Elevated microbially-derived metabolites in autism

 

 

 

A new study reports that many children with autism have elevated levels of microbially-derived metabolites (MDMs) in their urine. The authors propose that this pattern is so common that it defines a distinct subtype of autism, which they call ASD-MDM (Autism Spectrum Disorder associated with Microbially-Derived Metabolites).

The authors claim that approximately 90% of autistic children have ASD-MDM and also suggest that ASD-MDM is a distinct subtype of autism. But that would mean almost all autism is ASD-MDM, so it would not really be a focused sub-type. 

It is striking that there are 22 authors listed, but only 52 ASD children studied. There are some familiar names among the 22.

Elevated microbially-derived metabolites in autism: a possible diagnostic screening test for a distinct ASD phenotype

The study is interesting and deserves attention. However, like many autism studies, it raises as many questions as it answers.

 

What did the researchers find?

The researchers measured a range of metabolites produced by gut bacteria and yeasts in the urine of 52 children with autism and 47 typically developing controls.

The metabolites fell into three broad categories:

• Phenylalanine and tyrosine-derived metabolites such as p-cresol and p-cresol sulfate
• Tryptophan-derived metabolites such as indoxyl sulfate and various indole compounds
• Yeast-associated metabolites such as arabinitol

Many of these compounds were significantly elevated in the autism group.

The most convincing findings involved p-cresol, p-cresol sulfate, phenylacetylglutamine and indoxyl sulfate. These metabolites have been reported repeatedly in previous autism studies and are among the best-replicated metabolic findings in the autism literature.

Using a scoring system based on the number of metabolites exceeding the range seen in any control child, the authors reported that approximately 78–90% of children with autism had at least one markedly elevated microbial metabolite.

 

What is new?

The most important contribution of this study is not the individual metabolites. We have known about elevated p-cresol for many years. It has been covered extensively in previous posts and in Stephen’s comments.

The novelty lies in combining multiple microbial metabolites into a single framework and proposing that they collectively define a biological subtype of autism.

This is an attractive idea.

Autism is clearly not a single disorder. Two people can receive the same diagnosis while having entirely different underlying biology. One person may have a monogenic disorder, another a mitochondrial dysfunction, another a channelopathy, and another an immune-mediated condition.

The notion that a substantial subgroup of autistic children may have a characteristic pattern of microbial metabolites is therefore entirely plausible.

 

Reasons for caution

The authors make some ambitious claims regarding diagnosis and screening. Several limitations should be kept in mind.

First, the study was very small, involving just under one hundred participants. This is adequate for a pilot study, but much too small to establish a diagnostic test with confidence.

Second, the control group was unusual. The autism group was predominantly male, which is expected, but the control group contained more females than males. This creates the possibility that some of the observed differences may be influenced by sex-related differences rather than autism alone. Comparing autistic boys with very restricted diets to typical girls with rich varied diets, springs to mind.

Sex Distribution of Study Participants

	ASD Group	Typically Developing (TD) Controls
Male	41	20
Female	11	27
Total	52	47
Male (%)	79%	43%
Female (%)	21%	57%
Male:Female Ratio	3.7:1	0.74:1

Third, the study collected no information on diet or medication use. This is a major limitation. Many autistic children have restricted diets, gastrointestinal problems, food selectivity, supplements or medications that can influence both the microbiome and the metabolome. Without these data, it is difficult to determine how much of the observed metabolic profile is attributable to autism itself.

Diet is one of the strongest known determinants of microbial metabolism. Many young autistic children, particularly those with more severe autism, consume highly restricted diets consisting of a small number of preferred "safe foods", often ultra-processed foods and very little dietary fiber. Such eating patterns can profoundly alter both the composition of the gut microbiome and the metabolites it produces. A boy whose diet consists largely of chicken nuggets, fries, white bread and sweetened drinks may be expected to have a very different microbiome from a girl consuming a varied diet rich in fruit, vegetables and fiber, regardless of whether either child has autism.

Super Size Me was a 2004 documentary by Morgan Spurlock in which he ate only food from McDonald's for 30 days.

The rules included:

Every meal had to come from McDonald's.

If asked whether he wanted to "super size" a meal, he had to accept.

He tried to eat three meals a day.

He reduced his exercise to match the average American activity level.

