Tuesday, 30 June 2020

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

Today’s post has two themes, one relates to Transitory Autism, where a toddler with autism appears to “grow out” of the condition and the other is another substance produced in the gut, like we saw earlier with Propionic acid, that can produce “autism”. 

 Increased intestinal transit time and bacteria produce P-Cresol

If your gut produces a lot of propionic acid, instead of butyric acid, you can appear to have autism.
Today we see that producing too much P-Cresol in your gut produces symptoms of autism.
I suspect in most cases P-Cresol is making severe autism worse, rather than making a neurologically healthy, but likely constipated, person exhibit autism.
Elevated P-Cresol is associated with increased intestinal transit time and not Clostridium type bacteria.  We know that elevated P-Cresol is reduced after oral supplementation with oligofructose-enriched inulin.  It is suggested that certain probiotic bacteria might also lower P-Cresol.  A microbiota transplant, from a healthy subject, reversed P-Cresol abnormalities in a mouse model.
Interestingly, elevated P-Cresol alters the microbiome in the gut, so there may be a vicious circle.  An altered microbiome elevates P-Cresol and elevated P-Cresol produces an altered microbiome.
The Italian research on this subject suggests that in some people, resolving chronic constipation might solve most of the problem. 
If your gut is producing toxic chemicals, it is not surprising that the studies using microbiota (fecal) transplants show transformative results in some children.

Fermentation in your Gut
Today it looks like we have another chemistry lesson.
We have come across all sorts of chemicals in this autism blog with all kinds of acronyms, like SCFA (short chained fatty acid).
You have all kinds of autism treatments, like Nemechek and his Propionic Acid (an SCFA) lowering protocol. We saw in an earlier post how injecting a mouse with propionic acid (PPA) makes it autistic and that giving it NAC returns the mouse to its original state. The Koreans have just moved this research forward and found what is happening in the brain.  Propionic acid reduces the number of dendritic spines.  See the lower right illustration.

Propionic Acid  (PPA) decreases density of dendritic spines in hippocampal neurons

Propionic acid induces dendritic spine loss by MAPK/ERK signaling and dysregulation of autophagic flux

Propionic acid (PPA) is a short-chain fatty acid that is an important mediator of cellular metabolism. It is also a by-product of human gut enterobacteria and a common food preservative. A recent study found that rats administered with PPA showed autistic-like behaviors like restricted interest, impaired social behavior, and impaired reversal in a T-maze task. This study aimed to identify a link between PPA and autism phenotypes facilitated by signaling mechanisms in hippocampal neurons. Findings indicated autism-like pathogenesis associated with reduced dendritic spines in PPA-treated hippocampal neurons. To uncover the mechanisms underlying this loss, we evaluated autophagic flux, a functional readout of autophagy, using relevant biomedical markers. Results indicated that autophagic flux is impaired in PPA-treated hippocampal neurons. At a molecular level, the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway was activated and autophagic activity was impaired. We also observed that a MAPK inhibitor rescued dendritic spine loss in PPA-treated hippocampal neurons. Taken together, these results suggest a previously unknown link between PPA and autophagy in spine formation regulation in hippocampal neurons via MAPK/ERK signaling. Our results indicate that MAPK/ERK signaling participates in autism pathogenesis by autophagy disruption affecting dendritic spine density. This study may help to elucidate other mechanisms underlying autism and provide a potential strategy for treating ASD-associated pathology.


Fermentation in your colon, right now

In the graphic above you can see the types of chemicals that are produced in your gut by fermentation.
Fermentation is the chemical breakdown of a substance by bacteria, yeasts, or other microorganisms. 
In the graphic you can see SCFA and BCFA.  At the top right you can see Phenol.
I had never heard of P-Cresol, so I looked it up.
From high school chemistry many people may recall Benzene (C6H6).  It is drawn as a ring.

·      knock off an H and add an OH and you have Phenol.

In the top of the graphic about fermentation in your gut are phenol compounds.

If you start with phenol, knock off another H, add a CH3 (methyl radical) and you get P-Cresol  CH3C6H4(OH). 
A more helpful name they could have used in the research is methylphenol.

So now we know that if you ferment protein in your gut, certain bacteria will end up producing compounds related to phenol, one of which is P-cresol.
It looks like protein staying too long in the colon is a big part of the problem.
Other potential nasties in your gut
It is pretty clear that there will be numerous other chemicals produced in your gut that are not so good for you.

