CNP

Oct.10,

2014.

Sinaia

Ede Frecska, Department of Psychiatry

University of Debrecen

That should be your gut flora

Your microbiota

Question #3:What are the two dumbest

species on Earth?

A monkey which calls itself Homo sapiens sapiens and its best friend

Canisfamiliaris. They don’t know what is the best for them to eat.

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 Brown

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?Are there undesirable species

in a healthy gut?

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 seriesStargate SG-1, 1997

The Tau'ri’s 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

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

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

Diet and gut flora

• The three major enterotypes of the gut flora

are quasi-selective in processing the three

major dietary components (carbohydrates,

fats, and proteins)

• Enterotypes are not dictated by age, gender,

body weight, or national divisions

• But their distribution is greatly influenced by

the distribution of the dietary components

• We have no other organ as much sensitive

to lifestyle changes!

1. Arumugam M. 2011, Nature; 2. Muegge BD. 2011, Science

Weapons of mass destruction

Western diet results in sub-optimal, dysbiotic pattern of the gut flora species

“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 CNS1

• The in-and-out transport of the soluble form of amyloid-β-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 the

retention of sABP within the CNS3

• BBB permeability is also increased by deficits of endothelial cells4

The blood-brain barrier in Alzheimer’s 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

Inflammatory 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

Vitamin D

deficiency

• Cytokine activation by endotoxin infusion elicits typical

major 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-α, 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-γ, TNF-α ↑

Cytokines in depression

A dysbiotic gut flora shifts the balance to Th1

Stress

Depression

Leaky gut

Lysosomal

overload

LPS influx andendotoxemia

Chronic, low-grade

inflammation

Gut floraPro-

inflammatoriccytokine balance

Good morning! to the gut flora

(an example of primate food for humans)

“Canopy-type smoothie” breakfast for 2 persons:

‒ 1 small apple with skin

‒ 1 small pear with skin

‒ 1 kivi with skin

‒ 1 banana without skin

‒ 2 salad leaves

‒ 2 white cabbage leaves

‒ 2 red cabbage leaves

‒ 2 napa cabbage leaves

‒ a couple of spinach leaves

‒ 1 big mushroom

‒ 1 spoonful of cinnamon

‒ small amount of nutmeg, clove and ginger

‒ 1/2 avocado or some virgin olive oil

‒ honey as sweetener

‒ 6 oz lemonade or hibiscus (Jamaica flower) tea

NO SOY, NO DAIRY. GLACIER MILK, EGG AND BUGS OK!