Primary and Secondary Dysfunctions in Autism - plus Candesartan

Sometimes the secondary event can completely overshadow the primary event.  
The above relates to dust explosions (in large silos containing grain, sugar etc.) rather than autism.

As we continue to investigate the science behind autism and associated possible therapies, it is becoming necessary to introduce some further segmentation.

I have referred to autism “flare-ups” many times, but even that term means very different things to different people.

We now have many examples of autism treatments (NAC, Bumetanide etc), once effective, suddenly stopping working in certain people.  This needs explaining.

We know from the research that in most cases, autism is caused by multiple “hits”, only when taken together do they lead to autism.

We also see the “double tap” variety of autism, when relatively mild autism later develops into something more serious, following some event, or trigger.  

Thanks to the internet, we know have numerous n=1 examples of certain drugs showing a positive effect in some people.  You do have to discount all those people trying to sell you something, or support the cause of others trying to sell you something.  We also have full access to all those people who have patented their clever ideas, although 99% never develop them.

Within all this information there are some very useful insights, which can help further our understanding of autism

Candesartan

A case in point is Candesartan, which one reader of this blog brought to my attention, in the comment below.  This drug is used to treat high blood pressure and is often combined with a diuretic.

A very recent study relating to neurodegenerative disease and Parkinson's especially:

http://www.sciencedaily.com/releases/2015/05/150512150022.htm

discusses the use of a new drug as well as another blood pressure drug sometimes used in conjunction with Bumetanide called Candesartan. Their goal in this study was to explore how to attenuate chronic microglial activation (a hallmark of autism) by targeting toll-like receptors TLR1 and TLR2 via these two drugs.

Candesartan also modulates NKCC2 activity:

http://www.ncbi.nlm.nih.gov/pubmed/18305093

which is interesting considering the original cited research above deals with attenuating microglial activation, rather than modulating the chloride levels within GABA inhibitory neurons as Bumetanide does.

Note that Bumetanide affects both NKCC1 and NKCC2 transporters.  NKCC1 is present in the brain at birth, but should not be present in the adult brain.  However, it appears to remain in a large sub-group of those with autism, causing GABA to remain excitatory.  NKCC2 is found specifically in the kidney, where it serves to extract sodium, potassium, and chloride from the urine so that they can be reabsorbed into the blood

This drug is, along with Minocycline, is one of the few that is known to have an effect on microglial activation.

In a clinical trial, Minocycline was shown to have no effect on autism.

I do feel this kind of assessment is too simplistic; so I was interested to see the actual effect of Candesartan in autism, albeit with n=1.

Conveniently somebody has filed a patent for the use of Candesartan in autism.  Within the document is the n=1 case report of its effect.

Example of treatment with Candersartan in autism

[00047] A 16 year old boy with autism was evaluated for behavioral management. He was frequently aggressive, primarily directed to himself but to others as well. These episodes were usually unprovoked but would also occur when his parents attempted to re direct him. The child was essentially non verbal except for echolalia. His comprehension to verbal re direction was limited, making non pharmacological interventions to his aggression limited.

[00048] His neurological exam was otherwise normal.

[00049] An MRI, EEG were normal. Routine studies, including examination for fragile x and other metabolic disorders were negative.

[00050] Prior medication trials included anti convulsants which were without benefit and atypical neuroleptics, which resulted in weight gain and unsatisfactory effects on behavior.

[00051] After obtaining consent from his parents, Candesartan was started. An initial dose of 8 mg resulted in significant attenuation of aggressive behavior. Blood pressure remained stable. After 2 weeks, the dose was raised to 16 mg. Further improvement in aggression was noted with no adverse lowering of blood pressure.

[00052] The patient has remained on Candesartan with beneficial anti aggression effects being maintained over one year.

[00053] A preferred dose found by the inventor to treat autism is approximately O.lmg/kg. In children, a liquid form may be used.

So we can conclude from this that in a non-verbal 16 year old boy with autism, with significant aggressive tendencies, this drug successfully reduced aggression.  Since he was on the drug for a year, there were no other major changes, such as language or cognitive function, otherwise they would surely be mentioned to support the patent.

