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 Atopic March - updated: Leading to Autism and ADHD in some children?

 

I was thinking yesterday about the link between eczema (atopic dermatitis) and autism following a comment regarding a therapy I must have mentioned long ago (l-histidine with zinc). The therapy did work well for this child.

This then brought me back to one of my pet subjects, which is the minimization of the risk of future autism. I did write a section in my book on this subject, but it remains a work-in-progress. My elder son wants to avoid autism in his future children. If there are simple, safe, inexpensive steps that can be taken, that also provide broader health benefits then it would be crazy not to take them.

This brings me to the subject of the so-called atopic march. I have updated it to include its effects on the brain, increasing the risk of autism and ADHD and also suggest that in fact there may be slightly different atopic journeys, rather than a singular march with the same start and end points.

 

The atopic march

The traditional "atopic march" describes the progression from atopic dermatitis (eczema) in infancy to food allergies, asthma and allergic rhinitis later in childhood. While this framework has been useful for decades, it may be too simplistic.

Perhaps there is not one atopic march, but several.

Recent years have seen an explosion of research into the gut microbiome, immune development, mast cells and neurodevelopment. Numerous studies continue to investigate probiotics as a treatment for eczema, allergies and even autism. However, there is a recurring problem: many of these studies are performed in children who may already be too old to receive the maximum benefit.

The first few months of life appear to be a critical developmental window. During this period, the gut microbiome, immune system and brain are all developing simultaneously. Alterations during this time may have lifelong consequences.

One particularly intriguing study from Finland was originally designed to investigate eczema prevention. What makes this study especially interesting is that the intervention began before many people would even think about treating the microbiome. Mothers received the probiotic Lactobacillus rhamnosus GG during the final 2–4 weeks of pregnancy. After birth, the infants received the probiotic for only the first six months of life.

A possible link between early probiotic intervention and the risk of neuropsychiatric disorders later in childhood: a randomized trial

Remarkably, this relatively brief intervention, lasting just a few months around the time of birth, was followed by measurable differences many years later.

In other words, the researchers were not treating eczema, ADHD or autism. They were attempting to influence the earliest stages of microbiome development. This timing is important because the infant microbiome is initially seeded by microbes acquired from the mother during birth, breastfeeding and close maternal contact. By giving the probiotic to both mother and infant, the researchers may have been influencing the microbial ecosystem at the very moment it was being established.

Years later, when the children were followed into adolescence, the researchers found not only a reduction in eczema but also a surprising reduction in diagnoses of ADHD and Asperger syndrome. If the finding proves to be real, it would suggest that a six-month intervention during infancy may have influenced developmental trajectories more than a decade later. The study was small and requires replication, but the findings were striking. 

Group	Children	ADHD or Asperger syndrome by age 13	Percentage
Probiotic (LGG)	40	0	0%
Placebo	35	6	17%

One reason the Finnish study has not been easily replicated is the sheer difficulty of performing such research. To repeat the study properly, researchers would need to recruit women during pregnancy, administer the intervention before birth, continue treatment during infancy, and then follow the children for 10–15 years while carefully tracking neurodevelopmental outcomes. Such studies are expensive, logistically challenging and suffer from inevitable participant drop-out over time. Furthermore, because probiotics are inexpensive and cannot easily be patented, there is limited commercial incentive to fund a trial that may take more than a decade to produce results. As a consequence, many probiotic studies focus on older children and adults where results can be obtained within months rather than years, even though the greatest biological impact may occur during the earliest stages of development.

At the same time, other observations point in a similar direction:

• Early pet exposure reduces the risk of eczema.
• Children raised on farms have lower rates of allergic disease.
• Early probiotic use can reduce the risk of atopic dermatitis.
• Food allergies are increasingly viewed as part of the atopic march.
• Autism and ADHD are associated with higher rates of allergic disease in many studies.

The common denominator may be early-life immune and microbiome development.

