Butyric Acid– my choice of short-chained fatty acid (SCFA), as a potential anti-inflammatory autism therapy

Stockholm in spring

Hot on the heels of the last post that showed that regulatory T cells (Tregs) may indeed be a useful target to treat inflammation in autism, today’s post is about the particular short chained fatty acid (SCFA) that I have chosen to treat it.

There are seven SCFAs:- Formic acid, Acetic acid, Propionic acid, Butyric acid, Isobutyric acid, Valeric acid, Isovaleric acid.

Based on my homework, I have chosen Butyric Acid.

Some of my posts do not lead to therapeutic interventions, but the posts on Treg and SCFA are going to lead to some good options, particularly for those with GI problems.

As usual with effective interventions, there are multiple possible modes of action. 

Since I have introduced epigenetics to this blog, I will also highlight a paper showing the epigenetic effects of Butyric Acid.  My real objective is to increase Tregs, as a means of shifting the balance between the proinflammatory IL-6 and the anti-inflammatory IL-10.

Monty, aged 11 with ASD, does not have GI problems and has a very mixed and healthy diet, so I have not really looked at the myriad of possible GI therapies.  However, in this blog we have seen that the integrity of the Blood Brain Barrier (BBB) is critical in autism and that, in fact, it has variable permeability (it can self-repair).  I suggest that increased permeability might lead to worsening behaviour and observed flare-ups/regressions.

We have also seen that the mechanisms controlling the BBB overlap with those governing the Intestinal Epithelial Barrier (the gut-blood barrier).

The SCFAs that appear to be able to repair the Intestinal Epithelial Barrier have been shown to be able to circulate throughout the body, reach, and then cross the Blood Brain Barrier.  As a result it is certainly plausible that increasing SCFAs and Tregs will benefit those both with, and without, GI problems.  What is clear from the research and anecdotal evidence is that those with ulcerative colitis (UC) do very much benefit.  People with UC will have a compromised Intestinal Epithelial Barrier.  Some people with autism may have both a slightly permeable Blood Brain Barrier and a compromised Intestinal Epithelial Barrier (leaky gut).

I have also established from the research that a moderate increase in Butyric Acid has many measurable good effects and for this reason it is already widely used as an additive in animal feed.  It results in more healthy chickens, with less inflammatory disease and measurably lower levels of e-coli and salmonella.  I expect there is also more meat and less fat.

First, Why Bother?

About 20% into my current autism investigation, one of Monty’s grandmothers suggested that I had now done enough and should stop.   Clearly I did not.  She also told me “just make sure he does not get violent, when he is older”.  As a retired doctor, she is aware of what the end result would be.

At the time I thought “easier said than done”.

A year or so later, I am able to control my son’s mood, anxiety and indeed occasional aggression.  It is not perfect, but it is about 80% perfect.

This makes a huge difference to daily life. 

We just returned from a week in Stockholm, Sweden.  We were on buses, trains, trams, boats, taxis and planes.  We were in museums, shops, cafes and restaurants.  Behaviour was “almost” perfect and with some “fine tuning”, it was actually big brother who was the troublesome one.

Grandma number two has just been reading the well-known book, "The Reason I Jump".

“Written by Naoki Higashida when he was only thirteen, this remarkable book explains the often baffling behaviour of autistic children and shows the way they think and feel - such as about the people around them, time and beauty, noise, and themselves. Naoki abundantly proves that autistic people do possess imagination, humour and empathy, but also makes clear, with great poignancy, how badly they need our compassion, patience and understanding.”

Yesterday, she told me all about why some people with autism self-injure.  It is just something they have to do and you just leave them to it; just make sure they do not do any serious damage.

As you might imagine, I will not be waiting in line to read such a book.

As I explained to Grandma, people with autism self-injure for mostly biological reasons and you can figure out many of them.  Then they will not self-injure.  They will then be happier and higher functioning. 

It also means that when they are full grown adults they will not pose a threat to their carers and develop such “complex needs” that they have to be institutionalized, at great emotional and financial cost.  I suppose Grandma number one had this in mind.

So why bother? because I can.

The epigenetic effects of butyrate

The following paper looks at the positive therapeutic effects of butyrate in terms of epigenetics.  In the paper on Tregs in the last post, the Harvard researchers were attributing some of these effects to the increase in Tregs.  I do not mind who is right, and quite possibly both groups are right.

