Butyric Acid and Autism

Following on the previous posts about Tregs (regulatory T cells) and Short Chained Fatty Acids (SCFAs), today we get to the final steps and some more scientific data.

Butyric acid seems to be the best choice of an SCFA, as a possible anti-inflammatory autism therapy.

We have a research study that measured Butyric acid and compared the levels in people with and without autism.  It also splits out those with and without any GI issues.

We have another study showing that Butyric acid “attenuates novel object recognition deficits and hippocampal dendritic spine loss in a mouse model of autism.” This is as relevant as you want to believe.

Since Butyric acid is widely used worldwide for animals and in Asia for humans, we have a great deal of data available.

The research shows that moderately increasing the level of Butyric acid does do good, but go too far and you lose the benefit. (Farmers do not over feed your chickens)

In both humans and animals two different methods are used:-

1.     Supplement with sodium/calcium/magnesium butyrate

2.     Supplement with Clostridium butyricum, bacteria/probiotic to stimulate the natural fermentation process in the colon.

A problem with the first method is the taste and smell. Butyric acid can be used to make a stink bomb.  Also some people find magnesium acts as a laxative and some people do not want to use sodium.  Sodium acts counter to potassium in the body, and we have seen earlier that, possibly due to potassium channel dysfunction, we generally want more potassium and less sodium.

Taking this into account, I prefer the second option, which follows a well-trodden path.  In Japan alone, over 200,000 packages of the Miyairi 588 probiotic have been sold since commercial production began in 1940.  The product has been used in various forms, ethical and OTC drugs, veterinary drugs, feed and food supplements.

The research on Sodium Butyrate

This compound is used in both human and animal research.  It is sold in tiny quantities as an OTC supplement and in large commercial quantities as an animal feed additive.

It is sold to improve gut integrity and reduce inflammatory disease.  In animals the key selling point is faster weight gain.  In humans I do not expect weight gain, in fact quite the reverse.

A very easy to read presentation is for the animal version:-

Novyrate Gut Integrity Additive

The supplement sold to humans just says:- 

Butyrate is a short chain fatty acid that is a potent detoxifier of ammonia and neurotoxins. It encourages the formation of friendly bacteria in the gut.

 The Research on Miyairi 588

Miyairi 588, a form of Clostridium butyricum, is produced by a Japanese pharmaceutical company.  They have recently gained approval for its use in Europe for chickens, pigs and turkey.  Now they have applied to sell the human version.  So there is plenty of information available in English.

Probiotics are microorganisms and in or to know the potency you need to know the number of organisms in your pill.  The more potent tablet, Miyarisan Strong says it has at least 0.45 million.

  

CLOSTRIDIUM BUTYRICUM MIYAIRI 588 NOVEL FOOD APPLICATION

PROBIOTICFOOD SUPPLEMENT

Studies Related to Efficacy

Here is one example of the animal research which shows exactly what I expect, based on the research by Wendy Garrett at Harvard.  She found that raising SCFAs, raised Tregs which then lowered the pro-inflammatory cytokine IL-6.

Wendy’s research was on mice, the following Chinese research was on chickens and my interest is humans.

Sodium butyrate maintains growth performance by regulating the immune response in broiler chickens.

Abstract

1. The experiment was conducted to investigate the effects of dietary sodium butyrate on the growth performance and immune response of broiler chickens. In experiment 1, 240 1-d-old chickens were allocated into 4 dietary groups (0, 0·25, 0·50 or 1·00 g sodium butyrate/kg) with 6 replicates each. In experiment 2, 120 1-d-old chickens were fed a control diet (without sodium butyrate) or 1·00 g sodium butyrate/kg diet. Half of the chickens fed on each diet were injected intra-peritoneally with 0·5 g/kg body weight of Escherichia coli lipopolysaccharide (LPS) at 16, 18 and 20 d of age. 2. There was no effect of dietary sodium butyrate on growth performance. On d 21, serum interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) were decreased in chickens given 1·00 g sodium butyrate/kg, serum superoxide dismutase (SOD) and catalase activities were significantly increased, and malondialdehyde (MDA) was decreased by dietary sodium butyrate at 0·50 or 1·00 g/kg. On d 42, serum IL-6 was markedly decreased by dietary sodium butyrate, while 1·00 g sodium butyrate/kg greatly reduced MDA and increased catalase. 3. LPS challenge significantly reduced the growth performance of chickens. Serum IL-1β, IL-6, TNF-α, corticosterone, alpha-1 acid glycoprotein (AGP) and prostaglandin E(2) (PGE(2)) were increased in LPS-challenged chickens. Dietary sodium butyrate supplementation maintained the body weight gain and feed intake. Sodium butyrate supplementation inhibited the increase in IL-6 and AGP in serum at 16 d of age and TNF-α, corticosterone, AGP and PGE(2) at 20 d of age. Similar inhibitory effects of sodium butyrate in serum glucose and total protein concentrations were also found at 20 d of age. 4. The results indicated that dietary sodium butyrate supplementation can improve the growth performance in chickens under stress and that this may be used to moderate the immune response and reduce tissue damage.

  

Butyric Acid levels in Humans 

We all have Butyric Acid in our colons; it is produced there via fermentation of fibres in our diet.  Depending on what bacteria you have in your colon and what food you eat, you will have a different amount.

Elevated Fecal Short Chain Fatty Acid and Ammonia

Concentrations in Children with Autism Spectrum Disorder

In spite of the title of the above paper, when you look at the above chart, if you rule out 10% that are outliers, you can see that nothing correlates with anything (GI disturbance, gluten free diet, autism or not).

So who does currently benefit from extra Butyric Acid?

·        Humans with Ulcerative Colitis in clinical trials and the early adopters who read about the trials

·        Japanese people with GI disturbance

·        Farmers who feed it to their chickens, turkeys and pigs

Too much may not be good

There is some research showing that large amounts of Butyric acid may not be good and this likely holds true for animal and humans.  Note the very large variation in humans in the chart above.

The recent EU approval of animal version of Clostridium butyricum  called Miya-Gold® for use with turkeys notes that:

“…  a meta-analysis pooling data from these trials showed significant improvement in daily weight gain and feed to gain ratio when Miya-Gold® was supplemented at the minimum recommended dose of 1.25 108 CFU/kg feed.”

  

So a good starting point for humans is likely at the lower end of the suggested human dose. The suggested dose is 3 to 18 human tablets a day.

The good news is that these tablets are inexpensive.  630 tablets cost $17 including shipping from Japan.  If they do nothing for autism, they probably will do some good for the family pet, assuming you have no chickens.

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.