The protective effects of pets and farm exposure are often discussed in the context of the hygiene hypothesis, although the modern interpretation is really a microbial exposure hypothesis. Children growing up around animals are exposed to a much greater diversity of microorganisms. Rather than overwhelming the immune system, these microbial exposures appear to help educate and calibrate it. Studies of children raised on traditional farms consistently show lower rates of eczema, asthma and allergic disease. The immune system evolved in a world rich in microbial exposures, and it may require those signals to develop normally.

This brings us to an important point. The infant microbiome does not arise spontaneously. Much of it originates from the mother. During birth, breastfeeding and close maternal contact, microbes are transferred from mother to child. These pioneer organisms help establish the infant gut microbiome and play a critical role in training the developing immune system. In many ways, the microbiome acts as one of the earliest teachers of the immune system, helping it learn the difference between harmless substances and genuine threats.

This process of immune calibration appears to occur very early in life. Once established, the microbiome becomes increasingly stable and resistant to change. This may explain why probiotics often show their greatest effects when administered during pregnancy or infancy, while studies in older children and adults frequently produce much smaller results. By the time many interventions are attempted, the window during which the microbiome is shaping immune development may already be closing.

Perhaps the most remarkable aspect of the Finnish study is not the probiotic itself, but the timing. The intervention was completed by six months of age, yet the outcomes were measured at 13 years of age. This is precisely what one would expect if the microbiome plays a role in calibrating the developing immune system during a narrow critical window early in life.

Mast cells may also deserve greater attention. They play important roles in eczema, food allergies, asthma and anaphylaxis, but they are also found in the gut and nervous system. Some researchers have proposed that abnormal mast-cell activity could contribute to neurodevelopmental symptoms in susceptible individuals.

Another clue that early immune modulation may alter the trajectory of the atopic march comes from studies of ketotifen, an antihistamine and mast-cell stabilizer. In one notable study of infants with atopic dermatitis, children receiving ketotifen were significantly less likely to develop asthma during the follow-up period. The researchers also reported improvements in the severity of atopic dermatitis. These findings suggest that, at least in some children, modifying mast-cell activity and allergic inflammation early in life may alter the subsequent progression of allergic disease.

Prevention strategies for asthma — secondary prevention

If the classical atopic march can be interrupted before eczema progresses to asthma, it raises a broader question. Could other early interventions—such as probiotics, microbial exposure from pets and farm environments, or targeted immune modulation—also alter developmental trajectories extending beyond allergy and into neurodevelopment in susceptible children?

This raises an interesting possibility. For a subgroup of children, the atopic march may not end with asthma and hay fever. Instead, immune dysregulation, microbiome alterations and barrier dysfunction could also influence neurodevelopment, increasing the risk of ADHD or autism.

The proposed sequence might look something like this:

Microbiome disturbance / barrier dysfunction → Eczema → Food allergy → Mast-cell activation → ADHD / Autism susceptibility

or perhaps

Microbiome disturbance → Food allergy → Eczema → Neurodevelopmental effects

In other words, there may be multiple entry points and multiple destinations.

Importantly, this hypothesis does not suggest that eczema causes autism, nor that most children with eczema will develop autism. Rather, it suggests that some children may share an underlying biological pathway affecting the skin, gut, immune system and brain.

If this hypothesis contains even a grain of truth, it has profound implications. It would mean that interventions aimed at modifying the microbiome or immune system may be most effective during infancy, before symptoms of autism or ADHD are apparent. By the time a child is diagnosed at age 3, 5 or 10, the critical developmental window may already have passed.

The irony is that we continue to perform large numbers of probiotic studies in older children and adults, where effects are often modest. The greatest opportunity may lie much earlier, during the period when the microbiome and immune system are still being assembled.

The challenge for researchers is to identify which children belong to this subgroup before the window of opportunity closes.

The classical atopic march has evolved over time. Perhaps the next evolution will be to recognize that, in some children, the journey extends beyond allergies and into neurodevelopment.

  

Conclusion

 In the Finnish study, the intervention was actually in both the mother and the infant:

• Mothers took Lactobacillus rhamnosus GG during the final 2–4 weeks of pregnancy.
• After birth, the infants received the probiotic until 6 months of age.

It would be very easy to implement this.

Dog and farm animal exposure (pregnant mother and later the baby) might be more difficult for some, but easy for others.