By the end of the month he reported:

·        Weight gain of about 11 kg (24 lb)

·        Increased cholesterol

·        Abnormal liver function tests

·        Reduced energy

·        Mood changes

If it had been 2026, they would have analyzed changes to his microbiome and looked at his urine metabolites. You can imagine the results.

The film became very influential and helped draw attention to the health effects of fast food.

 

Fourth, the study did not directly examine the gut microbiome. Instead, it measured microbial metabolites excreted in urine. Elevated urinary metabolites may reflect altered microbial activity, but can also be influenced by intestinal permeability, liver metabolism, sulfation capacity and kidney function. The study therefore provides direct evidence of altered metabolite profiles, but only indirect evidence of gut dysbiosis.

Finally, this was largely a study of classic childhood autism rather than the full autism spectrum. The participants were predominantly male and had an average CARS score of 41, consistent with substantial autistic symptoms  (A CARS score above about 37 is generally considered severe autism). The findings therefore cannot automatically be generalized to those with Level 1 or 2 autism, or those diagnosed later in life. It remains possible that elevated microbial metabolites are particularly common in children with more severe autism and gastrointestinal dysfunction.

 

Only urine was tested

An important limitation of this study is that the researchers did not directly examine the gut microbiome itself. They analyzed urine samples and measured concentrations of metabolites thought to be produced by gut bacteria or yeasts, such as p-cresol sulfate, p-cresol and indoxyl sulfate. This approach was chosen because these metabolites may provide a functional readout of microbial activity and can be measured using a simple, non-invasive urine test. However, elevated urinary metabolites do not necessarily prove the presence of gut dysbiosis, since their levels can also be influenced by diet, intestinal permeability, liver metabolism, sulfation capacity and kidney excretion.

A stronger study would have combined urinary metabolomics with stool microbiome sequencing, dietary assessments, medication histories and measurements of gastrointestinal symptoms. Such an integrated approach would have helped determine whether the abnormal metabolites truly arose from altered microbial populations and whether specific bacteria or fungi were responsible. Therefore, while the study provides convincing evidence that many autistic children have abnormal patterns of microbial metabolites, it provides only indirect evidence that gut dysbiosis itself is the underlying cause, and its conclusions should be interpreted accordingly.

  

Cause or consequence?

This is perhaps the most important question.

The paper often implies the following sequence:

Gut dysbiosis → microbial metabolites → autism

But the reverse sequence is also possible:

Autism → altered diet, gut motility and gastrointestinal function → microbial metabolites

The study cannot distinguish between these possibilities.

To demonstrate causation, researchers would need to identify elevated metabolites before autism symptoms emerge and show that those metabolites predict later diagnosis.

That would be a much stronger result.

 

Why this matters

Despite the limitations, this study fits remarkably well with a growing body of evidence suggesting that gut-derived metabolites can influence brain function.

P-cresol is particularly noteworthy because it has been associated with mitochondrial dysfunction, immune activation, impaired intestinal barrier function and behavioural abnormalities in animal models.

The repeated appearance of p-cresol and related compounds across many studies suggests that these findings should not be dismissed.

What remains unclear is whether these metabolites are merely biomarkers or whether they actively contribute to symptoms.

 

The broader perspective

Readers of this blog will know that I have never viewed autism as a single condition with a single treatment. Instead, I view autism as a behavioural diagnosis that sits on top of multiple underlying biological disorders.

Some people may have:

• Mitochondrial dysfunction
• Ion channel dysfunction
• Folate pathway abnormalities
• Neuroinflammation
• Gastrointestinal dysfunction
• Microbial metabolite abnormalities

and often several of these at the same time.

The goal should not be to debate whether autism is genetic or environmental, neurological or gastrointestinal.

The goal should be to identify the specific abnormalities present in each individual and address them where possible.

This study adds weight to the argument that microbial metabolism deserves investigation as part of that process.

 

The clinically important question

The most interesting question is not whether microbial metabolites can help diagnose autism.

The most important question is whether reducing abnormal metabolites improves symptoms.

If a child has markedly elevated p-cresol sulfate or indoxyl sulfate, can we normalize those levels?

If we do, does language improve? Does anxiety improve? Do gastrointestinal symptoms improve? Does adaptive functioning improve?

Those are the questions that matter to families.

