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Monday, 8 May 2017

Pan-agonists of PPARs and PGC-1α in Mitochondrial Disease, Autism and Sport


Today’s post should be of interest to those concerned about mitochondrial disease and mTOR.


mTOR is a very important signaling cascade that often dysfunctional in autism. Many aspects of autism and its comorbidities can be traced back to mTOR.
The going is easier with a PPAR pan-agonist 

mTOR integrates the input from upstream pathways, including insulin, growth, and amino acids.   mTOR also senses cellular nutrient, oxygen, and energy levels. The mTOR pathway is a central regulator of metabolism and physiology, with important roles in the function of tissues including liver, muscle, adipose tissue, and the brain.  It is dysregulated in human diseases, such as diabetes, obesity, certain cancers and indeed autism.

One important process affected by mTOR is the creation of new mitochondria in your cells.  Each cell has many mitochondria, but in some people there are not enough and/or they may not work properly.  
In the above post we saw that Oxidative phosphorylation (or OXPHOS in short) is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing energy.  This takes place inside mitochondria.

The five enzymes required have simplified names: complex I, complex II, complex III, complex IV, and complex V.

The most common problem in autism is a lack of complex 1, this leads to a lack in the production of energy (ATP) in cells.  In your muscles this will appear as a lack of exercise endurance and in your brain as a lack of cognitive function.

On that rather intimidating chart (below), all about mTOR, tucked away at the bottom right is PGC-1α.
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) is the master regulator of mitochondrial biogenesis.

PGC-1α may be also involved in controlling blood pressure, regulating cellular cholesterol homoeostasis, and the development of obesity.

PGC-1α is thought to be a master integrator of external signals. It is known to be activated by a many factors, including:-


·         Exercise  (gradual endurance training)


·         PPARδ , PPARγ and it was thought PPARα


·         AMPK (Metformin, or AICAR)


·         Sirt-1 (resveratrol and other polyphenolic ‎compounds)

Interestingly, massage therapy appears to increase the amount of PGC-1α which leads to the production of new mitochondria. Many autism parents believe in various massage therapies. 

Metformin is a very old drug to treat diabetes, it does activate AMPK but unfortunately it also inhibits the Complex 1 mitochondrial enzyme. This might explain why one reader of this blog found it had a negative effect in her son.  In some types of cancer metformin can be used to “starve” the cancer cells of energy and stop them proliferating.

AICAR was thought to have been used by cyclists in the 2009 Tour de France, it is a heart drug from the 1980s. It activates AMPK and increases nitric oxide production from endothelial nitric oxide synthase.













Here is the lower right part enlarged:-





  

The above chart, while complex does not give the complete picture regarding PPAR.

It appears that the type of PPAR that is needed to activate PGC-1α  is actually PPARδ  (PPAR delta). For a long time researchers thought it was PPAR α (PPAR alpha).


PGC-1 alpha induces mitochondrial biogenesis in muscle and its activity has been related to insulin sensitization. Here, we report that fibrates induce PGC-1 alpha gene expression in muscle both in vivo and in vitro. However, only activation via PPAR delta but not PPAR alpha underlies this effect. PPAR delta induces PGC-1 alpha gene transcription through a PPAR-response element in the PGC-1 alpha promoter. Moreover, PGC-1 alpha coactivates the PPAR delta-responsiveness of its own gene. A further positive autoregulatory loop of control relies on the induction of PPAR6 expression by PGC-1 alpha. These data point to a distinct value of PPARdelta rather than PPAR alpha agonists in the improvement of oxidative metabolism in muscle.



Peroxisome proliferator-activated receptors (PPARs)

There was a post in this blog a long time ago about all the PPARs. There are three types (alpha, delta and gamma) just to confuse us, sometimes delta is called beta.