NAC during pregnancy is another simple one. It was also show very effective in reducing miscarriages and increasing the “take-home baby rate.”

We also saw Prof Ramaekers using folinic acid during pregnancy where future parents test positive for folate receptor antibodies. This requires the future parents taking the FRAT test.

In older children and adults probiotics can have a benefit, but the dramatic effect only occurs when given prior to the immune system being (mis)calibrated. In the older age-group it appears that you need something more potent – FMT works in some cases. 

The Finnish study only refers to level 1 autism (then called Asperger's syndrome).

I imagine if you could repeat this study and also include all the common issues like

• Dyslexia
• Dyscalculia
• Developmental language disorder
• Dyspraxia (developmental coordination disorder)
• Learning disabilities generally
• Level 2 and 3 autism

you would see some shocking results. 

You would not have 0% incidence of each disorder in the probiotic group, but I bet you would see a substantial reduction.

Autism regression around aged 9-18 years old – is it catatonia?

 

From the title of today’s post you can see that this is one for parents of older children and indeed some adults. I should add that personally I am not a fan of observational diagnoses like catatonia, because I am interested in the biological cause of the unwanted behaviors, as a means to find effective therapy. Catatonia is a very broad term, but in current psychiatry that is what we have.

I was recently contacted by a mother whose adolescent son had regressed severely and she wanted to know what she had done wrong. She had not done anything wrong of course. Now she has to figure out what triggered the changes and how to reverse them. Catatonia is one possibility and it has not been covered in this blog.

The word catatonic drifted into casual English. Today, people use it informally to describe anyone who is completely unresponsive, frozen, or motionless.

As a medical term a diagnosis of catatonia is typically confirmed when an individual displays three or more of the following features:

Stupor & Mutism. Profound unresponsiveness to the outside world, along with a lack of, or severely reduced, speech.

Catalepsy & Waxy Flexibility. The tendency to passively hold bizarre, fixed postures against gravity or to maintain a position exactly as it is set by someone else.

Negativism. An active or passive resistance to instructions or movement.

Posturing. The spontaneous holding of unnatural, active postures for long periods.

Stereotypy & Mannerisms. Repetitive, non-goal-directed movements (such as rocking or pacing) or odd caricatures of normal actions.

Excitement/Agitation. Frenzied or purposeless motor activity that does not seem influenced by external stimuli.

Echolalia & Echopraxia. The involuntary mimicking of someone else's speech or movements.

 

Catatonia often occurs in people with schizophrenia, bipolar, or major depressive disorders. It can also be triggered by autoimmune diseases, brain injuries, or even severe infections. About 10% of people with autism will develop symptoms of catatonia. It can affect any level of autism.

Puberty can be the trigger for catatonia, but it can also develop much later in adulthood. 

Diagnosing catatonia looks different depending on the patient's age. For instance children are much more likely to present with refusal to eat or drink and mutism, which caregivers sometimes mistake for stubbornness or behavioral issues.

Autism-related catatonia can manifest differently than it does in non-autistic populations. It is often characterized by a distinct pattern of gradual, late regression rather than a sudden, acute physical freeze.

The "Late Regression" Timeline

While autism is usually diagnosed in early childhood, catatonia typically hits during adolescence or early adulthood.

The Early Warn Signs (Ages 10–14) Before full-blown catatonia develops, young teens with autism often exhibit a gradual increase in obsessive-compulsive routines, extreme physical slowness, or brief episodes of "freezing".

Full Onset (Ages 15–19) Full-syndrome catatonia typically solidifies during the peak of pubertal development. It is rare to see the full syndrome in autistic children under the age of 15.

Unique symptoms in autistic individuals

Because symptoms overlap with common autistic traits, catatonia can be difficult to recognize.

Loss of Function (Severe Regression). A sudden or progressive inability to complete daily activities they previously mastered (e.g., getting dressed, bathing, or using utensils).

Severe "Freezing" and Stuckness. Getting physically stuck mid-motion—such as freezing in a doorway or holding a cup halfway to their mouth for minutes.

