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.

 

Mopping up harmful gut metabolites with Carbon (AB 2004) or Silicone (Enterosgel) to improve GI and behavioral problems in Autism

 

We have seen in previous posts that certain metabolites produced in the gut can worsen existing autism and even create autism in mouse models.

Much has been written about propionic acid, which when produced in the gut, rather than the beneficial butyric acid, causes behavioral problems.  This is what underlies the Nemechek Protocol, developed by Patrick Nemecheck, DO.  In his therapy you try to increase butyric acid production using inulin as a dietary fiber.  It does work for some people, but they are in the minority; in a small group it makes matters worse.

We also saw that P-cresol, another chemical produced by fermentation in the gut, can trigger autistic behaviors.

P-Cresol, like Propionic acid – a cause of Transitory Autism for some and a further burden for others

A few years ago in the research we did come across a “wonder” bacteria called B. fragilis (Bacteroides fragilis).  This bacterium was able to reverse autism in the mouse model of maternal immune activation (MIA).  The actual mechanism was by reducing a gut metabolite called 4EPS.  It turns out that 4EPS is closely related to P-cresol. The B. fragilis bacteria is essential to healthy gastrointestinal function, but it must not enter the bloodstream because it can cause a fatal blood infection. 

Antibiotics and Autism(s) – Pass the Bacteroides Fragilis?

 

How to defeat 4EPS

You would think that the easiest way to get rid of that harmful 4EPS would be simply to take B. fragilis, as a probiotic.

An Australian company called Axial decided instead to use a special form of carbon taken orally to “mop up” the 4EPS. The research drug is called AB-2004.

This carbon cannot be selective for 4EPS, so it will also “mop up” other things as well.

It does look like elevated 4EPS in autism is also associated with GI problems and that anxiety is the key feature of autism that is made worse.

I think you could describe AB-2004 as a therapy to restore GI integrity in autism that will also reduce anxiety is a sub-group.

If you have autism with anxiety, but perfect GI function, it does not look like you are going to benefit from AB-2004.

 

What about Silicone rather than Carbon? 

I was recently introduced to a product normally used to treat IBS-D (irritable bowel syndrome with Diarrhea).  The other type is called IBS-C, with C being for constipation.

It seems that some people with autism and GI problems respond very well to the OTC product Enterosgel, which claims to mop up harmful substances using a silicon gel (polymethylsiloxane polyhydrate) in combination with purified water

As with the experimental AB-2004, the silicone gel cannot be selective for any particular metabolite.

There are clinical trials looking at the benefit of Enterosgel in IBS-D.

 

Here is a current trial in the United Kingdom:

 

RELIEVE IBS-D trial

You can actually measure 4EPS in urine, (as you can P-cresol).  It would not be hard to see if Enterosgel lowers the elevated 4EPS found in people with autism + GI dysfunction. 

Of note is that for our reader Dragos in Romania, Enterosgel worked wonders in his adult son with IBS-C plus challenging behaviors, rather than IBS-D. 

  

4EPS  

The microbiota modulates gut physiology and behavioral abnormalities associated with autism 

A Serum Metabolite Induces ASD-Related Behavior

MIA-dependent increases of specific metabolites, and their restoration by B. fragilis, suggest that small molecules may play a role in ASD-related behaviors. To test this hypothesis, we examined whether increasing serum 4EPS is sufficient to cause any ASD-related behavioral abnormalities in naïve mice. Mice were treated with 4EPS potassium salt (Figures S7A–C) or vehicle, daily from 3 weeks of age (when MIA offspring display gut permeability) to 6 weeks of age (when behavior testing begins). Remarkably, systemic administration of the single metabolite, 4EPS, to naïve wild-type mice is sufficient to induce anxiety-like behavior similar to that observed in MIA offspring (Figure 6C). Relative to vehicle-treated controls, mice exposed to 4EPS travel comparable distances in the open field but spend less time in the center arena (Figure 6C). Also, in the PPI test, 4EPS-treated mice exhibit increased intensity of startle in response to the unconditioned primary stimulus, but no significant alterations in PPI (Figure 6D), representing anxiety-associated potentiation of the startle reflex (Bourin et al., 2007). Conversely, there are no significant differences between 4EPS-treated versus saline-treated mice in marble burying or USV behavior (Figures S7D and S7E), suggesting that elevating serum 4EPS levels specifically promotes anxiety-like behavior. While not a core diagnostic criterion, anxiety is a common co-morbidity that may contribute to cardinal ASD symptoms. Furthermore, it is possible that complex behaviors may be modulated by combinations of metabolites. In summary, these data reveal that elevated systemic levels of a metabolite regulated by gut microbes causes an ASD-related behavior, suggesting that molecular connections between the gut and the brain maybe associated with autism.

