The Microbiome and the Gut-Brain Connection (Part 2)

Introduction

In the previous article, we asked why the Gut-Brain exists explaining that vital neurotransmitter precursor amino acids are produced in the Enteric Nervous System (ENS) along with some vital vitamins.

We also need to regulate food intake by stimulating our body to want to feed and another mechanism to cease feeding.

This system as mentioned is  Homeostatic Energy Balance that requires multiple sensor signals from the digestive system to the Hypothalamus in the master brain regulating feeding by the Lateral Nucleus and satiety by the Ventromedial nucleus. 

As we pointed out, the down side of the Gut-Brain connection occurs when all is not well in the ENS, such as gut dysbiosis allowing pathogenic bacteria to release their toxic metabolites that cross the brains VIP access, the Blood Brain Barrier.  

The Microbiome and brain disorders

Now let’s take a look at the microbiome and Brain disorders disease.    Firstly, Lactobacillus (beneficial species, Phylum: Firmicutes) and Bifidobacteria (beneficial species. Phylum: Actinobacteria) are known to metabolize glutamate (a non essential-made in the body, amino acid found in muscle (6g), brain (2.3g), kidneys (0.7g), liver (0.7g), blood (0.04g)- average dietary intake is 10-20g, while the body manufactures 50g of free glutamate/day).  

A major inhibitory neurotransmitter GABA (gamma-amino Butyric acid)) is used to reduce neuronal excitability throughout the nervous system is manufactured by brain cells using Glutamate.  

If this bacterial metabolism is disrupted, due to microbiome imbalance and a healthy dietary intake is low, the host may experience anxiety, depression, and synaptogenesis* (in early development where synaptic pruning occurs between birth and sexual maturation where the brain’s ‘wiring’ is being adapted). Glutamate deficiency can also cause cognitive impairment as in AD.

*Synapses are junctions between two nerve cells, consisting of a minute gap across which impulses pass by diffusion of a
neurotransmitter (Google definition).

It has also be found that the expression of BDNF (Brain derived neurotrophic Factor) protein is decreased in patients with schizophrenia and Alzheimers disease.  BDNF influences the inhibition of apoptosis of healthy brain cells and the neurogenesis (the growth of new neurons) and synapse junctions and thus promotes normal cognitive function.

The correlation between BDNF levels and the microbiome was established by the use of ‘germ free mice’ (without a microbiome).

Upon analyses of the Hippocampus (responsible for emotion,memory and the autonomic nervous system and located in the middle of the brain in a region called the medial temporal lobe), and the Cortex (the major part of the brain that control sensory, motor and association areas) both areas displayed disruption of the mice who were expressing anxiety and progressive cognitive dysfunction.

Seizures

Furthermore, gut dysbiosis can cause epilepsy and seizures, by the accumulation of toxins in the brain. 

In epilepsy, once the brain reaches an indeterminate threshold of toxin buildup, it sends an electrical signal to discharge the toxins as frequently seen in epileptic fits. 

So what causes seizures in the brain ?. 

Seizures can occur due to an imbalance between inhibitory and excitatory neurotransmission between neurons and in the specific case of seizures, excessive Glutamate, an excitatory neurotransmitter used extensively throughout the brain structure becomes cytotoxic. 

This imbalance can be triggered by the combination of excess glucose and Insulin while the brain is using glucose as an energy source.

Normally, neurotransmission is a balance between GABA an inhibitory neurotransmitter and Glutamate.

Interestingly, the ketogenic diet encourages the brain to run on ketones as opposed to glucose, since the diet converts the liver into a fat burner as apposed to burning carbohydrates and thus glucose, so it is the liver that produces ketones as the bodys fuel source including the brain. 

As a consequence ketogenesis supports Gaba and not Glutamate which tends to redress the imbalance and the seizures should subside.

If the patient is a diabetic, then the excessive glucose and insulin levels will return to normal as well. 

Epileptic seizures could be caused by pathogenic toxic metabolites being produced in the gut and entering the master brain, but poisonous refined processed food, excessive man made carbohydrates, and refined sugar leading to poisonous glucose can upset gut balance, so chances are that once these man made foods are avoided and probiotic foods are consumed the gut should return to normal and the toxin onslaught should cease. 