The "Shutdown" Phenomenon. Severe passivity where the individual stops talking (mutism), avoids all eye contact, and refuses to eat or drink.

Hyperactive and Self-Injurious Behaviors. Rather than just freezing, autistic individuals frequently display hyperactive catatonia, which includes repetitive, automatic, and severe self-injury (like severe head-banging) that is unrelated to communicative distress.

Fluctuation Symptoms are notoriously variable—an individual may seem heavily affected or locked in place in the morning but move relatively normally by evening.

 

Why does it happen?

In autism, catatonia is frequently triggered by extreme environmental stress, major life transitions (like leaving school), trauma, severe anxiety, or co-occurring mood disorders.

 

Biological drivers

While psychological and environmental stress (such as extreme anxiety, bullying, or major routine changes) frequently act as the spark, catatonia is ultimately a neurological breakdown. The primary biological triggers, chemical imbalances, and genetic factors that cause the brain to enter a catatonic state include:

1.     Neurotransmitter imbalances

The most widely accepted biological explanation for catatonia is a sudden, severe imbalance of chemical messengers in the brain circuits that control movement and behavior:

·        GABA Deficit: GABA is the brain's primary calming/inhibitory neurotransmitter. In catatonia, there can be a sudden drop in GABA-A receptor activity. Because the brain loses its ability to regulate or slow down signals, motor pathways lock up. This explains why benzodiazepines (which increase the sensitivity to a given amount of GABA) can often rapidly reverse the condition.

·        Glutamate Overdrive: Glutamate is an excitatory chemical. A spike in glutamatergic activity, specifically involving NMDA receptors, can overstimulate the brain's motor networks, forcing the body into fixed, rigid postures.

·        Dopamine Drop: A sudden drop in dopamine activity—specifically at D2 receptors—paralyzes the brain’s reward and movement centers. This mimics the chemical state seen in Parkinson's disease, creating severe physical slowness or total immobility.

 

2.     Neuroimmune and autoimmune triggers

The immune system can directly attack the brain, causing acute neuroinflammation that triggers catatonia.

·        Autoimmune Encephalitis: Conditions like anti-NMDA receptor encephalitis occur when the body mistakenly produces autoantibodies that attack NMDA receptors in the brain. Catatonia is a primary symptom in up to 70% of these cases.

·        Systemic Infections: In medically vulnerable or autistic individuals, severe underlying infections (like a urinary tract infection, pneumonia, or a severe viral illness) can trigger a massive cytokine response. This inflammation breaches the blood-brain barrier, disrupting motor circuits and inducing catatonic behavior.

 

3.     Structural brain differences

Neuroimaging studies show that catatonia often stems from communication failures within specific brain loops (the cortico-striato-thalamo-cortical circuits) which govern motor planning.In autistic individuals with catatonia, MRI scans frequently reveal abnormally small cerebellar structures. Because the cerebellum is responsible for fine-tuning motor actions and smooth coordination, these structural differences make the motor loop highly vulnerable to completely breaking down under stress.

4.     Genetic susceptibility

Catatonia can have a hereditary link. Genetic studies on families with a vulnerability to periodic catatonia have identified specific genetic alterations. Interestingly, susceptibility regions on chromosomes 15 and 22 are heavily implicated in both autism and catatonia, suggesting a shared genetic architecture that primes certain individuals for the condition.

5.     Medication effects & withdrawal

Abrupt biological shifts caused by pharmaceutical substances can paralyze the motor system:

·        Dopamine Blockers: Exposure to strong antipsychotic medications can sometimes block dopamine receptors so aggressively that it induces catatonia .

·        Sedative Withdrawal: Suddenly stopping medications that calm the central nervous system (such as benzodiazepines or barbiturates) causes a rebound biological shock, stripping away the brain’s chemical brakes and inducing a catatonic freeze. Always taper the dosage.

  

Mainstream therapy for catatonia 

The treatment goal is to resolve any physical freezing first, then address the underlying psychiatric or medical cause.

Clinicians use a strict, stepped protocol ranging from medications to medical procedures. The first-line medication is Lorazepam (Ativan), a benzodiazepine. Lorazepam increases GABA-A activity, restoring the brain's missing chemical brakes. Intravenous Lorazepam is given to confirm the diagnosis if symptoms improve rapidly.