The authors point to previous studies of microbiota transfer therapy that reported reductions in p-cresol sulfate accompanied by improvements in gastrointestinal and autism-related symptoms. Whether those findings can be replicated in larger controlled studies remains to be seen.

 

A look at the detailed results

 

Looking more closely at Tables 4 and 5

The paper presents two sets of metabolite data that are easy to confuse. Table 4 contains results from the initial semi-quantitative (untargeted) metabolomics analysis, while Table 5 contains results from the subsequent quantitative (targeted) analysis using authentic chemical standards.

Readers should focus primarily on Table 5, because it represents the validation phase of the study. Table 4 was designed to identify potentially interesting metabolites, but untargeted metabolomics is prone to both measurement error and occasional metabolite misidentification. In contrast, the metabolites in Table 5 were measured directly against known standards, allowing both their identity and concentration to be determined with much greater confidence.

In simple terms, Table 4 generated the hypotheses, while Table 5 tested them.

One of the most interesting aspects of the paper is that some dramatic findings from Table 4 became much less impressive in Table 5. Several tryptophan-derived metabolites appeared to increase by more than 1000% in the discovery phase, but these effects were greatly reduced or no longer statistically significant when measured using quantitative methods. This is not unusual and illustrates why validation studies are so important.

On the other hand, some findings survived the transition from discovery to validation. Most notably, p-cresol, p-cresol sulfate, phenylacetylglutamine and indoxyl sulfate remained significantly elevated in the autism group. These are therefore the metabolites that deserve the greatest attention.

The overall picture from comparing Tables 4 and 5 is that the evidence for widespread abnormalities in microbial metabolism remains convincing, but the evidence for some individual metabolites is weaker than the headline figures from the discovery phase might suggest. The quantitative data in Table 5 provide the most reliable basis for interpreting the study and assessing its clinical relevance.

 

Useful observations from Tables 4 and 5

1. p-Cresol survives both discovery and validation

The strongest finding is not a new metabolite but an old one.

In Table 4:

• p-Cresol increased by 151%
• p-Cresol sulfate increased by 54%

In Table 5:

• p-Cresol increased by 76%
• p-Cresol sulfate increased by 139%

Many findings became weaker during quantitative validation, but p-cresol and p-cresol sulfate remained significant. This strengthens the case that elevated p-cresol metabolism is a genuine feature of a subgroup of autistic children.

 

2. Phenylacetylglutamine may deserve more attention

Phenylacetylglutamine (PAGln) is increasingly recognized as a microbiome-derived metabolite with important biological effects.

In Table 4:

• 64% increase
• 32% of ASD children exceeded the highest control value

In Table 5:

• 80% increase
• Highly significant (p = 0.002)

Compared with p-cresol, PAGln receives relatively little attention in autism research but may prove to be an important marker of altered aromatic amino acid metabolism.

 

3. Tryptophan metabolism appears abnormal in many children

Although the individual metabolites differed between the two analyses, the overall signal remained.

The study reports:

• 64% of ASD children with elevated tryptophan metabolites in Table 4
• 42% in Table 5

This suggests that altered microbial metabolism of tryptophan may be common in autism. This is particularly interesting because tryptophan is the precursor of serotonin, melatonin and kynurenine pathway metabolites.

 

4. Indoxyl sulfate deserves attention

Indoxyl sulfate is another well-known microbial metabolite.

In Table 5:

• 171% increase
• Statistically significant (p = 0.03)

Like p-cresol sulfate, it has been linked to inflammation, oxidative stress and mitochondrial dysfunction. It may be one of the more biologically important findings in the study.

 

5. The abnormalities are highly heterogeneous

Perhaps the most important finding is that no individual metabolite identified most autistic children.

For example:

• p-Cresol sulfate: 21% above the control range
• p-Cresol: 19%
• Hydroxybenzoic acid: 17%
• Indole-3-acryloyl glycine: 17%
• Arabinitol: 10%

Different children had different abnormalities. This strongly supports the view that autism consists of multiple biological subtypes rather than a single disorder with a single biochemical signature.

 

6. The yeast findings are relatively weak

The paper devotes considerable attention to yeast metabolites, but the quantitative data are less convincing.

Only arabinitol remained significant in Table 5. Other proposed yeast markers, including citramalic acid, tartaric acid and tricarballylic acid, were not statistically significant.