The epigenetic effects of butyrate: potential therapeutic implications for clinical practice

Butyrate is a short chain fatty acid derived from the microbial fermentation of dietary fibers in the colon. In the last decade, multiple beneficial effects of butyrate at intestinal and extraintestinal level have been demonstrated. The mechanisms of action of butyrate are different and many of these involve an epigenetic regulation of gene expression through the inhibition of histone deacetylase. There is a growing interest in butyrate because its impact on epigenetic mechanisms will lead to more specific and efficacious therapeutic strategies for the prevention and treatment of different diseases ranging from genetic/metabolic conditions to neurological degenerative disorders. This review is focused on recent data regarding the epigenetic effects of butyrate with potential clinical implications in human medicine.

In later posts I will give more of the research evidence in favour of butyrate and you will see how chickens currently get better intestinal care than humans.

As suggested in the original post on Tregs and SCFAs, there will be different methods to raise Butyrate levels.  It can be achieved directly via supplementation, with sodium butyrate, and indirectly by adding a butyrate-producing bacteria, such as Clostridium Butyricum.  This is widely used in Asia as a probiotic, but is available elsewhere.

Epigenetics and Autism

I have touched on the subject of epigenetics in a previous post; it is a new area of science that shows how the environment can modify your genes.  Rather than you being purely a product of your parents’ genes, you actually also have both your own environmentally acquired epigenetic changes, and some of the acquired epigenetic changes of your ancestors.

These acquired epigenetic changes are caused by things like emotional trauma, chemical insults and even smoking.

Epigenetic control systems generally involve three types of proteins: “writers”, “readers”, and “erasers.” Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around). So-called “readers” bind to these marks, thereby influencing gene expression; erasers remove the marks.

 

In theory epigenetic changes should be reversible, but this is not simple.

You may recall in an earlier post about asthma, we learnt that it is very hard to treat former smokers.  Once a person has smoked heavily, a change occurs whereby the body remains in permanent oxidative stress and conventional asthma drugs are not very effective.  The fact that the person gave up smoking 20 years previously does not help.  The only way to treat the patient is to first treat them with an antioxidant and NAC was the most effective; even then the result is not so good.

Epigenetics and Autism

It is said that autism is caused by a combination of genetic and environmental factors; but it might be better stated that autism is caused by genetic and epigenetic factors.  Those epigenetic factors would include all the accumulated environmental factors affecting that person and his ancestors.

As modern life becomes more distant from the village life of our ancestors, you can imagine a gradual build-up of environmental and stress factors.  If you cannot erase some of those marks, you will reach a point where the “tainted” DNA will produce aberrations.  Such aberrations might trigger cancer in one person and autism in another. 

Epigenetic Drugs

Cancer was identified very early as being a likely consequence of epigenetic changes.  Cancer research is very well funded and some epigenetic drugs are already available.  The idea is that epigenetic drugs should selectively target reversible epigenetic changes

A particular problem is that the drug has to act very selectively.

If you were able to erase all those chemical marks on someone’s DNA, there would most likely be some unwanted and unanticipated changes.

One pioneer in this field is a US firm called Acetyton Pharmaceuticals.

 

Epigenetic Research in Autism

The good news is that research has recently started in this area, and it might eventually lead to the possibility of reversing some of those unwanted epigenetic changes.

Here is rather heavy study from Kings College in London:-

Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits

 

Autism spectrum disorder (ASD) defines a group of common, complex neurodevelopmental disorders. Although the aetiology of ASD has a strong genetic component, there is considerable monozygotic (MZ) twin discordance indicating a role for non-genetic factors. Because MZ twins share an identical DNA sequence, disease-discordant MZ twin pairs provide an ideal model for examining the contribution of environmentally driven epigenetic factors in disease. We performed a genome-wide analysis of DNA methylation in a sample of 50 MZ twin pairs (100 individuals) sampled from a representative population cohort that included twins discordant and concordant for ASD, ASD-associated traits and no autistic phenotype. Within-twin and between-group analyses identified numerous differentially methylated regions associated with ASD. In addition, we report significant correlations between DNA methylation and quantitatively measured autistic trait scores across our sample cohort. This study represents the first systematic epigenomic analyses of MZ twins discordant for ASD and implicates a role for altered DNA methylation in autism.

 

For those of you who prefer some milk in your coffee, those helpful people at the MIND Institute in Sacramento have produced a series of video lectures on this very subject.

Here is the full list:

Environmental Epigenetics: New Frontiers in Autism Research

 and here is one particular video.