Electroconvulsive therapy (ECT) is the definitive treatment for severe cases. ECT is deployed if a patient shows no improvement after intensive Lorazepam trials. ECT is performed safely in a hospital setting under general anesthesia and muscle relaxants.

Maintenance Therapy: Long-term, periodic ECT may be required for individuals with chronic conditions.

Second-line options include glutamate antagonists like Amantadine or Memantine, if first-line choices fail. Alternative GABA agents like Zolpidem (Ambien) are sometimes utilized to break treatment-resistant freezing. Medications to Avoid: Traditional dopamine-blocking antipsychotics (like haloperidol) are generally not useful. Antipsychotics can worsen the motor paralysis or trigger Neuroleptic Malignant Syndrome.

 

Peter’s thought’s on mainstream therapy

The 30+% of level 3 autism who respond to bumetanide would have an extreme negative (paradoxical) reaction to Lorazepam (Ativan). They would get very aggressive and “go nuts.”

In most countries ECT is highly regulated. It clearly is effective for some people, but it looks a rather crude therapy to me.

The mainstream therapies look very “thin” to me. I think much more should be possible.  

I think the term catatonia is much too vague and you need to know why these changes have occurred, then you can figure out a therapy.

PANS can trigger the symptoms of catatonia. In many counties PANS is still not recognized as a diagnosis. PANS (Pediatric Acute-onset Neuropsychiatric Syndrome) would not respond to a benzodiazepine drug like Lorazepam, but would instead require immunotherapy, which is completely different.

As usual we come back to getting an observational like catatonia, autism or trendy new ones like ARFID (picky eating) is just the first step in the process. Then you need to find out why? What biological or behavioral factors are driving these symptoms. Then you can figure out how to treat them, or indeed choose not to treat them, if you are so inclined.

  

Could it be OCD rather than catatonia?

One reason catatonia can be difficult to recognize in autism is that several of its symptoms overlap with severe obsessive-compulsive disorder (OCD). In fact, some studies have found that obsessive-compulsive symptoms are very common in autistic individuals who later develop catatonia.

Parents often report that their child begins:

• Writing the same words repeatedly
• Talking about the same topics over and over
• Performing increasingly rigid rituals
• Becoming distressed when routines are interrupted
• Withdrawing socially

These symptoms may point to OCD, catatonia, or a combination of both.

The key distinction is that OCD is driven by obsessions and compulsions, whereas catatonia is characterized by a loss of initiative and a decline in function. An autistic teenager with OCD may be extremely active in performing rituals, while a teenager with catatonia may become progressively slower, less spontaneous, and increasingly "stuck."

Questions that may help distinguish the two include:

• Does the person become anxious if prevented from performing the behavior?
• Are they physically slower than before?
• Do they need prompting to start everyday activities?
• Have they lost skills they previously mastered?
• Are they spending long periods inactive or frozen?

The two conditions can coexist. In some cases, severe OCD may precede the development of catatonia.

Investigations

When a child, teenager, or adult with autism experiences a significant regression after years of relative stability, it is worth looking beyond the autism diagnosis itself.

One investigation I would seriously consider is an EEG (electroencephalogram). Epilepsy or "just" abnormal electrical activity in the brain can sometimes present as:

• Regression
• Social withdrawal
• Changes in communication
• Cognitive decline
• Repetitive behaviors
• Episodes of staring or unresponsiveness

Several studies have reported higher rates of epilepsy among autistic individuals who develop catatonic symptoms.

An EEG may not identify the cause of the regression, but it is a relatively straightforward way to investigate an important and potentially treatable neurological contributor.

Other investigations may include:

• Sleep assessment
• Review of medications
• Assessment for OCD and anxiety disorders
• Evaluation for depression
• Screening for autoimmune or inflammatory conditions where clinically indicated

The important point is that autism itself is not usually a progressive condition. When someone loses skills after years of stability, it is worth asking what has changed and whether there is a treatable condition contributing to the decline.