I can of course look further into why Candesartan might have been effective.

Our blog reader suggested this research:-

Unraveling mystery of a-synuclein inneurodegenerative disease and reversing its course

"The real job of microglia is to keep the brain healthy by getting rid of pathogens as well as cellular debris," says Maguire-Zeiss, "However, in a diseased state microglia can become chronically activated, leading to a continuous onslaught of inflammation which is damaging to the brain."

In this study, the Maguire-Zeiss lab found that only a certain size structures of misfolded α-synuclein can activate microglial cells -- normal protein and even smaller forms of misfolded α-synuclein cannot. Then the researchers sought to discover precisely how microglia responded to misfolded α-synuclein; that is, which of its many "pattern recognition receptors" reacted to the toxic protein.

Microglia use many different pattern recognition proteins, called toll-like receptors (TLR), to recognize potential threats. The investigators found that misfolded α-synuclein caused TLR1 and TLR2 to come together into one complex (receptor), creating TLR1/2. They traced the entire molecular pathway from the protein's engagement of TLR1/2 at the cell surface to the production of inflammatory molecules.

Then Maguire-Zeiss and her team tested a drug, developed by researchers at the University of Colorado, which specifically targets TLR1/2. They also tested the hypertension drug candesartan, which can target TLR2. Both agents significantly reduced inflammation.

I found some other possible explanations:-

Angiotensin II AT1Receptor Blockade Ameliorates Brain Inflammation

Brain inflammation has a critical role in the pathophysiology of brain diseases of high prevalence and economic impact, such as major depression, schizophrenia, post-traumatic stress disorder, Parkinson's and Alzheimer's disease, and traumatic brain injury. Our results demonstrate that systemic administration of the centrally acting angiotensin II AT₁ receptor blocker (ARB) candesartan to normotensive rats decreases the acute brain inflammatory response to administration of the bacterial endotoxin lipopolysaccharide (LPS), a model of brain inflammation. The broad anti-inflammatory effects of candesartan were seen across the entire inflammatory cascade, including decreased production and release to the circulation of centrally acting proinflammatory cytokines, repression of nuclear transcription factors activation in the brain, reduction of gene expression of brain proinflammatory cytokines, cytokine and prostanoid receptors, adhesion molecules, proinflammatory inducible enzymes, and reduced microglia activation. These effects are widespread, occurring not only in well-known brain target areas for circulating proinflammatory factors and LPS, that is, hypothalamic paraventricular nucleus and the subfornical organ, but also in the prefrontal cortex, hippocampus, and amygdala. Candesartan reduced the associated anorexic effects, and ameliorated associated body weight loss and anxiety. Direct anti-inflammatory effects of candesartan were also documented in cultured rat microglia, cerebellar granule cells, and cerebral microvascular endothelial cells. ARBs are widely used in the treatment of hypertension and stroke, and their anti-inflammatory effects contribute to reduce renal and cardiac failure. Our results indicate that these compounds may offer a novel and safe therapeutic approach for the treatment of brain disorders.

However the underlying mechanism may indeed be (yet again) activating PPAR γ.

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP modelof Parkinson's disease


This paper suggests that the effect of Candesartan on microglia is :-


"Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions."

Primary Autism Dysfunctions

I define Primary Autism Dysfunctions as those core dysfunctions that are always present.

So in the case of Monty, aged 11 with ASD, the primary dysfunctions include:-

·        GABA_A dysfunction, due to over expression of NKCC1,  leading to excitatory imbalance

·        Oxidative stress

In some other people the primary dysfunctions are quite different:-

·        Mitochondrial disease

·        etc...

I think that most aggressive behavior resulting from these dysfunctions can be traced back to communication problems and frustration.  So if the person is non-verbal and cannot get what he/she wants, aggression may follow; or if the person has pain and cannot understand it or seek help he may lash out at his care giver.