  • α (alpha) - expressed in liver, kidney, heart, muscle, adipose tissue, and others
  • β/δ (beta/delta) - expressed in many tissues but markedly in brain, adipose tissue, and skin
  • γ (gamma) - although transcribed by the same gene, this PPAR through is expressed in three forms:
    • γ1 - expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen
    • γ2 - expressed mainly in adipose tissue
    • γ3 - expressed in macrophages, large intestine, white adipose tissue.

It does seem that activating alpha, gamma and delta has potential benefit.

The PPAR alpha agonist PEA is available as a supplement and as food for medical purposes In Italy and Spain.  It has been proposed for various inflammatory and pain syndromes. A large trial at a Skoda car factory in 1972 showed that PEA was protective against flu and the common cold.


Fibrate drugs are PPAR alpha agonist drugs used to lower cholesterol. A key point here is that these drugs also activate other types of PPAR as well.
PPAR gamma agonists are widely used to treat diabetes.  They improve insulin sensitivity and decrease some inflammatory responses. They lower cholesterol.
PPAR delta has various antidiabetic effects and agonism of PPAR delta changes the body's fuel preference from glucose to lipids. Recently it was shown that PPAR delta can be activated to promote biogenesis of mitochondria.
It does appear likely that there is some interaction between the PPARs.
Using the mild PPAR gamma agonist, Sytrinol, which gives a long term cholesterol lowering effect, gives a short term cognitive and behavioral improvement in autism.
Pioglitazone is used to lower glucose levels in type 2 diabetes and is a PPAR gamma agonist.  It has been shown to have a positive effect in autism and more trials are in progress. It also binds to a lesser extent to PPAR alpha.
Our reader Maja is investigating whether Sytrinol will maintain its initial good effect when combined with a mild PPAR alpha agonist, like PEA. 

Pan-agonists of PPAR

Bezafibrate appears to be the best known “pan-agonist” of PPAR alpha, gamma and delta.

The PPARpan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome 

   
Bezafibrate as treatment option in patients with mitochondrial complex I (CI) deficiency

These results support bezafibrate as a promising treatment option for specific subgroups of patients with CI deficiency.

Less well known is the natural substance Berberine. 




The multifaceted drug Telmisartan, from a recent post, is also a pan-agonist of PPARs. It is usually quoted as being a PPAR delta agonist. 




AICAR

The drug AICAR is thought of as an AMPK activator rather than a PPAR agonist, but it does affect all three types of PPAR.

Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK.


Conclusion

It looks like some athletes, seeking an advantage, are already using the above strategies to improve their exercise endurance; having more mitochondria is of course a competitive advantage.  A list of all the substances banned in sport might be another good source of therapies not only for autism, but also dementia.
Since mitochondrial dysfunction is a feature of Parkinson’s, Huntington’s and Alzheimer’s there are some investigations ongoing. There is even a trial to perk up the mitochondria in people with Bipolar using Bezafibrate.
It is odd that Sytrinol has only a short term positive effect in most people with autism, although our reader RG’s daughter has a long term benefit. I suspect some people may need a pan-agonist, there may be some interaction/crosstalk/ feedback that we are not aware of.
It would be nice to have some data on the relative potency of Bezafibrate,  Telmisartan and Berberine across alpha, delta and gamma receptors, otherwise we are left with trial and error.
The advantage of Berberine is that it is an OTC supplement.
AICAR is also interesting.









29 comments:

  1. Very interesting posts lately Peter. My typically developing 10 year old was just diagnosed with prediabetes... and as you know my 6 year old son has pitt Hopkins. What dosing would you suggest for berberine?

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    1. Audrey, very many people report good effect from berberine in diabetes. Adults seem to use 1,000mg to 2,000mg split in two doses. Since you daughter is 10, you might want to start at a half dose. I would start at say 500mg twice a day and then go re-check her blood sugar level.

      Almost all antioxidants also have a positive effect on insulin sensitivity. ALA is widely used and again you can check if it works by measuring blood sugar levels.

      You might want to get other tests done to see if she has any other aspects of metabolic syndrome (high uric acid, high cholesterol etc).