What about all that ammonia (NH3) produced in your colon?
You could write a book just about these potential gut nasties.

Back to P-Cresol
It turns out that high levels of P-Cresol can produce transitory autism.   
The study below showed that:-
·      you can make mice “autistic” by feeding them with P-Cresol
·      The affected mice developed altered gut bacteria (microbiota)
·      Transplanting the altered microbiota will make another mouse autistic
·      Transplanting healthy microbiota to a P-cresol mouse reverses its autism


Perturbations of the microbiota-gut-brain axis have been identified in autism spectrum disorders (ASD), suggesting that the microbiota could be involved in the development or maintenance of abnormal social and stereotyped behaviors in ASD patients. Yet, the underlying mediators and mechanisms remain unclear. We hypothesized that microbial metabolites produced by the gut microbiota contribute to behavioral deficits in ASD. We focused on p-Cresol, a microbial metabolite previously described as abnormally elevated in ASD patients.


Wild-type mice were chronically treated with p-Cresol in drinking water to mimic intestinal exposure. We combined behavioral phenotyping, electrophysiology, microbiota 16S sequencing and fecal microbiota transplantations to decipher the consequences of p-Cresol exposure.

We showed that p-Cresol selectively induced behavioral alterations reminiscent of ASD core symptoms: social behavior deficits, stereotypies and perseverative behaviors, but no changes in anxiety, locomotion or cognition. We further showed that p-Cresol decreases the activity of dopamine neurons in the ventral tegmental area (VTA), a key brain region for social reward processing. In addition, we reveal that p-Cresol remodels the intestinal microbiome, impacting specific bacterial taxa associated with social behavior deficits and stereotypies. We further demonstrated that social behavior deficits are transferred to control mice after transplantation of microbiota from p-Cresol-treated mice. Finally, both social interactions and VTA dopamine neurons activity were normalized in p-Cresol treated mice after transplant of microbiota from control mice.


Our study suggests that the microbial metabolite p-Cresol could be involved in the development of autistic behaviors through remodeling of the gut microbiota.

How relevant is a P-Cresol mouse to a human toddler?
The research is distinctly Italian and we come across Dr Persico again.
It seems that P-Cresol is elevated in toddlers with severe autism, but not so much in older children with autism
If you lowered the level of P-cresol in these children you would likely reduce the severity of their autism.

Autism spectrum disorder (ASD) is a neuropsychiatric disorder with onset during early childhood and life-long consequences in most cases. It is characterized by impairment in social interaction and communication, as well as by restricted patterns of interest and stereotyped behaviors. The etiology of autism is highly heterogeneous, encompassing a large range of genetic and environmental factors. Several lines of evidence suggest that, in addition to broader diagnostic criteria and increased awareness, also a real increase in incidence primarily due to greater gene-environment interactions may also be occurring. Environmental exposure to the organic aromatic compound p-cresol (4-methylphenol) is relatively common and occurs through the skin, as well as the gastrointestinal and respiratory systems. However, the largest and most widespread source of this compound is represented by some gut bacteria which express p-cresol synthesizing enzymes not found in human cells. Urinary p-cresol and its conjugated derivative p-cresylsulfate have been found elevated in an initial sample and recently in a replica sample of autistic children below 8 years of age, where it is associated with female sex, greater clinical severity regardless of sex, and history of behavioral regression. Potential sources of p-cresol excess in ASD, such as gut infection, chronic constipation, antibiotics, abnormal intestinal permeability, and environmental exposure, are being investigated. P-cresol may contribute to worsen autism severity and gut dysfunction, often present in autistic children. It may also contribute to a multibiomarker diagnostic panel useful in small autistic children.

The results summarized in Section 3, spurred our interest into assessing urinary levels of p-cresol in 59 non-syndromic autistic children and in 59 tightly age- and sex-matched controls (Altieri et al., 2011). Urinary p-cresol was measured in first morning urines by high performance liquid chromatography-ultraviolet (HPLC-UV) with multi-wavelength diode array detector (DAD). Urinary concentrations of p-cresol were significantly higher in autistic children compared to controls (123.5± 12.8 vs. 91.2±8.7 μg/ml, Pb0.05). This elevation was surprisingly age-dependent, as it was clearly detectable only up until and including age 7 (134.1±20.1 vs. 70.3±6.7 μg/ml, P=0.005), with urinary p-cresol levels normalizing at age 8 and beyond. Levels of p-cresol were correlated neither with body mass index nor with urinary cotinine levels, excluding spurious contamination from passive smoking.
Instead, p-cresol levels were significantly higher among:
(a) female autistic children compared to males (Pb0.05);
(b) more severely affected autistic children, regardless of sex (Pb0.05);
(c) children who underwent regression at autism onset, based on parents reporting loss of language skills after acquisition of more than 5 spoken words and loss of social abilities after initial acquisition (Pb0.05).

