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Monday, 14 October 2013

IBS, IBD and Autism, leading to Cholinergic Signaling and the Vagus Nerve


This post is all about those stomach problems typical of many kids with ASD and some of their neuro-typical close relatives. Since Monty, aged 10 with ASD, does not have any of these problems, it is not something I have looked into earlier.  As you will see later in this post, by understanding the underlying science, we can move another step towards inhibiting systemic inflammation, which affects all people with ASD.
 
Irritable bowel syndrome (IBS) and Inflammatory Bowel Disease (IBD),
First of all we need to differentiate two common conditions with very similar symptoms.  IBS is the less serious condition, though it causes lots of discomfort.
 
Irritable Bowel syndrome - IBS
Irritable bowel syndrome (IBS) sufferers show no sign of disease or abnormalities when the colon is examined.

IBS does not produce the destructive inflammation found in IBD. It does not result in permanent harm to the intestines, intestinal bleeding, or the harmful complications often occurring with IBD. People with IBS are not at higher risk for colon cancer, nor are they more likely to develop IBD or other gastrointestinal diseases
The exact cause of IBS is unknown.   The most common theory is that IBS is a disorder of the interaction between the brain and the gastrointestinal tract, although there may also be abnormalities in the gut flora and immune system.

Inflammatory Bowel Disease -  IBD
Inflammatory bowel disease is a group of inflammatory conditions of the colon and small intestine. The major types of IBD are Crohn's disease and ulcerative colitis

Crohn’s disease has a strong genetic component and is far more prevalent among smokers.  The usual onset is between 15 and 30 years old.
Ulcerative colitis is an auto-immune disease with no known cause.  The symptoms are very similar to Crohn’s disease, but there are some stark differences.  Ulcerative colitis is far less prevalent among smokers

Autistic Colitis / Ulcerative Colitis
The Inflammatory Bowel Disease (IBD) that seems to be relevant in Autism is ulcerative colitis, so much so that Wakefield and Krigsman sought to name a sub-type Autistic Enterocolitis.  Due to all the furore about vaccinations and autism, the research of these two gastroenterologists has been blacklisted.

Dr Krigsman has an informative website and has published some interesting research.
If you spend all day looking via the endoscope  at children with ASD, you are bound to notice a thing or two.  Ignoring what Krigsman observes is bizarre.

In case you are wondering what he does, he is going through the mouth to do an Upper Endoscopy; for the Colonoscopy he goes in from below.  He does both procedures under general anaesthetic.  That will be painless; I once had an endoscopy under general anaesthetic and you have no bad effects.  I had the misfortune to have another one without any anaesthetic, which was one of the most unpleasant experiences of my life.
Ulcerative colitis looks like a nasty condition but Krigsman finds it is generally treatable with some combination of anti-inflammatory medication, antimicrobials, probiotics, digestive enzymes and dietary restriction.

One thing he does not mention is nicotine, more of that later.

GERD
Gastroesophageal reflux disease (GERD) is a very common disease.  The acid within the stomach rises up into the esophagus and in doing so, damages its lining.

Most children will outgrow their reflux by their first birthday. However, a small but significant number of them will not outgrow the condition. This is particularly true when a family history of GERD is present.   It is estimated that 15% of adults of adults are affected by GERD.
Krigsman find that in kids with ASD and their siblings, GERD is relatively common.

 
Mechanisms linking IBS and IBD to Autism
I have already written about the link between food allergies, autism and behaviour.  In those posts it was histamine released from mast cells (along with cytokines and other nasties) that was the culprit.  The treatments included antihistamines and mast cell stabilizers (Ketotifen, Intal etc).  I would presume this would fall into the IBS category.

When it comes to IBD, things get interesting.
In 1936 the Nobel Prize for Physiology was awarded to Sir Henry Dale and Otto Loewi.  One had identified the neurotransmitter acetylcholine and the other had shown how the vagus nerve releases acetylcholine to control heartbeat.

It later became apparent how important the vagus nerve is.  The vagus nerve is a modulator of inflammation throughout the body.  Acetylcholine, the principle neurotransmitter released by the vagus nerve, can exert its anti-inflammatory effect via binding to nicotinic acetylcholine receptors (nAChRs), which are expressed on macrophages and other immune cells.
 
In a recent post I showed that autistic brain samples have diminished acetylcholine and nicotinic receptor activity.  I showed how this could be corrected either by drugs that mimic acetylcholine (eg nicotine or acetylcholine) or with an acetylcholinesterase inhibitor (Galantamine or Donepezil).

I found it very interesting that IBD can be successfully treated by mild smoking (3 cigarettes a day) or with nicotine patches. 
This then connects various comorbidities in a very useful way and opens up therapeutic directions.  The vagus nerve is also key to epilepsy.  Vagus nerve stimulation is currently used to treat epilepsy and depression.

Experimentally, vagus nerve stimulation is already used in autism.  

CONCLUSIONS:


Patients with ASD and intractable epilepsy respond as favorably as all other patients receiving VNS therapy. In addition, they may experience a number of QOL improvements, some of which exceed those classically observed following placement of a VNS device.

 

Kevin J. Tracey
A neurosurgeon and inventor, Kevin Tracey, is the man behind the inflammatory reflex.  The inflammatory reflex is a neural circuit that regulates the immune response to injury and invasion. All reflexes have an afferent and efferent arc. The Inflammatory reflex has a sensory, afferent arc, which is activated by cytokines, and a motor, or efferent arc, which transmits action potentials in the vagus nerve to suppress cytokine production. Increased signaling in the efferent arc inhibits inflammation and prevents organ damage.
We will be looking at his research and the Cholinergic anti-inflammatory pathway, in later posts


 

2 comments:

  1. Inflammation is clearly a factor in at least some cases of ASDs. Clearly a CRP would be a useful addition to the basic tests done at diagnosis - in the UK a panel is done, but it has many clear drawbacks. If there is inflammation, the body will raise its serum ferritin. I know of no research - you may - where iron levels in ASDs have been cheacked alongside inflammatory markers. If the body is keeping iron levels low in its attempt to reduce chronic inflammation then (a) serum ferritin will tell us little or nothing about the iron status of the child and (b) the child may well struggle as it grows, with the huge demands on iron supply growth brings. Iron depletion may well be part of the cascade effect from inflammation which has serious effects on mood, behaviour, memory etc. It might also be expected to have an impact on thyroid function, heart rhythmn and a host more areas which would trigger further cascades.
    One important point - the touch sensitive, highly pain sensitive, anxiou ASD subgroup would be under represented in any research involving scans or blood takes - indeed, in almost all research. I've never seen that fact commented on anywhere.
    If you have already looked at this, please let me know! Last of all, are you a scientist or do you have any qualifications?

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    Replies
    1. Here is a very useful paper on various markers of inflammation

      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2991432/

      it is by Paul Ashwood, who is British living in California. I am sorry but I do not think there is a mention of iron.

      As someone who has had to restrain his child with ASD while blood samples are taken, I can only agree with you. It is possible, but highly unpleasant for parents. X rays no problem. EEG, MRI never tried. There is a video on my blog of an EEG being done on an autistic boy, the parents are amazed how smoothly it goes.

      I have lots of qualifications, but not in medicine. I have Masters degrees from Imperial College and INSEAD.

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