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    2. Thanks so much peter. Just ordered it and will try the berberine on my son too. We are ordering more tests, but right now she has elevated liver enzymes.:(

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  2. My 23 yr old son is a double tap autism case, with the initial diagnosis at 3 and a second hit closer to five that strongly affected his attention and short term memory and his blossoming language. We are unable to get any of those things back.
    Of the many things he is on, NAC (which I learned about on this blog a couple years ago) seems to be the primary thing that we cannot live without as rages (which developed in more recent years) take over without it.
    Pantogam Aktiv with clonazepam was the other thing that noticeably decreased stereotypy and calmed his body.
    Quercitin helped his skin (which looks to be painful and blistery almost) which seems to worsen and improve without warning.
    He developed a tolerance to that. Currently baclofen doesn’t seem to be replacing it in a noticeable way. We are still doing bumetanide, galantamine, and recently started Levocarnitine and unbiquinol, as he has seemed more lethargic over the past year. Exercise (biking particularly) has always been a very positive thing for him.
    We work with Dr Rossingnol but we seem to be shooting in the dark with no real clear understanding of what is going on.
    Is there a profile to be gleaned from what has worked and what seems to not work?
    Thanks for your help.

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    1. I would investigate whether there is an issue with mast cells, which might be linked to the skin problems.

      The "wonder treatment" for some people is the calcium channel blocker verapamil, which is covered in depth in this blog.

      I recently have found that histidine, which you can buy cheaply in bulk powder form, really does help with mast cell degranulation/allergy. You could try 1g twice a day. With long term use, it may deplete zinc levels, but first see if it helps. It will just take a couple of days to see if it helps.

      Your second tap could have been mitochondrial disease, but Dr Rossingnol should have checked for that. If not, ask him. There are plenty of ways to treat it.

      Even if allergy is not his problem, it is likely he has some immune dysfunction, with elevated inflammatory cytokines etc. This can be checked by lab test. There are many ways to modify the immune response, surprisingly you can even do this with a probiotic (Biogaia Protecis or Gastrus). Some people, like my son, do not tolerate Gastrus.

      Since he is an adult it is easier to try some other interesting options. I would try Atorvastatin for a few days.

      Exercise is very good for mitochondria, but has many other benefits. You could try a PPAR pan-agonist, Bezafibrate, Telmisartan and Berberine all look interesting. I think Telmisartan may be the best one and am testing it on myself.

      If NAC is so helpful, you might want other antioxidants. If he is happy to drink it, you could give him 200ml a day of beetroot juice. You can make it 30% apple juice to improve the taste. This has betaine in it but also generates NO (nitric oxide) which improves blood flow, which is why cyclists drink it. It should also increase cerebral blood flow, which will do no harm.

      Broccoli powder should make sulforaphane and turn on nrf2 which turns on his antioxidant genes.

      I hope that helps. Most interventions show effect very quickly, so you can quickly run through them one by one.

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    2. The other thing to try regarding the skin problems, if mast cell related, is Sodium Cromoglicate. If you have a mast cell disorder an immunologist/allergist will help you more than an autism doctor. Mast cell disorder could be your son's "second tap", he would not be the first.

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    3. Curious about the zinc/histidine comment, surely histidine should help with zinc absorption for those deficient (common in ASD?)

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    4. Some research suggests that dietary zinc supplemented with L-histidine is more bioavailable to the brain than zinc provided as a supplement like zinc chloride.

      Other research suggests that large amounts of L-histidine can deplete levels of zinc.

      There are also so-called zinc-histidine complexes and zinc histidine complexes are better absorbed than the supplement zinc sulfate in humans.

      Some supplements contain both zinc and histidine.

      It is somewhat contradictory.

      Histidine is therapeutic in some people with allergy, because even though it is the precursor to histamine, raising histidine levels inhibits mast cells releasing their histamine.

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    5. Indeed it is contradictory, suppose blood tests are probably the only way to find out (!)