The results support the existence of a yeast-associated subgroup, but not a major role for yeast in most autistic children.

 

7. The quantitative data support a lower prevalence than the headline claim

The paper's headline message is that approximately 90% of autistic children have elevated microbial metabolites.

However, the quantitative data suggest:

• 57% with elevated phenylalanine-related metabolites
• 42% with elevated tryptophan-related metabolites
• 16% with elevated yeast metabolites
• 78% with at least one elevated microbial metabolite

The validated figure is therefore closer to 78% than 90%.

 

8. A possible aromatic amino acid subtype of autism

Taken together, the clearest pattern involves metabolites derived from phenylalanine, tyrosine and tryptophan.

These amino acids are precursors for important neurotransmitters including:

• Dopamine
• Noradrenaline
• Serotonin
• Melatonin

The study therefore suggests that a substantial subgroup of autistic children may have altered microbial metabolism of aromatic amino acids. This broader observation may ultimately prove more important than any individual metabolite measured in the study.

What matters clinically?

The most important question raised by these findings is not whether they can be used to diagnose autism. The more important question is whether these metabolites are merely biomarkers or whether they contribute directly to symptoms.

If elevated p-cresol sulfate, p-cresol, phenylacetylglutamine or indoxyl sulfate prove to be biologically active drivers of symptoms, then they become potential treatment targets. This would fit with a growing body of evidence suggesting that at least some forms of autism involve treatable metabolic and physiological abnormalities.

From a personalized medicine perspective, the most valuable contribution of this study is not the proposed diagnostic test but the identification of potentially actionable metabolic pathways that may define a distinct subgroup of autistic individuals.

 

Conclusion

This study provides further evidence that abnormal microbial metabolites are common in autism and may define a biologically meaningful subtype.

The findings are intriguing and broadly consistent with decades of research on p-cresol and other gut-derived compounds.

However, the study does not prove that gut dysbiosis causes autism, nor does it establish a clinically validated screening test.

What it does provide is another reminder that autism is heterogeneous and that meaningful progress is likely to come from identifying and treating specific biological abnormalities rather than assuming that all autistic people share the same underlying pathology.

For those interested in personalized medicine, that is perhaps the most important message of all.

 

How might altered microbial metabolism of aromatic amino acids be treated?

The study suggests that a substantial subgroup of autistic children have abnormal microbial metabolism of the aromatic amino acids phenylalanine, tyrosine and tryptophan, leading to elevated levels of compounds such as p-cresol, p-cresol sulfate, phenylacetylglutamine and indoxyl sulfate. While no proven treatment exists specifically for this metabolic pattern, several approaches could potentially be helpful.

The most obvious strategy is to modify the gut microbiome itself through dietary changes, prebiotics, probiotics, synbiotics or, in selected cases, Microbiota Transfer Therapy (MTT). The goal would be to reduce production of potentially harmful metabolites and encourage a healthier microbial ecosystem.

Another approach is to increase populations of beneficial bacteria that preferentially ferment dietary fiber into short-chain fatty acids such as butyrate rather than producing aromatic metabolites.

Improving intestinal barrier function may also reduce absorption of microbial metabolites into the bloodstream. Compounds such as butyrate and some probiotics have been proposed for this purpose.

Since several of the metabolites identified in the study are sulfate conjugates, supporting sulfation and glutathione pathways through interventions such as NAC or taurine may also deserve further investigation.

Because p-cresol and related compounds have been linked to oxidative stress and mitochondrial dysfunction, mitochondrial support therapies may help reduce downstream effects even if they do not address the underlying source of the metabolites.

Finally, gastrointestinal motility should not be overlooked. Chronic constipation increases the time available for bacterial fermentation of amino acids and may contribute to the production of p-cresol and related compounds. Treating constipation and other gastrointestinal problems may therefore be an important part of the solution.

At present, the evidence is strongest for identifying these metabolites as biomarkers rather than proven treatment targets. The key question for future research is whether reducing elevated microbial metabolites leads to meaningful improvements in autism symptoms, gastrointestinal function and quality of life.

 

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? 

 

Vitamin D in Autism – too much or too little?

Reader’s of this blog will be aware that serotonin plays a major role in autism, and also in many other mental health conditions, like depression.