The currently available evidence summarized in this review provides initial support for postnatal exposure to elevated p-cresol and/or p-cresylsulfate as a pathoplastic contributor to the severity of behavioral abnormalities and cognitive impairment in autistic children. In particular, p-cresol and/or p-cresylsulfate seemingly belong to a restricted set of gut- or environmentally-derived compounds potentially able to worsen behavioral abnormalities and cognitive impairment in small autistic children. Studies performed in specific cellular and animal models, as well as prospective follow-up studies involving baby siblings (i.e., “high-risk” neonates born to parents with one grown-up child already diagnosed with ASD) will be instrumental in determining whether early prenatal exposure to environment- or maternal gut derived p-cresol may provide pathogenic contributions, significantly increasing the risk of autism spectrum disorder in the offspring. It will also be important to determine the precise origin of elevated p-cresol in small autistic children and to define its influence on the spectrum and intensity of clinical signs and symptoms of ASD, on developmental trajectories, and on endophenotypic subgroupings of small children with ASD. Replication studies will also need to determine whether elevated urinary p-cresol/p-cresylsulfate in ASD is specific to some racial and ethnic groups or represents a generalized finding. If positive, these studies spur hope into the design of cresol-resistant probiotics possibly able to improve behavioral abnormalities when targeted to ASD children with elevated urinary p-cresol.

Several studies have described in autistic patients an overgrowth of unusual gut bacterial strains, able to push the fermentation of tyrosine up to the formation of p-cresol. We compared levels of urinary p-cresol, measured by high-performance liquid chromatography-ultraviolet, in 59 matched case-control pairs. Urinary p-cresol was significantly elevated in autistic children smaller than 8 years of age (p < 0.01), typically females (p < 0.05), and more severely affected regardless of sex (p < 0.05). Urinary cotinine measurements excluded smoking-related hydrocarbon contaminations as contributors to these differences. Hence, elevated urinary p-cresol may serve as a biomarker of autism liability in small children, especially females and more severely affected males.

The uremic toxin p-cresol (4-methylphenol) is either of environmental origin or can be synthetized from tyrosine by cresol-producing bacteria present in the gut lumen. Elevated p-cresol amounts have been previously found in the urines of Italian and French autism spectrum disorder (ASD) children up until 8 years of age, and may be associated with autism severity or with the intensity of abnormal behaviors. This study aims to investigate the mechanism producing elevated urinary p-cresol in ASD. Urinary p-cresol levels were thus measured by High Performance Liquid Chromatography in a sample of 53 Italian ASD children assessed for (a) presence of Clostridium spp. strains in the gut by means of an in vitro fecal stool test and of Clostridium difficile-derived toxin A/B in the feces, (b) intestinal permeability using the lactulose/mannitol (LA/MA) test, (c) frequent use of antibiotics due to recurrent infections during the first 2 years of postnatal life, and (d) stool habits with the Bristol Stool Form Scale. Chronic constipation was the only variable significantly associated with total urinary p-cresol concentration (P < 0.05). No association was found with presence of Clostridium spp. in the gut flora (P = 0.92), augmented intestinal permeability (P = 0.18), or frequent use of antibiotics in early infancy (P = 0.47). No ASD child was found to carry C. difficile in the gut or to release toxin A/B in the feces. In conclusion, urinary p-cresol levels are elevated in young ASD children with increased intestinal transit time and chronic constipation.

Urinary P-Cresol Is Elevated in Young French Children With Autism Spectrum Disorder: A Replication Study 

The aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex- and age-matched controls (p50.05). This increase was limited to ASD children aged 8 years (p50.01), and not older (p ¼ 0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p50.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.