In a proof-of-concept test of the this hypothesis, we reveal that the microbially-modulated metabolite 4EPS, which is elevated in the circulation by MIA and restored by B. fragilis treatment, is sufficient to induce anxiety-like behavior in naïve mice. These data indicate that metabolomic changes contribute to the onset and/or persistence of autism-related behavioral abnormalities. Notably, we show that commensal microbes are required for the production of serum 4EPS in mice. Several species of Clostridium are believed to be producers of the precursor 4-ethylphenol (Nicholson et al., 2012), consistent with our findings that levels of the Lachnospiraceae family of Clostridia and serum 4EPS are elevated in MIA offspring, and both are corrected by B. fragilis treatment. Moreover, the structural similarity of 4EPS to p-cresol, which also derives from Clostridium species (Persico and Napolioni, 2013), suggests they may be produced through similar biosynthetic pathways (see Figure S6A). Although not all autism-like behaviors are affected by 4EPS alone, our results warrant the examination of several other serum metabolites, perhaps in combination, for their potential to impact the spectrum of autism-related behaviors. 

 

The Gut Microbiota and Autism Spectrum Disorders

AB-2004, its orally administered, drug candidate that has demonstrated the ability to repair leaky gut and improve repetitive behavior, anxiety, and ASD-related sensorimotor gating deficits by removing key microbial metabolites in animal models with Autism Spectrum Disorder (ASD).

 

The main highlights from the poster presentation titled, “Characterization of GI barrier integrity and gut microbiome-derived metabolites in BTBR, Shank3 and Cntnap2 mouse models of ASD and demonstration of AB-2004 as a potential mitigating therapeutic” include:

 

·     The Cntnap2-/- mouse model accurately recapitulated the leaky gut phenotype and elevated levels of the gut microbiome-derived metabolite 4-EPS that have been reported in ASD patients

·     Treatment with AB-2004 effectively restored GI integrity and reduced elevated 4-EPS levels in Cntnap2-/- mice

·     The Cntnap2-/- model has been identified as a promising and translationally relevant animal model for the development of microbiome-inspired therapies for the effective treatment of GI and behavioral dysfunctions in ASD

·     These data support the development of AB-2004 as a treatment for GI dysfunction in ASD and potentially behavioral symptoms through reduction of pathologically active microbiome-derived metabolites Axial is currently screening ASD adolescents for its Phase 1b/2a clinical trial of AB-2004.

Scientific evidence has shown there may be a link between bacteria commonly found in the digestive tract, and the brain which could contribute to certain characteristics, such as irritability, in children with ASD. AB-2004 is designed to adsorb certain substances produced by gut bacteria to reduce their ability to enter the bloodstream and reach the brain.   

 

The active ingredient in AB-2004 is a highly engineered form of spherical carbon designed with human safety and biological selectivity in mind, making it very different from activated charcoal. Each sphere of AB-2004 consists of a network of pores that allows it to selectively adsorb metabolites that may contribute to characteristics associated with ASD like irritability and anxiety.

 

Axial reports findings of elevated 4-EPS in children with ASD 

The findings showed that concentrations of the bacterial metabolite, 4-ethylphenylsulfate (4-EPS) were elevated as much as six-fold in serum samples from children with ASD compared to healthy controls in replicate analyses.