      One curious thought is Chez's carnosine study on ASD that you discussed here: https://epiphanyasd.blogspot.co.uk/2014/07/carnosine-for-autism-alternative-to-n.html

      Carnosine is a dipeptide made up of beta-alanine and.. histidine :)

      Beta-alanine doesn't seem that great for most phenotypes of ASD, I wonder what his results would have been like if he'd supplemented histidine instead, particularly given his copper transport hypothesis?

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    6. Peter,
      Are you trying out high doses of Telmisartan for PPAR agonist activity, like 80mg BID or TID?

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    7. No, I would not use a high dose of such a drug. Studies suggest it has effects on PPAR at low doses. A low dose would be 10-20mg once a day.

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  3. Peter I left a comment on the previous post, I think is the last,I don´t know if this kind of behaviors could have to do with electrical activity, if could be a kind of seizure, or as said Tyler once,an extreme form of tic or compulsion. When I asked why did he do it, he answered he had no idea. I wanted to know your opinion,if there is any intervention I should try.
    Valentina

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  4. Ok, many questions with no answear,I think I will have te get used to this behaviors in my son,I hope not very often

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    1. Here is some research I just read today which deals with brain injury and why it may cause impulsivity in people:

      Press Release:

      https://www.sciencedaily.com/releases/2017/05/170508130907.htm

      Paper:

      http://online.liebertpub.com/doi/10.1089/neu.2016.4813

      What is most interesting about this is that even after someone suffering a TBI has recovered from the injury and regardless of whether the injury was mild or severe, interleukin-12 levels are still elevated and impulsivity is still elevated.

      I am not sure of what interventions off the top of my head would specifically lower levels of interleukin-12 or whether this particular cytokine is relevant in your son's case, but it is very interesting a particular inflammatory cytokine seems to cause behavioral problems independent of a TBI.

      However, I did a quick search on "autism interleukin-12" and came across several papers, and here is one of them showing elevated levels of interleukin-12 in autism.

      http://www.psychiatry-research-eg.com/texts/EJP/2015/5-8/EgyptJPsychiatr36281-5753994_155859.pdf

      Perhaps if IL-12 levels can be attenuated in cases of autism where they are elevated, then perhaps some of these strange impulsive and unpredictable behaviors we all see as parents and which others can only gawk at can be attenuated as well.

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    2. Hi Tyler,Peter,thanks.I ordered Miyarisan on ebay, a friend will bring it to me from Spain at the end of the month. I don´t know if it could attenuate IL 12, but besides its anti inflammatory effects, could butyrate have a protective effect in seizures or epileptiform activity?
      Valentina

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  5. Hi Peter, Tyler, and community,

    I had asked a question in the previous post, but once a post is not the latest one, messages aren't always top of mind, so I'm reposting as I would really appreciate input from Peter, Tyler, and the learned community.

    So I had posted the following paper, which identified Neurotrophic Factors as a potential cause of ASD, and which can Be rescued with a CNTF Small Peptide Mimetic called P6:

    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118627

    So as the rats were getting P6 injected into their brain, not really something we'd want to trial, and I did find a potential oral version (MemoProve) but to Peter's point, it's likely much less effective than P6.

    BUT ... and here's where it gets interesting...Tyler kindly provided info on Dihexa and noted a site were this is available. So I went on the site, and another product caught my eye, called P21. It caught my eye cause it reminded me of P6, so I looked it up and found this:

    http://www.longecity.org/forum/topic/65066-cntf-based-peptide-p21/

    This seems to indicate that P21 is a version of P6 that is better absorbed in the brain as it can more easily cross the BBB. The version I saw on the site Tyler had listed is a nasal spray, inarguably easier to administer than P6.

    My question to the knowledgeable posters (Peter, Tyler, etc.) is this - this is supposed to be a CNTF mimetic, like P6 - can the body build up an immune response (i.e. antibodies) to P21? The concern being that the body then attacks CNTF. I thought I read somewhere that the body doesn't generally develop an antibody response to P21? The sequence is Ac–DGGL(A)G-NH2 . Any other issues that could arise from P21 use that you can see?