How might epigenetics relate to the etiology of ASD?


  

Conclusion

Epigenetics would help explain the increasing prevalence of ASD in the most developed countries.  It also opens the door to potentially highly effective treatment mechanisms to many currently incurable conditions.

Perhaps, by chance, one of the new epigenetic drugs developed for cancer will have a positive effect in ASD.

 
 

 

The Singing Statin, the BCL-2 Gene and Epigenetics

This post has something for both the casual reader and the scientists among you.  Today I will start with the science.

Epigenetics

Epigenetics are chemical markers that can appear on your DNA as the result of some environmental exposure, like diet or stress.  Methylation is a type of epigenetic change in which methyl groups are added to DNA and switch on or off the underlying gene.  This can have severe consequences depending on which gene is affected.

Identical Twins

It seems that if one identical twin has autism, there is a 70% chance that the other twin will be autistic.  In 30% of the cases the twin is neurotypical.  Researchers have very cleverly started to analyse pairs of twins from this 30% group and look for epigenetic marks.  This would highlight genetic causes of autism.

Apoptosis

Apoptosis is a tricky word to spell, for somebody like me, but is actually something quite simple; it is programmed cell death.  Apoptosis happens in all of us, all day long.  If it gets out of control, it becomes bad and something called atrophy will occur.  Too little apoptosis can result in irregular cell growth and cancer.

 

Candidate Genes

Using the epigenetics approach, in 2010 a study was published that identified two “candidate” genes linked to autism.  They were BCL-2 and RORA.

According to that study, BCL-2 is an anti-apoptotic protein located in the outer mitochondrial membrane that is important for cell survival under a variety of stressful conditions.  In other words BCL-2 inhibits cell death.

According to another source, BCL-2 is “one of the foremost anti-apoptotic molecules”.

A very recent study has identified more such genes, using the same approach.

 

If you are really interested in the genetics of autism, there is actually a database of all the indicated genes, maintained by the Simons Foundation.

  

BCL-2 and autism

Going back to 2001, researchers had already noted that the autistic brain was deficient in BCL-2 and they suggested that:-

“These results indicate for the first time that autistic cerebellum may be vulnerable to pro-apoptotic stimuli and to neuronal atrophy as a consequence of decreased BCL-2 levels.”

The study is called :- Reduction in anti-apoptotic protein Bcl-2 in autistic cerebellum

As we have already learned, in the autistic brain the important Purkinje Cells are reduced in number by half due to atrophy.  If BCL-2 can indeed reduce this excessive apoptosis, it should be a friend indeed.

 

Stimulating production of Bcl-2

Fortunately the clever people working with Professor Wood, at the University of Minnesota, have been studying cholesterol regulation in the brain for some time.  Here is what they have been up to:-

“The lab has recently made the novel discovery that statins both in vivo and in vitro stimulate gene expression and protein levels of one of the foremost anti-apoptotic molecules, Bcl-2. Currently, studies are focused on mechanisms of statin-induction of Bcl-2”

Or in plainer English, statin drugs increase your level of BCL-2 and so reduce cell death.
 

If you want to read more here is an open access paper:-  Simvastatin Stimulates Production of the Antiapoptotic Protein Bcl-2 via Endothelin-1 and NFATc3 in SH-SY5Y Cells

 

The Singing Statin

Now we have finished with the pure science and we move back to the practical world of applied science.

Monty, aged 9, has been taking atorvastatin for a few weeks.  After day one, he developed the urge to play the piano outside of lesson time.  Every day since, he has played more and more.  Now his piano teacher says she thinks he has absolute pitch.  It turns out that this is far more common in the autistic population and there is a great deal of research that has been done on this and music/autism in general.  Here is a short article on the subject.

Now in an earlier post we established the importance of the stress hormone cortisol and also the interesting finding that you can reduce it by singing.  Then I got people asking about, “what about just listening to music” or “what about playing an instrument”.  I did not do the research, but I think nothing works like a good sing.

So yesterday I was delighted to hear that Monty has started to sing spontaneously in his room.  He put on his Mozart CD and started to sing, with his own lyrics and not just in English, but also in his second language.

I have to thank Mr Pfizer and in fact Mr Bruce Roth for bringing us Atorvastatin (called Lipitor or Sortis, depending on where you live).  Mr Roth invented it in 1985.

Perhaps BCL-2 could be better named the Singing Gene?