In essence eating man made food not only creates dysbiosis within the enteric nervous system but cause cognitive havoc in the master brain.

Rasmussen encephalitis is described as a rare chronic neurological disorder, characterised by unilateral inflammation of the cerebral cortex, drug-resistant epilepsy, and progressive neurological and cognitive deterioration. a condition where one half of the brain is being destroyed by the immune system which by definition is an autoimmune disease.

Neuropathological and immunological studies support the notion that Rasmussen’s encephalitis is probably driven by a T-cell response to one or more antigenic epitopes, with potential additional contribution by autoantibodies. which is another clue that the immune system is in chaos.

The patient begins to experience frequent seizures, so after MRI scanning they see the inflammation and damage being done, but for some reason conventional medicine interpret inflammation as bad, so they prescribe antiinflammatory steroids which causes weight gain but does nothing to eleviate the symptoms.

Furthermore, conventional medicine need to get their clocks fixed, since this clinical diagnosis was put forward by neurosurgeon Theodore Rasmussen in 1950, when the microbiome was unknown. But we know much more now.

Instead of fixing the enteric nervous system where the source of the problem comes from, the barbarians of allopathic health care want to either perform a complete disconnection of the affected hemisphere (hemidisconnection), either as (functional) hemispherectomy or hemispherotomy, or install an electronic brain pacemaker into the skull that sends a dampening electrical impulse to counteract the electical signal from the seizure.

So I ask you what would you choose for a loved one, a child perhaps ??, to disconnect one half of their brain causing blindness in one eye, paralysis on one side of your body, or have a piece of the skull cut out to make room for a electrical signalling device, or just change your diet to heal your gut.

Toxins

Our microbiome contains a ‘blue-green algae derivative bacterial species Cyanobacteria which assists in the manufacture of  B and K vitamins. In fact. This bacteria evolved in our microbiome to help ferment sugars we digest into acids and alcohols.  

There is a dark side to this bacteria, it also produces Beta-Methylamnio-l-alanine (BMAA) an unnatural amino acid, which is also a neurotoxin (be careful not to eat shark-fin soup since high concentrations of BMAA is present in shark fins).

BMAA can also cross the blood brain barrier, and once there, becomes trapped in proteins, forming a reservoir for slow release over time, and is hypothesized to have an interactivity with NMDA (N-methyl-D-aspartate) a glutamate receptor found in nerve cells. .

NMDA works within the Central nervous system regulating synaptic plasticity ( strengthen and weaken synapses ) and cognition.

When BMAA comes into contact in the glutamate receptor of the NMDA molecule, it acts as an excitotoxin ( killing nerve cells by excitation ).  

It is this antagonistic effect that is found in patients brains suffering from Parkinsons (Complex of Guam), and .Alzheimers disease.

Autism and the Microbiome

To explain the association between the microbiome and Autism I must draw again on the empirical knowledge of Dr Natasha Campbell Mcbride who informs us that children suffering from ADHD/ADD, Dyspraxia, Dyslexia, behavioral and learning problems, allergies, asthma, and eczema tend to overlap and these children tend to have not one condition, but a multitude of these conditions.

She also points out that very often children who have severe eczema in infancy develop autistic features in later life. All of her many patients have digestive issues.

In 2016 Ruth Ann Luna microbial geneticist at the Texas Children’s Hospital, Microbiome Center in Houston, announced the first results of an on-going study into the intestinal microbiomes role in autism related GI distress and behavioral problems.  

Other autism researchers have found unusual species within the gut bacterial colonies. It appeared that in this study, and earlier research, associated with autism, the following bacterial species were identified in the stool Sarcina ventriculi, Barnesiella intesihominus, Clostridium bartlettii, Clostridium bolteae, Haemophilus parainfluenzae (appeared during a 3 day period when the child was suffering GI pain,diarrhea and self injury, and as researchers commented that this bacterium normally resides in the respiratory tract), Table 1 displays these bacterial Phylum:

Table 1

Bacterial Species Phylum Class
Sarcina ventriculi, Firmicutes Clostridia Commensal found normally in skin and large intestine (colon)
Barnesiella intestihominis an abundant colonic anaerobe (exist w/o Oxygen)
Clostridium bartlettii, Firmicutes Clostridia Commensal strain
Haemophilus parainfluenzae Protobacteria Gammaproteobacteria Commensal found in Lung disease.