    IF: 1) The paper about Neurotrophic factors is correct, including P6 correcting the problem AND IF 2) P21 crosses the BBB from an intranasal spray AND IF 3) you can improve ASD via modulation of neurotrophic factors after birth / several years, one would imagine that a P21 nasal spray would so some good. But there are a few assumptions in there, and your insights would be much appreciated.

    Thanks very much in advance!

    AJ

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    1. AJ, the same company (EVERPharma) that makes MemoProve and Cerebrolysin funds some of the P21 research.

      P6 was previously shown to exert its neuro-protective effect by modulating CNTF/JAK/STAT pathway and LIF signaling and by enhancing brain derived neurotrophic factor (BDNF) expression.

      If you want to raise BDNF, it might be best to look at safe established ways to do this. The easiest is to do aerobic exercise.

      I think you need to see some results of P21 being used in humans, for example with Alzheimer's, before thinking too much about it.

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    2. Very interesting follow up AJ. I will have to take a look-see myself. As far as my opinion goes on this, I think the only way to know is to trial it and see what the outcome happens to be in your child (assuming the intervention is safe and what not).

      At the moment I have no insights on this until I delve a bit deeper.

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    3. Hi Peter and Tyler,

      Thank you both for your responses!

      I am hesitant to try P21, because my daughter is actually improving all the time and I don't want to affect her trajectory with anything that has a risk of affecting her improvement. If my child was very severe, no improvements, etc, I would consider it but I'll wait until there is more research on it.

      I am really looking forward to reading Tyler's take on it. My biggest concern was having antibodies to P21 develop, which is so much like CNTF that I didn't want the body to attack CNTF. What I don't know is whether the body would even mount an attach on P21, at least based on the size of the molecule.

      Thanks again!

      AJ

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  6. Hi everyone,

    Here are a few new papers of interest, which include such subjects of interest as Histamine and Bumetanide:

    1. Altered expression of histamine signaling genes in autism spectrum disorder

    http://www.nature.com/tp/journal/v7/n5/full/tp201787a.html

    2. Serum glycopattern and Maackia amurensis lectin-II binding glycoproteins in autism spectrum disorder

    http://www.nature.com/articles/srep46041

    3. Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders

    http://www.nature.com/tp/journal/v7/n5/full/tp2017101a.html

    Hope this is helpful! I will review and post any interesting findings, and hope everyone will do the same.

    AJ

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    1. AJ, your histamine paper is consistent with parent reports that some people with ASD respond well to H1 and/or H2 antihistamines.

      Histamine and mast cells are very relevant to a fairly large sub-group of autism.

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    2. Hi Peter,

      I thought you would find this interesting as you've been ahead of the curve, commenting on histamine for a while.

      I do have a question for you on histamine - my daughter (thankfully, unlike me!) has shown no allergy issues whatsoever. Would that indicate that histamine is not an issue for her? My issues are 1) socialization 2) speech 3) cognitive, and thankfully no issues with GI, allergy, or even sleep.

      Thanks in advance Peter!

      AJ

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    3. AJ, your daughter is still young and may yet develop allergies. It goes in steps, for example people who develop asthma usually first develop atopic dermatitis.

      My son's allergy started out very mild, but it was enough to trigger behavioral problems from the age of 8.

      I think there are different issues in play; histamine is not supposed to cross the blood brain barrier. My son has a big problem with histamine produced outside the brain and so only May-October.

      Your study suggests that the people with autism may have a problem deactivating histamine in the brain and that some may have too many H1 and H2 receptors. This would explain the readers who say their child improves on H1 antihistamines but has no allergy. Some people also improve on H2 antihistamines.

      The H1 antihistamines that best cross into the brain will make you drowsy, but in some people modern antihistamines like Claritin improve behavior, without any visible allergy present.

