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?