The present and previous results (Altieri et al., 2011), confirm that urinary amounts of the toxic compound p-cresol and of its derivatives, especially p-cresylsulfate, are significantly elevated in a sizable subgroup of small autistic children. These results were replicated in two case-control samples belonging to distinct ethnic groups, recruited in different geographical areas in Europe and screened at two independent clinical sites. Unbiased metabolomic and microbiomic approaches will have to define the degree of connection between elevated urinary p-cresol, skewed urinary metabolomic profiles and gut flora composition in our ASD patients. Clinical studies involving large cohorts will also be needed to conclusively define possible dose-dependent influences on the spectrum and severity of clinical signs and symptoms of ASD, as well as on endophenotypic subgroupings. Finally, perspective studies of high-risk infant siblings will be instrumental in determining the potential of urinary p-cresol and/or p-cresylsulfate as biological markers for an ASD diagnosis in small children and for predicting developmental trajectories

Figure 2. Total urinary p-cresol concentrations by age group, in 33 ASD patients (grey bars) and in 33 age-matched, sex-matched and ethnically matched controls (white bars). Data are presented as mean ± S.E.M. Numbers inside each column represent sample sizes. **p50.01 for global case-control contrasts in 22 pairs aged 3–8.

P-cresol Alters Brain Dopamine Metabolism and Exacerbates Autism-Like Behaviors in the BTBR Mouse

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction/communication, stereotypic behaviors, restricted interests, and abnormal sensory-processing. Several studies have reported significantly elevated urinary and foecal levels of p-cresol in ASD children, an aromatic compound either of environmental origin or produced by specific gut bacterial strains. 
Methods: Since p-cresol is a known uremic toxin, able to negatively affect multiple brain functions, the present study was undertaken to assess the effects of a single acute injection of low- or high-dose (1 or 10 mg/kg i.v. respectively) of p-cresol in behavioral and neurochemical phenotypes of BTBR mice, a reliable animal model of human ASD. 
Results: P-cresol significantly increased anxiety-like behaviors and hyperactivity in the open field, in addition to producing stereotypic behaviors and loss of social preference in BTBR mice. Tissue levels of monoaminergic neurotransmitters and their metabolites unveiled significantly activated dopamine turnover in amygdala as well as in dorsal and ventral striatum after p-cresol administration; no effect was recorded in medial-prefrontal cortex and hippocampus. 
Conclusion: Our study supports a gene x environment interaction model, whereby p-cresol, acting upon a susceptible genetic background, can acutely induce autism-like behaviors and produce abnormal dopamine metabolism in the reward circuitry.
Preliminary data point toward possible correlations between urinary p-cresol concentrations and ASD severity measured using the Childhood Autism Rating Scale (CARS) [12]. Multiple mechanisms could account for the negative influences of p-cresol on neural function, ranging from membrane depolarization and increased susceptibility to seizures [18], to decreased Na+-K+ ATPase activity [19], to blunted conversion of dopamine (DA) to norepinephrine (NE) due to inhibition of dopamine-β-hydroxylase [20].

This study demonstrates that acute p-cresol administration to an animal model of ASD induces behavioral abnormalities closely resembling core symptoms of ASD and comorbidities frequently observed in autistic individuals. These results underscore the importance of gene x environment interaction models, able to merge genetic predisposition and evidence-based environmental exposure to specific neurotoxic compounds into a unitary scenario. From a mechanistic standpoint, these results move the field beyond well-established paradigms in the autism literature, such as the imbalance between glutamate and GABA to explain insistence on sameness and the co-morbidity with epilepsy [62], or the role of 5-HT in reference to hyperserotonemia, disruption of circadian rhythmicity, neuroinflammation and neuronal excitability [63,64,65]. In a complementary view, they point toward critical dopaminergic roles in autistic symptoms as being relevant as stereotypic behaviors, hyperactivity, anxiety and motivational drive towards inanimate objects. Thirdly, urinary gut-derived neurotoxic compounds, such as p-cresol, could serve as useful ASD biomarkers, whose specificity now deserves to be assessed in samples of young non-autistic children affected with chronic constipation. Finally, the correction of chronic constipation and microbiota transfer therapy represent two reasonable and testable approaches, aimed at partly ameliorating autistic behaviors by reducing the absorption of neurotoxic compounds of environmental origin or derived from specific gut-bacterial strains [66]. Studies addressing the efficacy of these therapeutic approaches will largely benefit from parallel assessments of urinary biomarkers, such as p-cresol and other gut-derived compounds, in order to provide mechanistic insights into their effects on the longitudinal time course of autistic symptoms.

The paper below covers all kinds of issues and is a good read:

Functional analysis of colonic bacterial metabolism: relevant to health?

