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Tuesday 7 September 2021

The Kynurenine Pathway in Autism and its modification using Sulforaphane or the probiotic Lactobacillus Plantarum 299v

 

 A pathway to somewhere, hopefully

Today’s post was prompted by our reader George’s observation that the probiotic Lactobacillus Plantarum 299v increased speech in his adult son.  This widely available probiotic is commonly used to treat IBS (Irritable Bowel Syndrome) and I did mention it in a recent post about Eubiotics.


Eubiotics for GI Dysfunction and some Autism


Increased speech is a target for many people treating autism and this probiotic is known to be safely used long term - so it is interesting.

Since I already had this probiotic at home, I made a trial and I observed a very similar effect to what happened several years ago when Monty started to use Sulforaphane / broccoli sprout powder. 

The effect of broccoli powder was a brief period of euphoria about 20 minutes later and a then a marked increase in verbalization.  The effect on mood was seen by some other readers, but not the majority. I recall back then a very happy parent who was feeding broccoli powder to his child via a G-tube. A gastrostomy tube, often called a G-tube, is a surgically placed device used to give direct access to your child's stomach for supplemental feeding, hydration or medication.  Some children with autism will not eat and so are fed via a G-tube.

Broccoli powder tastes pretty bad, but this is one problem you will not experience when taking it via a G tube.

I was surprised that even some people with mild autism found broccoli powder beneficial. In diabetics it improves insulin sensitivity and so reduces the amount of insulin they need to inject.

This post is about the science, but before reading all the science, I made my trial of Lactobacillus Plantarum 299v.  One capsule a day works very nicely. The science is optional.

I wondered what might be the shared effect of these two very different therapies - broccoli and L.P. 299v.  There is indeed a plausible explanation, the Kynurenine pathway.

 


Click on the graphic, to enlarge

This may all look rather complicated, but there are some terms we are already very familiar with. We know that Serotonin is the happy hormone and we know that Melatonin is the sleep hormone.

It all starts with Tryptophan, one of those amino acids. It is essential in humans, meaning that the body cannot synthesize it and it must be obtained from the diet. Good sources include milk, turkey and bananas. If you take bumetanide, you likely already eat a lot of bananas due to their potassium content.

95% of tryptophan is metabolized to Kynurenine, a very odd sounding word. So it must be that less than 5% becomes Serotonin and Melatonin. Two enzymes, namely indoleamine 2,3-dioxygenase (IDO) in the immune system and the brain, and tryptophan dioxygenase (TDO) in the liver, are responsible for the synthesis of kynurenine from tryptophan.

The so-called kynurenine pathway of tryptophan is altered in several diseases, including psychiatric disorders such as autism, schizophrenia, major depressive disorder and bipolar disorder.

The supplements Tryptophan and 5-hydroxytryptophan (5-HTP) are widely used for many conditions ranging from depression to autism.

 

The kynurenine pathway is a metabolic pathway leading to the production of nicotinamide adenine dinucleotide (NAD+).

 

NAD+ is very important.

 

Increasing the level of NAD is itself an autism therapy in the research. 

New Preclinical Study Finds Niagen® Corrects Social Deficits in Mouse Model of Autism

First-of-its-kind preclinical study shows that Niagen® (nicotinamide riboside) resolves social deficits and anxiety-like behaviors in male mice

The amount of Tryptophan that ends up as the cute-sounding Picolinic acid is determined by how much of the enzyme ACMSD is present.

Quinolinic acid (QUIN) and Kynurenic acid (KYNA) are two neuroactive KP metabolites that have received considerable attention for their modulation of the NMDA receptor. While QUIN shows neurotoxic effects by over activation of the NMDA receptor, KYNA offers neuro-protection by blocking receptor function. Emphasis has been placed upon the importance of maintaining a balanced ratio between these two metabolites.

Picolinic acid (PIC) also shows antagonistic properties towards the toxic effects of QUIN via an unknown mechanism.  There are a number of biological factors that can potentially affect PIC levels and synthesis in the CNS including age, circadian rhythms and hormonal and nutritional factors.