This research builds on previous work published by Axial's Co-founder and Caltech Professor, Sarkis Mazmanian, Ph.D., that demonstrated causality between 4-EPS and anxiety-like behaviors in the "maternal immune activation" (MIA) mouse model of ASD. The MIA model recapitulates key features of the autism phenotype, including increased anxiety, stereotypic behaviors, and decreased vocalizations and social behaviors. Dr. Mazmanian found changes in the gut microbiome (dysbiosis), increased intestinal permeability (IP), and elevated levels of the putative bacterial metabolite 4-EPS in MIA mice, compared to controls. Oral treatment with B. fragilis, a human commensal gut bacterial species, resulted in restoration of gut microbial profiles, decreased IP, and markedly reduced serum concentrations of 4-EPS.

The current study aimed to evaluate 4-EPS levels in children with ASD compared to samples from control children. Two analyses were performed, a 4-EPS targeted analysis in 103 pediatric subjects and a non-targeted serum metabolomics study involving 230 children (cohorts from the "Childhood Autism Risks from Genetics and the Environment" study ongoing at the Univ. of California Davis). 4-EPS concentrations were found to be significantly elevated in children with ASD vs. healthy controls in both analyses. In addition, elevated levels were associated with worse social performance on two separate measurements. The impact of this elevation on behavior, and the impact of treatment with B. fragilis and with Axial's small molecule therapeutic, AB-2004, will be the subject of subsequent human clinical studies.

 

Anxiety Linked to Gut Microbial Metabolite in Mouse and Human

In a small, single-cohort pilot study reported simultaneously in a Nature Medicine article titled, “Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial“(trial registration no. ACTRN12618001956291), Mazmanian’s team tested an oral drug (AB-2004) that adsorbs 4EPS in the gut in 30 adolescents with autism. In addition to reducing 4EPS levels in blood and urine, and improving gut health, a subset of the tested participants showed reduced irritability and anxiety.

 

  

What is Enerosgel?  (click the link)

 

 

Conclusion 

I imagine both AB-2004 and Enterosgel are removing numerous metabolites from the digestive tract.

We know that at least 3 metabolites (Propionic acid, P-cresol and 4EPS) can induce autism in a previously not autistic mammal.  There are undoubted other metabolites that will be added to this list.  In the case of Propionic acid the autism was reversable using NAC (N-acetylcysteine).

Since you will have to wait years for AB-2004 to become an approved drug, if indeed it ever happens, you might just have to hope that Enterosgel is equally effective at mopping up that 4EPS with silicone.

It is pretty clear that the Australians are targeting anxious Aspies with GI problems, with AB-2004.

Is Enterosgel going to benefit those with autism and without GI dysfunction?  I think it is less likely, but it could happen.  The effect might not relate just to 4EPS. 

 

 

Enterosgel for food allergy? 

I do wonder about the use of Enterosgel following an acute food allergy.

Many people take the mast cell stabilizer cromolyn sodium (Nalcrom) to deal with food allergy.  Indeed, for some people, instead of eliminating the food they are allergic to, they take Nalcrom.

Apparently, some people with food allergies are taking Enterosgel regularly.

What happens if you consume a food substance by mistake that you are allergic too?

This is what happened recently to Monty while on holiday in Greece.  Two small red patches appeared on either side of his face and his mood and behavior changed dramatically.  It was like his pollen allergy triggered summertime raging, but it was not due to pollen allergy.

The effect of an allergic reactions continues even after you remove the allergen.  If you are allergic to bee stings you might end up needing a steroid injection to settle your immune system down.  In the immediate term you can take an oral H1 antihistamine.

Monty had his H1 antihistamine and a single oral dose of Prednisone; after 3 days he was back to his usual self.

People who get severe allergic reactions carry an Epipen (an epinephrine autoinjector).

In Monty’s case there is never a severe allergic reaction, but there is a severe behavioral reaction to a modest allergic reaction.  I think this is likely to be quite common in people with autism and challenging behaviors.  It often goes untreated, or is poorly treated using anti-psychotic drugs, which then cause serious side-effects including tardive dyskinesia (motor tics), obesity, males growing breasts (drug-induced gynecomastia) etc.

Even though Monty has no GI problems, perhaps I should acquire some Enterosgel to use in case of a future acute food allergy attack?