With the use of molecular techniques, numerous studies have evaluated the composition of the intestinal microbiota in health and disease. However, it is of major interest to supplement this with a functional analysis of the microbiota. In this review, the different approaches that have been used to characterize microbial metabolites, yielding information on the functional end products of microbial metabolism, have been summarized. To analyze colonic microbial metabolites, the most conventional way is by application of a hypothesis-driven targeted approach, through quantification of selected metabolites from carbohydrate (e.g., short-chain fatty acids) and protein fermentation (e.g., p-cresol, phenol, ammonia, or H2S), secondary bile acids, or colonic enzymes. The application of stable isotope-labeled substrates can provide an elegant solution to study these metabolic pathways in vivo. On the other hand, a top-down approach can be followed by applying metabolite fingerprinting techniques based on 1H-NMR or mass spectrometric analysis. Quantification of known metabolites and characterization of metabolite patterns in urine, breath, plasma, and fecal samples can reveal new pathways and give insight into physiological regulatory processes of the colonic microbiota. In addition, specific metabolic profiles can function as a diagnostic tool for the identification of several gastrointestinal diseases, such as ulcerative colitis and Crohn's disease. Nevertheless, future research will have to evaluate the relevance of associations between metabolites and different disease states.
Urinary levels of p-cresol and phenol have shown to be increased during high protein intake (37) and decreased after oral supplementation with oligofructose-enriched inulin (OF-IN) (25).


Effects of Lactobacillus Casei Shirota, Bifidobacterium Breve, and Oligofructose-EnrichedInulin on Colonic Nitrogen-Protein Metabolism in Healthy Humans

Pre- and/or probiotics can cause changes in the ecological balance of intestinal microbiota and hence influence microbial metabolic activities. In the present study, the influence of oligofructose-enriched inulin (OF-IN), Lactobacillus casei Shirota, and Bifidobacterium breve Yakult on the colonic fate of NH3 and p-cresol was investigated. A randomized, placebo-controlled, crossover study was performed in 20 healthy volunteers to evaluate the influence of short- and long-term administration of OF-IN, L. casei Shirota, B. breve Yakult, and the synbiotic L. casei Shirota + OF-IN. The lactose[15N,15N]ureide biomarker was used to study the colonic fate of NH3. Urine and fecal samples were analyzed for 15N content by combustion-isotope ratio mass spectrometery and for p-cresol content by gas chromatography-mass spectrometry. RT-PCR was applied to determine the levels of total bifidobacteria. Both short- and long-term administration of OF-IN resulted in significantly decreased urinary p-cresol and 15N content. The reduction of urinary 15N excretion after short-term OF-IN intake was accompanied by a significant increase in the 15N content of the fecal bacterial fraction. However, this effect was not observed after long-term OF-IN intake. In addition, RT-PCR results indicated a significant increase in total fecal bifidobacteria after long-term OF-IN intake. Long-term L. casei Shirota and B. breve Yakult intake showed a tendency to decrease urinary 15N excretion, whereas a significant decrease was noted in p-cresol excretion. In conclusion, dietary addition of OF-IN, L. casei Shirota, and B. breve Yakult results in a favorable effect on colonic NH3 and p-cresol metabolism, which, in the case of OF-IN, was accompanied by an increase in total fecal bifidobacteria.

Transitory Autism
Some people do grow out of their asthma, many people age out of their ADHD and some toddlers’ autism does fade away in early childhood.
I recall the developmental pediatrician who diagnosed my son at 3 years old, telling us that remarkable improvement up to the age of 6 does happen.  That did not happen in our case.
Back in 2015, I highlighted a study from 2002 in Italy where Michele Zappella, an Italian doctor interested in autism and Tourette’s syndrome found that a subgroup of children diagnosed with autism and tics recover by the age of six.

InflammatoryResponse to GAS (Group A Strep) and Dysmaturational Syndrome (Tourette’s Syndrome with Autism “Recovery” by 6 Years Old)

Of course, nobody has bothered to find out why that might be.
We have a small new longitudinal study from UC Davis in Sacramento, which again shows how severity of autism can change from 3 years of age to 6 six years of age.  Intervention made no difference, in spite of what Lovaas told us; so much for “evidence”.