 


 Source: The Physiological Action of Picolinic Acid in the Human Brain


Anthranilic acid (AA), once thought to be vitamin L, is very elevated in schizophrenia, and also in type-1 diabetes and arthritis.  AA is seen as a treatment target in these conditions. 

Now for the interesting part, the effect of the probiotic Lactobacillus Plantarum 299v on the Kynurenine pathway:

 

Probiotic Lactobacillus Plantarum 299v decreases kynurenine concentration and improves cognitive functions in patients with major depression: A double-blind, randomized, placebo controlled study


Highlights

· There was an improvement in cognitive functions in group of depressed patients receiving probiotic Lactobacillus Plantarum 299v (LP299v) compared to the placebo group.

 · There was a significant decrease in kynurenine concentration in the LP299v group compared to the placebo group.

 · There was a significant increase in 3-hydroxykynurenine : kynurenine ratio in the LP299v group compared with the placebo group.

· Decreased kynurenine concentration due to probiotic could contribute to the improvement of cognitive functions in the LP299v group compared to the placebo group.

  

And, the effect of Sulforaphane on the Kynurenine pathway: 

 

Altered kynurenine pathway metabolism in autism:Implication for immune-induced glutamatergic activity

Dysfunction of the serotoninergic and glutamatergic systems is implicated in the pathogenesis of autism spectrum disorder (ASD) together with various neuroinflammatory mediators. As the kynurenine pathway (KP) of tryptophan degradation is activated in neuroinflammatory states, we hypothesized that there may be a link between inflammation in ASD and enhanced KP activation resulting in reduced serotonin synthesis from tryptophan and production of KP metabolites capable of modulating glutamatergic activity. A cross-sectional study of 15 different Omani families with newly diagnosed children with ASD (n = 15) and their age-matched healthy siblings (n = 12) was designed. Immunological profile and the KP metabolic signature were characterized in the study participants. Our data indicated that there were alterations to the KP in ASD. Specifically, increased production of the downstream metabolite, Quinolinic acid, which is capable of enhancing glutamatergic neurotransmission was noted. Correlation studies also demonstrated that the presence of inflammation induced KP activation in ASD. Until now, previous studies have failed to establish a link between inflammation, glutamatergic activity, and the KP. Our findings also suggest that increased Quinolinic acid may be linked to 16p11.2 mutations leading to abnormal glutamatergic activity associated with ASD pathogenesis and may help rationalize the efficacy of sulforaphane treatment in ASD.

 

QA = Quinolinic Acid

KP = Kynurenine Pathway

 

The increased concentration of QA in ASD is also likely to be associated with increased oxidative stress. We previously showed that QA can significantly potentiate oxidative stress in human primary neuron cultures and that oxidative stress markers are increased in children with ASD.  Recently, a clinical study effectively used sulforaphane derived from the broccoli sprout to treat ASD resulting in improved behaviour.  Interestingly, sulforaphane was shown to attenuate the effect of QA-induced toxicity in rat brain by enhancing the antioxidant, glutathione. This study is coherent with our current finding of increased QA in children with ASD and our previous work showing decreased glutathione in the children with ASD.  Hence, the possibility that sulforaphane may act by attenuating QA-induce oxidative stress in ASD warrants further investigation.

 

Conclusion

Too much Quinolinic Acid (QA) does appear to be a damaging feature of autism and is produced by a malfunctioning Kynurenine pathway (KP).

The exact relevance of each part of the KP in diseases of the brain is still a work in progress, but it is clearly disturbed in a specific way in each particular CNS disorder, autism being just one.

Modifying the KP does look like a useful therapeutic avenue to follow, but it is not so simple to understand all of it.

It appears that Lactobacillus Plantarum 299v may improve some people’s autism via a mechanism that includes modification of the Kynurenine pathway (KP). It may also be the case that sulforaphane / broccoli powder has an effect that counters the disturbed KP. For whatever biological reason, the visible/audible effects of the two therapies appear to be remarkably similar.

As usual, you do not have to fully understand biological pathways, like the KP, to benefit from them.  In effect, it is all a question of where all the Tryptophan from your diet ends up – and for some people it does seem to matter.