Secondary Autism Dysfunctions

I define Secondary Autism Dysfunctions as additional dysfunctions that can appear and disappear over time, these are my "flare-ups".

These dysfunctions can be more disabling that the Primary Autism Dysfunctions and it appears these are the dysfunctions that may trigger un-prompted self-injury and other random aggression.

These secondary dysfunctions can be so strong that they completely outweigh the primary dysfunction, giving the effect that the treatment for the primary dysfunction has “stopped working”.

It appears that many  Secondary Autism Dysfunctions are linked to an “over activated immune system”.  It does appear that from the research that activated microglia is an expression of this immune state and we saw one researcher calling the microglia the brain's “immunostat”. 

So in the case of Monty, aged 11 with ASD, the secondary dysfunctions are:-

·        over activated immune system / activated microglia

·        mast cell degranulation as a trigger

·        Il-6 from dissolving milk teeth as a trigger

·        Emotional distress (aged 8, when his long-time assistant left) as trigger (Emotional distress is known to cause oxidative stress)

In other people the secondary dysfunctions may be similar or quite different, for example:-

·        over activated immune system / activated microglia

·        leaky gut with GI problems as a trigger

·        food intolerance as a trigger

·        bacterial infection, with remission while on antibiotics, as a trigger

·        etc …

So I think the trial of Minocycline may have failed because the subjects were only affected by Primary Autism Dysfunctions.

I think the 16 year old aggressive boy in the Candersartan patent most likely had big Secondary Autism Dysfunctions.  The drug reduced microglial activation and so damped the effect of whatever his particular triggers were.

So probably Minocycline should be trialed again, but only in people with autism and regular SIB and aggression.  Success would be measured as a reduction in violent events.

Drugs targeting Primary Autism Dysfunctions should show things like:-

·        Cognitive improvement

·        Increased speech

·        Improved social interactions

·        Reduction in stereotypy

·        Reduction in anxiety (in higher functioning cases)

So I could classify my own interventions as

Primary

·        Bumetanide

·        Low dose Clonazepam

·        NAC

·        Sulforaphane (broccoli)

·        Atorvastatin

·        Potassium

Secondary

·        Verapamil

·        Sytrinol/Tangeretin PPAR-γ agonist for microglia

·        Occasional use of Ibuprofen (anti IL-6 therapy)

·        Quercetin/Azelastine/ Fluticasone Propionate for mast cells

The over activated immune system/activated microglia needs a trigger

Just like a modern plastic explosive is completely harmless to touch and needs the combination of extreme heat and shock wave from a detonator, it appears that the activated microglia, commonly found in autism, is in itself harmless, like Play-Doh, without a trigger.

But with a trigger, you probably know what can happen next.

What about all those failed clinical trials? False Negatives?

So now you not only need to match the trial therapy with the correct sub-type of autism, but you also cannot reliably trial a drug for a Primary Dysfunction, if there is an "active" Secondary Dysfunction.

This is indeed the reason why I do not try new therapies during the summer pollen season.

Perhaps this partly explains why clinical trials in autism always seem to fail.

Minimizing Summertime Autism Flare-ups in 2015

When I first connected histamine to autism, I did not realize that this might be a common problem.  The most frequently viewed post on this blog is one on histamine and autism; so at least 10,000 people out there have googled “autism and histamine”.

Two years later, the therapy is still evolving and it should be said that, what works best for one person may not help in another person.  The main point is that in some people with autism, they face a summertime regression due to the effect of allergy.  So bad behaviours and aggression increase and good behaviours and indeed cognitive function decrease.  This appears to be the result of histamine and a pro-inflammatory cytokine called IL-6.

For the 2015 pollen season, which started early where we live, this is what we are using:-

Azelastine nasal spray, this is an H1 antihistamine that is also inhibits mast cells from “degranulating” and emptying their load of pro-inflammatory substances.  Once a day.

Quercetin is a cheap flavonoid that has numerous actions including on histamine H1 receptors, mast cells, and inflammation. 125mg two or three times a day.