      It is worthwhile making a short trial to see if any major improvement results from the use of an H1 or H2 antihistamine. It does work for some people and your study does support this.

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    4. Hi Peter,

      As always, thanks very much for the insights!

      Just to sure I understand, is it that H1 antihistamines that cross the BBB are more effective for our purposes but cause drowsiness, therefore we consider those that don't cross the BBB to avoid this?

      Can we use one that crosse the BBB at night, and one tact doesn't in the day, assuming each provided 12 hours of protection? This way the more effective one is in their system half the time?

      Thanks so much Peter!

      AJ

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    5. AJ, in reality the H1 antihistamines that are claimed not to make you drowsy, do still to a small extent cross the BBB. If you want the central/brain effect you either have a weak effect from say Claritin, or a strong effect that makes you sleepy.

      So I would try Claritin for a few days and see of you are one of the lucky minority we have a big improvement.

      I do not think there is a long term protective effect that you can get by giving antihistamines at bedtime, it will just make her sleep, which she does already with no problem.

      Some people use a very small fraction of a pill of Remeron/mirtazapine which affects several different receptors including H1. At small doses the main effect is on H1 and it makes you drowsy, after a couple of weeks that effect fades and some people have a cognitive improvement. There are comments in this blog about it.

      It did not give any cognitive boost in our case, but the effect on sleep is very strong, meaning a good way to reset the body clock for kids who wake up at 3am every day. The allergy effect is also stronger than standard antihistamines

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    6. Hi Peter,

      Thank you so much for your detailed explanation. I will try Claritin for a few days to see if there is any noticeable cognitive improvement.

      I really appreciate your insights Peter!

      AJ

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  7. Specific to this topic (mitochondrial disease) I just read one of the more interesting and potentially very important papers relevant to autism and mitochondrial disorders since a possible non-drug therapy could transpire from further research:

    Paper:

    http://science.sciencemag.org/content/352/6281/54

    In nutshell, the researchers showed that in a mouse model of Leigh syndrome (the most common pediatric mitochondrial disease which usually kills those afflicted within the second year of life), chronic hypoxia at 11% oxygen (sea level air is 21% oxygen) induces the hypoxia response in cells and the mice with Leigh syndrome lived much much longer. The results suggest that perhaps the low-levels of oxygen did not fix the broken mitochondrial respiratory chain in Leigh syndrome, but rather it prevented excess oxygen buildup which could cause oxidative stress if left unchecked. They confirmed this by giving hyperoxic oxygen (55% levels) and the Leigh syndrome mice died much sooner than at sea level oxygen levels (21%).

    Now since moving your family to Nepal or the Peruvian Andes is probably not practical, one takeaway from the research was that in addition to this chronic hypoxia mitochondrial improvements not being demonstrated in humans yet, it might be useful to see if intermittent hypoxia helps at all using commercial equipment used for elite athletes when they are sleeping so as to mimic exposure to high-altitudes as "it may allow for a nighttime therapy for which face masks and sleeping tents have already been devised by the sports industry".

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  8. Great post, Peter, indeed great. I've red it couple of times.
    I am thinking something lately…
    If bacteria from gut communicates with brain, as McFabe said, maybe that is the reason why all the supplements given to child as anti inflammatories, stopped working after couple of weeks.
    With reduction of inflammatory substances (IL-6, TNF...), the communication between microbiome and brain is probably distracted, so, bacteria must increase its secretion to maintain environmental conditions that are required for its survival.
    Then supplements stop working.
    First you must heal the gut (in regressive autism, gut`s symptoms are so common) and then deal with inflammation, not the other way around.
    That's why I am experimenting with inulin.

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    1. Maja, I totally agree that comorbidities, like GI problems, need to be treated first.

      In people with IBD it seems that there may be a lack of mucin to make the mucus membrane and that this might respond to more of the amino acid needed to make it. Nestle are researching Threonine supplementation to treat IBD. In the US Threonine is very easy and cheap to buy as a powder, but not in Europe.

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