Lactobacillus Plantarum 299v and sulforaphane / broccoli are not wonder autism therapies for most responders, but if there is an incremental benefit available, you may want to take it.

Another low hanging fruit? 

 







22 comments:

  1. Looks like bad news from the latest bumetanide stage 3 trial, i thought it would be obvious with those holding these trials not every kid is a responder. Where do you think this leaves us as far as it being licenced for autism in the next few years?

    https://pharmaphorum.com/news/server-cans-autism-hope-bumetanide-after-phase-3-fails/

    ReplyDelete
  2. Ross, these trials are very expensive and it does not look good as things stand. There will be post about this subject.

    As one researcher told me, the trial must not have been well planned. Perhaps those in charge at Servier should have read this blog and learned about previous failures.

    Very sad situation. Makes you want to treat autism by yourself and skip the stupidities


    ReplyDelete
  3. Peter I am sure you remember some of my older posts. This is pretty much the original inspiration for the BCAA therapy in that you block L-Kynurenine access to the brain via the competitive action of BCAA's (both L-Kynurenine and BCAA's use the same amino acid transporter), and then the therapy was supplemented by 5-HTP to replace lost serotonin synthesis in the brain (L-Tryptophan is also blocked in addition to its metabolite L-Kynurenine), and Nicotanimide Riboside (Niagen) to replace the lowered levels of the KP pathway leading to quinolinate and eventually NAD+ synthesis. That was the idea at least. BCAA's also block the dopamine pathway via competitively inhibiting dopamine's amino acid precursors Tyrosine and Phenylalanine.

    Of course BCAA's don't treat the cause of excess L-Kynurenine. When I came up with this it was literally like around 9-10 years ago and also remember some research suggesting exercise is also good at lowering free L-Kynurenine as the muscles will increase their uptake of Kynurenic Acid which is a metabolite of L-Kynurenine and while L-Kynurenine can cross the blood brain barrier, Kynurenic Acid cannot (it is produced in the brain directly as you have just shown).

    The worst of my son's behaviors seem to be behind us for a variety of reasons. He still very much has intellectual disability, but he is doing better with his school work everyday. Not sure if that is just him getting older and maturing or the many interventions we have employed over the years making a cumulative difference. Nevertheless, I am going to take your advice and look into Lactobacillus Plantarum 299v for my son as it sounds like a better way of reducing L-Kynurenine levels in the brain than BCAA drinks multiple times a day.

    ReplyDelete
    Replies
    1. Tyler, yes I recall all your posts and I did consider calling it Tyler's Kynurenine pathway.

      Lactobacillus Plantarum 299v has many effects and so it may well be helpful for your son. Time will tell if it can replace the BCAA drinks.

      Delete
  4. so first do I need try
    L-Kynurenine or Lactobacillus plantarum 299v

    ReplyDelete
  5. Off-topic but may be of interest to some:
    Effects of adding L-arginine orally to standard therapy in patients with COVID-19
    https://www.sciencedirect.com/science/article/pii/S2589537021004053
    Interesting because we are still allowed to buy arginine, for now.
    LG

    ReplyDelete
    Replies
    1. LG, there is quite a lot of evidence to support the use of nitric oxide (NO) to treat Covid, even in very conservative places like the UK. Some therapies involve inhaling NO, as in a UK trial, but you can also increase the body's own production of NO. You can also change where the body produces the NO, which is what Agmatine appears to do.

      Delete
  6. Hi Peter. I don't know if you have heard about it yet, but Neurochlore and Servier have declared their Bumetanide trial to be a failure and are giving up on any future trials. What does this mean for parents who have put a lot of hope on bumetanide ?

    ReplyDelete
    Replies
    1. I do not think Neurochlore are giving up, because they know bumetanide works. It just does not work for everyone.

      It is also highly likely that parents did not always give the trial drug, due the diuresis causing problems.

      The problem will be who is going to fund another trial?

      Parents always had 2 choices, be very cautious and wait a decade, or perhaps forever, to try possible therapies when they may get approved, or take a measured risk and try them now.