It must be understood that bacterial species found the in small intestine (the gut) and the large intestine ( the colon) are quite different, and the discovery of Haemophilus parainfluenzae, normally found in the Lung, is an example of microbiome imbalance, and when it occurs in the gut, other areas of the body are also affected.

The 2014 statistics reveal that in the US alone 1 in 68 boys and 1 in 189 girls are suffering from Autism which represents a tenfold rise in the past 40 years. Table 2 shows the 11 top countries for autism incidences:

Table 2

Country Incidence case ratio/10,000 children
Iceland 13
Portugal 16
China 16
Brazil 27
Australia 45
Canada 64
US 66 ( was 4 /10,000 in the 1970/80s )
Denmark 68
Sweden 72
UK 94 ( less than 10/10,000 in 1980 and more than   30/10,000 in 1990)
Japan 181 ( Japan abolished the MMR Combo vaccination due to 1.8 million children developing adverse affects)

An interesting study conducted in 2016 at the Baylor college of Medicine in Houston Texas  under the guidance of Mauro Costa-Mattioli demonstrated  the implant of one single bacterium species reversed Autism related social behavior in mice.

Sixty female mice were fed a high fat fast food diet for a number of days.  The mice bred until they bore offspring.  When the babies were born they stayed with the mother for 3 weeks being fed a normal diet.  

After a month the offspring displayed dysfunctional behavior socially.  Both the microbiome of both fast food fed mothers and the normal diet fed offspring were analyzed and compared using a technique called 16S ribosomal RNA gene sequencing.  

The comparison showed clear distinctions between both samples. The offspring who were caged together with other mice with normal microbiomes, and since mice eat each others excrement, within 4 weeks all mice with dysfunctional microbiomes had their microbiomes restored normally and their behavior improved.  It was the ‘fecal transplant..as it were that restored balance.  

The next step was to find out which specific bacterium affected social behavior of the mice.  A technique know as Whole Genome Shotgun Sequencing was used (shotgun sequencing involves randomly breaking up DNA sequences into small pieces and then reassembling the sequence by looking for regions of overlap).  The researchers found Lactobacillus reuteri had been reduced nine fold in the offspring when they were born.

By culturing a strain of this bacterium (isolated from human breast milk) and introducing it into the water of the offspring they found it corrected the social dysfunction, furthermore they discovered that this bacterium also promoted the production of ‘Oxytocin’, a human peptide hormone that is produced by the hypothalamus and released via the pituitary gland.

Oxytocin is released into the bloodstream in response to the activity of the cervix and uterus  during labor and stimulation of the nipples for breastfeeding. So this hormone plays a role in social bonding and sexual reproduction during and after childbirth.

Researchers also noticed that the dysfunctional social behavior was also driven by the lack of synaptic potentiation strength  within the brain’s reward centre called the Cortico-basal ganglia-thalamo-cortico loop (CBGTC).  The CBGTC is a system of neural pathways that provide the trigger to experience a ‘feeling of pleasure’ as a result of an external stimuli.  

This part of the brain is situated in the basal ganglia region ( an area of the brain responsible for voluntary motor control, procedural learning, eye movement, cognitive and emotional functions).

Other studies dealing with children with Autism uncovered reduced species of Prevotella copri (Commensal Phylum : Bacteriodetes) and Bifidobacteria which are more represented in normal children while other commensal bacterium Clostridia and Ruminococcus (Commensal Phylum : Firmicutes, Class:Clostridia) were more represented which is to be expected since it confirms microbiota imbalance.  

The Clostridia species namely the Clostridia propionicum strain has the ability to convert lactate into propionate as mentioned in a previous article, which can have adverse affects on the human host. In one study propionic acid, was fed to rats that exhibited autistic type behaviour confirming that overgrowth of opportunistic (commensal) flora due to gut microbiome imbalance, as in this case, provides a link to one causal effect toward Autism.

To highlight further the microbiome/autism link a study published in December, 2 scientists Sarkis Mazmanian (microbiologist) and Paul Patterson (neuroscientist) at the California Institute of Technology took the microbiome of mice who had leaky gut syndrome in addition to exhibiting autistic behavior (repetitive actions, limited communication and socialization), and their microbiomes with probiotic (beneficial) bacterial species Bacteroides Fragilis  which corrected not only the leaky gut, but normalized their behavior as well.

