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:
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?
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?