP within the CNS
3

BBB permeability is also increased by deficits of endothelial cells
4

The blood-brain barrier in Alzheimers disease
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
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.
Curr Opin Psychiatry 2011, 24(6):519-525
I nflammatory mechanisms in major depressive disorder.
inflammation depression
BMC Medicine 2013, 11(200):1-16
So depression is an inflammatory disease,
but where does the inflammation come from?
poor diet
leaky gut
stress
obesity
atopy
Vit. D
deficiency
Cytokine activation by endotoxin infusion elicits typical
major depression (sickness behavior) in healthy subjects
1

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
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
Stress
Depression
Leaky gut
Lysosomal
overload
LPS influx and
endotoxemia
Chronic, low-
grade
inflammation
Gut flora
Pro-
inflammatoric
cytokine balance