Verapamil is an L-type calcium channel blocker and also a mast cell stabilizer. 40mg three times a day

Fluticasone propionate 50 µg (micrograms) – see below.  It is a steroid that has recently been shown to have some unexpected effects on mast cells.  

I have found that oral antihistamines were effective for only a couple of hours, but their effect varies widely from person to person.

In theory, Rupatadine should be the most effective anti-histamine, since it is also a potent mast cell stabilizer.  The old first generation antihistamines (that make you drowsy) could in theory be better than the new ones like Claritin, Zyrtec, since they can also cross the blood brain barrier (BBB).

Ketotifen and cromolyn sodium should also be useful, but if the allergy is pollen related, you really need the nasal spray (nasalcrom etc) to get the most effect.  In some countries they sell eye drops and not the nasal spray.  Usually the eye drops are more diluted than the nasal spray.  For example, the Azelastine eye drops contain 50% less Azelastine than the nasal spray, but are otherwise the same.  Where we live they have run out of the nasal spray but not the eye drops, so you could refill the spray with eye drops and double the number of sprays to get the same dose.

Drugs like Claritin and Zyrtec are H1 antihistamines and also partial mast cell stabilizers; they have a positive behavioral effect in some people with ASD, who are apparently allergy free.

New for 2015

I expect that two recent anti-inflammatory therapies, the Tangeretin flavonoid and the Miyairi 588 bacteria/probiotic may have a beneficial, indirect, effect on our usual summertime regression.

A more convention approach is to add fluticasone propionate to reduce the inflammation caused by allergy.  This drug is a steroid and widely used either as an inhaler to control asthma and COPD, or as a nasal spray to treat allergies.

As Flixotide inhaler, Monty, aged 11 with ASD and asthma, has already been taking fluticasone propionate for a few years.  We now use a tiny dose (50 µg), since his autism therapies have greatly reduced any asthma tendencies.

Fluticasone propionate nasal spray (Flixonase, Flonase etc) is widely sold as a treatment for hay fever and rhinitis and was recently combined with Azelastine (see above) as a treatment for moderate to severe allergies in a product call Dymista.

The combination of H1 antihistamine, mast cell stabilizer and anti-inflammatory all in one spray does seem a good idea.  The steroid dose using Dymista is actually lower than the usual dose of steroid when using Fluticasone propionate nasal spray alone.  You want to minimize the amount of steroid absorbed in the blood. When used as a spray/inhaler the amount is tiny, but still should be considered.

Dymista (Azelastine + Fluticasone propionate) does indeed work better than Azelastine alone.  There is no sign of allergy at all (no red eyes, sneezing, itchy nose), with Azelastine you still have an itchy nose.

In our case, the allergy symptoms, even minors ones, do correlate with the change in behaviour and cognitive function; so the target is no allergy symptoms at all.

If anyone has other therapies for summertime flare ups, feel free to share them.

Autism and Deafness? Then no Cochlear Implant for You

Monty, now aged 11 with ASD, has an assistant who comes in the afternoon to run our ABA-inspired home program, let’s call her Stella.

Stella is a student training to be a teacher for deaf people, so her knowledge of ABA comes from her time with Monty.  Nobody here uses ABA to teach the deaf.

Her latest task was to try and teach 3 eight year old children to count to ten.  The problem being that two of the children are deaf and can only say “yes” and “no” and the third child is deaf, autistic and non-verbal.

Using ABA she managed to teach the two deaf children to count out loud to ten and to match objects marked with each number.  Very good and the regular teachers were very impressed.

My comment was that it was a pity nobody taught them to say something more useful.  How about “hello”, “my name is Tom” etc.

What about the deaf boy with autism?  It turns out, where we live, if you are deaf and have other “complex needs” you do not get a cochlear implant.

Cochlear implants, when implanted while the deaf person is very young, can be hugely successful.  About 400,000 people worldwide have received them.  You end up with a different kind of sound than that experienced by non-deaf people, but it gives the brain inputs which allow it to identify and process speech and other sounds.

Cochlear Implants

  

A cochlear implant (CI) is a surgically implanted electronic device that provides a sense of sound to a person who is profoundly deaf or severely hard of hearing.