A metabolite that is produced by some commensal bacteria is an ethyl sulphate compound called ethylphenyl sulfate ( 4-EPS ) and a chemical relative to p-cresol ( another toxic metabolite produced by Clostridia Difficile ) was found in the bloodstream 46 times higher than normal in Autistic children.

The substance P-Cresol is also associated with Autism. As a result of this significant research of implanting the beneficial bacterial species Bacteroides Fragilis, John Cryan, a pharmacologist at University College Cork in Ireland stated:

“I think there is now sufficient proof of concept where people can start to look at probiotic bacteria to improve brain function in humans.”  

He further added:

“The next step, he says, will be to determine more precisely how different bacteria use the immune, metabolic and nervous systems to influence the brain.”  

However, we know so much of this activity already but there is still much to learn.

Doctor: Ray, can we try something?

Raymond: Yeah.

Doctor: Do you know how much 312 x 123 is?

Raymond: [saying digit after digit] 3-8-3-7-6.

Doctor: [amazed] He’s right.

Charlie: What?

Doctor: He’s right!

Charlie: He’s right?

Doctor: Yeah.

[the calculator shows 38376]

Doctor: Ray… How much is 4343 x 1234?

Raymond: [saying digit after digit] 5-3-5-9-2-6-2

Charlie: He’s a genius…

Doctor: Right.

Charlie: He’s a genius!

Doctor: Ray! Do you know how much a square root of 2130 is?

Raymond: 4-6 point 1-5-1-9-2-3-0-4.

[the calculator shows 46.15192304]

Raymond: 2-3-0-4.

Charlie: That’s amazing! He is amazing! He should work for NASA or something like that.

Doctor: [walking to Raymond] If you had a dollar… and you spent 50 cents, how much money would you have left?

Raymond: About 70…

Doctor: 70 cents?

Raymond: 70 cents.

Quote from the movie ‘Rainman’ 1988

Check out the Previous Article in this series:

Microbiome and Digestion

Microbiome and Disease Part 1

Microbiome and Disease Part 2

Microbiome and the Immune system

Microbiome and the Gut-Brain Connection Part 1

References/Acknowledgments :

  1. ‘History of Alzheimers’ Jesse Ballenger 2012
  2. ‘The truth about Ancel Keys: we’ve got it all wrong’ Denise Minger blog 2011
  3. International Glutamate Information services Website
  4. Gut and Psychology syndrome ( 2015 Book) Dr Natasha Campbell-Mcbride
  5. Mental Health website daily ‘8 ways to increase BDNF levels’ March 2015
  6. ‘Hippocampus ‘Wikipedia
  7. Microbiome website ‘Cynanobacteria’
  8. Authority nutrition website ‘6 graphs that explain why the ‘war’ on fat was a huge   mistake Kris Gunnors
  9. ‘the microbiome’s role in autisms related GI distress and behavioral problems’ case  study Ruth Ann Luna May 2016 Autism speaks website
  10. Science daily website ‘A single species of gut bacteria can reverse autism related social behavior in mice’ Mauro Costa-Mattioli 2016
  11. Healthygutbugs website ‘Fascinating connection between autism and bacteria in our gut’ Jennifer Portens Aug 2015
  12. Docere Wellnes Centre website ‘How autism is influenced by our microbiome’ Dr Michelle Hagel
  13. ‘Oxytocin’ Wikipedia
  14. ‘Long term Synaptic potentiation’ Book abstract Neuroscience 2nd edition 2001
  15. ‘Cortico-basal ganglia thalamo-corticol loop ( CBGTC)’ Wikipedia
  16. ‘The mechanism of propionic acid formation by Clostridium propioncum T.Johns  1952 Microbiology research website
  17. ‘Bacterium can reverse autism like behavior in mice’ Sara Reardon  2013Nature website
  18. ‘Microbes take charge’ Amber Dance 2014 NCBI
  19. Rasmussen’s encephalitis: clinical features, pathobiology, and treatment advances 2014 Sophia Varadkar et al NCBI (Pubmed)
  20. IDB Movie quotes (Rainman 1988)

Author: Eric Malouin