      Delete
  7. Hi, Peter, what do you think about autism, which is not actually autism and is autoimmune encephalitis, Denis 3 days after the MMR vaccine, he screamed and hit the floor for an hour, I went to the hospital with him and they said he had nothing, they gave us suppository diazepan to calm down and sent us home .... if Denis has autoimmune encephalitis ???? I came across an article about this: https: //www.ncbi.nlm.nih.gov / pmc / articles / PMC6598425 / # B41

    ReplyDelete
  8. Peter, if he had autoimmune encephalitis, do you think I could try memantine or D-cycoserine to see if anything changes, excuse me for bothering you with questions, but you were a better way for us to find out a lot about this. disease, thank you very much ....

    ReplyDelete
    Replies
    1. Dragos, there are several treatments used to treat autoimmune encephalitis.

      https://aealliance.org/patient-support/treatment/

      Autoimmune encephalitis can indeed appear with symptoms like autism.

      Some treatments are very expensive like Plasmapheresis. IVIG is not cheap, but steroids like Prednisone are very cheap.

      It was a long time ago and so I would look more broadly at what may help in autism. Memantine and D-cycloserine both do help in some cases.

      A bad reaction to a vaccine might trigger many possible events. It looks like the Johns Hopkins doctors link it to triggering mitochondrial disease, which will have the appearance of autism with intellectual disability (ID).

      You probably will not recall, but did the Diazepam make Denis better or worse?

      If it made him worse, that would indicate a bumetanide responder. Have you tried Bumetanide?

      Delete
  9. May I ask what source or brand you use for L. plantarum 299v? The only one I see is from Jarrow, which we will trial, but it is not particularly cheap.

    ReplyDelete
    Replies
    1. Sara, I buy a local brand that is not exported, it is cheaper than Jarrows $18.55 for 30 capsules, but no drastically. Some probiotics mentioned in this blog are much more expensive.

      The probiotics beginning with L. can very often be grown at home as a yoghurt/kefir, as people do with Biogaia Gastrus, which at the high dose needed is very expensive.

      Delete
    2. Thank you! It will be worth it if it does help, but I'm always trying to search for a cheaper alternative if possible. Would you expect that, as with sulforaphane, you would see the effect on a relatively short timescale?

      Delete
  10. Dear Peter, my son has 16p11.2 microduplication, we will try LP299v. Write me if there is any other suggestion what we can try? And where could I read about that mutation. Thank you very much

    ReplyDelete
    Replies
    1. Tamara, here is a good link with many links to further articles.

      https://www.malacards.org/card/chromosome_16p112_deletion_syndrome

      For example, it links to this coming trial of R-Baclofen. You can buy the very similar drug Baclofen today (which is a mixture of R-Baclofen and S-Baclofen).

      Safety, Tolerability, and Efficacy of Arbaclofen in 16p11.2 Deletion
      https://clinicaltrials.gov/ct2/show/NCT04271332

      Delete
    2. Thank you. My son has duplication. Microduplication

      Delete
    3. https://www.malacards.org/card/16p112_duplication

      https://www.genecards.org/cgi-bin/carddisp.pl?gene=DUP16P11.2

      Delete
  11. Hi Peter,

    i remember reading in your blog few days ago regarding sulphorophane stability being lowering the chance of getting benefit from it. Just being browsing around to buy my next bottle of broccomax, but saw this product (in the link below) which is 3-4 times of the Broccomax price, but it claims that it has high stability. Would you believe this or you think this might be sales pitch?

    https://naturesfix.co.uk/product/brocelite-plus-60-capsules/

    regards
    Timur

    ReplyDelete
    Replies
    1. Timur, you could look at products used in clinical trials, like Avmacol, or products recommended by the Johns Hopkins people.

      The only tricky part in making sulforaphane is the myrosinase enzyme part. You can add myrosinase to any cheap broccoli powder. Wasabi is rich in myrosinase. Daikon is rich in myrosinase and is sold as a cheap supplement. You just add the myrosinase just before taking the broccoli powder. You only need a tiny amount wasabi/daikon.

      Delete

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