Cochlear implants may help provide hearing in patients who are deaf because of damage to sensory hair cells in their cochleas. In those patients, the implants often can enable sufficient hearing for better understanding of speech. The quality of sound is different from natural hearing, with less sound information being received and processed by the brain. However, many patients are able to hear and understand speech and environmental sounds. Newer devices and processing-strategies allow recipients to hear better in noise, enjoy music, and even use their implant processors while swimming.

Cochlear implants for congenitally deaf children are considered to be most effective when implanted at a young age, during the critical period in which the brain is still learning to interpret sound. Hence they are implanted before the recipients can decide for themselves, on the assumption that deafness is a disability.

Children with cochlear implants are more likely to be educated orally, in the standard fashion, and without access to sign language (Spencer et al. 2003). They are often isolated from other deaf children and from sign language (Spencer 2003). Children do not always receive support in the educational system to fulfill their needs as they may require special education environments and Educational Assistants. According to Johnston (2004), cochlear implants have been one of the technological and social factors implicated in the decline of sign languages in the developed world.

Cochlear Implants and Autism

Since people with autism have various sensory issues, they are not considered suitable candidates for the only therapy that could give them the ability to hear.  At least that is the case in many countries.

The word is that in the first year it is hard to adjust to a Cochlear Implant and this is one reason why they have to be implanted while the person is very young.  It takes the brain a while to adjust, and the more plastic it is, the better it can adjust.

Since people with autism are not exactly flexible at the best of times and they can be prone to tantrums and violence, they are seen as a challenge too far.

This seems rather cruel to me and very short sighted.

As Stella said:- “for that first year, who is going to look after them?”

My response would be “who is going to look after them for the next 60+?”

After all, would you rather care for a sometimes violent toddler for 12 months during his adaptation to hearing, or a sometimes violent, deaf autistic adult for life?  I suppose they just drug the adults.

How common is deafness with autism?

According to some research, about 5% of people with deafness have autism and about 3.5% of people with autism have deafness.

I think when they say “autism” they mean serious autism, not the modern, all-inclusive, DSM 5 autism-lite.

What does the Research tell us?

As always, there is data on just about everything and this includes autism with deafness and the efficacy of Cochlear Implants.

Rather as I expected, it is not true that giving hearing to deaf people with autism is a bad idea.  The research actually shows the opposite.

Just as teaching deaf people to count aloud is possible, when you apply simple behavioral techniques, so is giving hearing to deaf people with autism.

Cochlear Implantation in Children With Autism Spectrum Disorder.

Results: Fifteen patients with history of ASD and cochlear implantation were analyzed and compared with 15 patients who received cochlear implant and have no other disability. Postoperatively, more than 67% of children with ASD significantly improved their speech perception skills, and 60% significantly improved their speech expression skills, whereas all patients in the control group showed significant improvement in both aspects. The top 3 reported improvements after cochlear implantation were name recognition, response to verbal requests, and enjoyment of music. Of all behavioral aspects, the use of eye contact was the least improved. Survey results in regard to improvements in patient interaction were more subtle when compared with those related to sound and speech perception. The most improved aspects in the ASD patients' lives after cochlear implantation seemed to be attending to other people's requests and conforming to family routines. Of note, awareness of the child's environment is the most highly ranked improvement attributed to the cochlear implant.

Conclusion: Cochlear implants are effective and beneficial for hearing impaired members of the ASD population, although development of language may lag behind that of implanted children with no additional disabilities. Significant speech perception and overall behavior improvement are noted.

Children with Cochlear Implants:  Complex Needs - Complex Outcomes

"Although the group of deaf children with complex needs is overall a heterogeneous one, there are subgroups that would benefit from further and detailed investigation in thinking about cochlear implantation, for instance deaf children with Down’s syndrome, Children with Autistic Spectrum Disorder, cerebral palsy."

  

Children With Cochlear Implants and Complex Needs: A Review of Outcome Research and Psychological Practice

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.