Vitamin D also regularly raises its head in discussions about autism.  You may recall the Somali autism clusters in Sweden and Minneapolis; researchers suggested that the Somali immigrants were not getting enough sun and therefore lacked vitamin D and so produced children with autism.  I did point out that another large Somali autism cluster exists in sun-drenched San Diego.

Even Martha Herbert talks about vitamin D deficiency and autism.

A while back we had a guest blogger, Seth Bittker, present his opposing view, that too much vitamin D added to food in the American diet may be contributing to the rise in autism there.

In same week that Seth has published his paper on this subject, yet another paper has appeared with the opposing view.  So who is right?

The case for (even) more Vitamin D

The first paper is:- 

Vitamin D hormone regulates serotonin synthesis. Part 1:relevance for autism

 

The authors make the following case:-

Serotonin and vitamin D have been proposed to play a role in autism, however, no causal mechanism has been established. Now, researchers show that serotonin, oxytocin, and vasopressin, three brain hormones that affect social behavior related to autism, are all activated by vitamin D hormone. Supplementation with vitamin D and tryptophan would be a practical and affordable solution to help prevent autism and possibly ameliorate some symptoms of the disorder.

After absorbing L-tryptophan from food, our bodies convert it to 5-HTP (5-hyrdoxytryptophan), and then to serotonin.

The supplements L-tryptophan and 5-HTP are widely available and have been used in ADHD and autism but there is no evidence that they are effective.  All that has been shown is that too little tryptophan is bad; there is nothing to show that abnormally large amounts do any good.

If you read the full paper there is an excellent explanation of the role of serotonin in autism.  It is beyond doubt that in many kids with ASD there is high blood serotonin, but low brain serotonin.

To fully treat autism, one thing to be done is to raise brain serotonin levels, without any nasty side effects.  SSRI drugs like Prozac, used to treat depression, do raise brain serotonin but often cause dependence and side effects (like suicidal thought).

It would be great if some vitamin D and tryptophan could do the job.

If you read the older literature, you will see that there is nothing new about the idea to supplement with Tryptophan in autism.  The results to date have been nothing special.

Here is a paper by Paul Whiteley and Paul Shattock:-
 

Effects of Supplementation with Tryptophan and derivatives.  

“It has been shown that a diet depleted of tryptophan is not beneficial for children with ASDs and that some symptoms are exacerbated. Presumably, the existing lack of available serotonin (and other tryptophan derivatives) was exacerbated under these circumstances. Supplementation with tryptophan would probably not be helpful in the majority of cases because the conversions along the important pathways are inhibited and tryptophan is likely to be converted along the IAG route, which would be unhelpful. Anecdotal clinical reports suggest that some children show benefits and others may get worse but no formal studies have been reported.

For this reason, and because tryptophan is a prescription-only drug*, we have looked at other methodologies. The active transmitter, serotonin, does not cross the blood brain barrier and so would be ineffectual in this respect. However, the precursor molecule 5-HTP does cross the blood brain barrier and reach the appropriate target areas. Some parents have reported impressive consequences, particularly with regard to sleep patterns; some physicians have been able to reduce the doses of e.g. risperidone (an anti-psychotic drug) by supplementing 5-HTP but, on the whole, the results have been less useful than would have been predicted.”

Vitamin D and Children with ASD

Children with autism are probably amongst the most “vitamin-supplemented” of any, since parents tend to give copious amounts of multi-vitamins and also vitamin D rich omega 3 fish oil.  It is hard to imagine that any of these children are deficient in vitamin D.

 

The case for too much vitamin D

In his paper, Bittker seeks to correlate the increase in vitamin D fortification in America with the rise in autism; he highlights groups that do not have vitamin D fortified food and where autism is far less prevalent.

Infant Exposure to Excessive Vitamin D: A Risk Factor for Autism

 

Conclusion

So who is right?  Well for sure too little tryptophan or vitamin D is bad for you; but are abnormally high levels good or bad?  In the case of tryptophan, plenty of people have tried supplementation in autism and ADHD and we would probably have heard if it produced a great effect.

Do large amounts of vitamin D help with autism? I very much doubt it, but it would be very easy to do a trial, assuming you found some parents who had not read the Bittker paper.

The good thing is that raising the low level of brain serotonin seems agreed by everyone as a prime target of any autism intervention. For me, vitamin D and tryptophan is not the answer.