Autism symptom severity change was evaluated during early childhood in 125 children diagnosed with autism spectrum disorder (ASD). Children were assessed at approximately 3 and 6 years of age for autism symptom severity, IQ and adaptive functioning. Each child was assigned a change score, representing the difference between ADOS Calibrated Severity Scores (CSS) at the two ages. A Decreased Severity Group (28.8%) decreased by 2 or more points; a Stable Severity Group (54.4%) changed by 1 point or less; and an Increased Severity Group (16.8%) increased by 2 or more points. Girls tended to decrease in severity more than boys and increase in severity less than boys. There was no clear relationship between intervention history and membership in the groups.

Scatterplot of individual ADOS CSS of all children in the sample at Time 1 and Time 3, by group membership. The DSG and SSG show a large range of individual severity scores at both Time 1 and Time 3 while The ISG shows a narrower range. Note, scores at Time 1 are plotted with jitter so that all individuals can be seen; participants plotted slightly below 4 actually received an ADOS CSS of 4

Optimal Outcome

A total of seven participants, 5.6% of the sample, had an ADOS CSS below the ASD cutoff at Time 3, thus potentially demonstrating optimal outcome. Six of these children were in the DSG (four girls and two boys) and one boy was in the SSG. These children had a mean severity level of 5 at Time 1 (range 4–7) and 1.8 at Time 3 (range 1–3). Their mean severity change was − 3.1 (range − 1 to − 6). All showed an increase in IQ over time, with IQ rising from a mean of 85.8 (range 75–95.8) to a mean of 105.3 (range 91–115). Adaptive functioning change (using the VABS-II composite score) was less consistent, as two children showed decreases and four showed increases over time (one child did not have a score at Time 1). Mean Time 1 adaptive function was 79.3 (range 71–92) and mean Time 3 was 89.6 (range 71–122).

Is Initial Autism Severity a Predictor of Severity Change?

For most children who were participants in this study, their autism symptom severity level at age 3 was not a good predictor of the severity change they underwent during early childhood.

Is Intervention History Associated with Differences in Severity Change?

The large majority of children in the Autism Phenome Project and GAIN study have received substantial amounts of intervention across childhood. Analysis of intervention history (total number of hours of intervention received and intensity of intervention) did not show significant differences between the groups.

Is IQ Associated with Differences in Severity Change?

IQ demonstrated a significant, negative relationship with symptom severity change; as IQ scores increased from age 3 to age 6, symptom severity levels decreased.

How is Adaptive Function Associated with Autism Severity Change?

Adaptive Functioning also demonstrated a significant, negative relationship with severity change. As symptom severity decreased from age 3 to age 6, adaptive functioning increased.

Optimal Outcome and Severity Change over Time

This study was initially motivated by the phenomenon of optimal outcome. Optimal outcome is traditionally defined as a decrease in autism symptoms in individuals previously diagnosed with ASD, so that they no longer meet diagnostic criteria (Fein et al. 2013). A total of seven participants, 5.6% of our sample, received an ADOS CSS below the ASD cutoff (1–3) at Time 3. Six of these children were in the DSG (four girls and two boys) and one boy was in the SSG. Since Optimal outcome is defined based on different aspects of function as well as autism symptom level (Fein et al. 2013), additional evaluations would have to be carried out concerning both the home and educational environments to confirm that these children have actually achieved optimal outcome.
Optimal outcome might also be interpreted more generally as indicating significant intra-individual change rather than the attainment of a specific cut-off score. This definition takes a wider approach to understanding the complex and variable ways in which children with autism grow and develop (Georgiades and Kasari 2018). If we apply this perspective to the current study’s results, the notion of optimal outcome would be relevant to many more children in the DSG who, while not decreasing below the ASD cut-off score, experienced substantial personal decrease in autism severity over time.

Why do some young children have “Transitory Autism”

It has long been known that some toddlers diagnosed with autism have very positive outcomes.

Our Developmental Pediatrician put it down to their brains being so plastic.
Other people think that autism is a hard-wired brain anomaly, fixed for good. 
The reality is that you can both create and then reverse “autism” in many models of autism, so at least some types are not hard wired.

We saw how you can induce autism with propionic acid and then reverse those changes by taking the antioxidant NAC.

If you have a low fiber diet and lack healthy gut bacteria you will produce too much propionic acid, and not enough butyric acid.

People with autism who respond to Rifamixin may be among those who were suffering from too much propionic acid.

It does look like some people’s milder autism is in their gut and that some toddler’s severe autism is made even worse by what is going on in their colon.


Signs of any abnormal GI function should always be investigated in someone diagnosed with autism.  Correcting dysbiosis (impaired microbiota/gut bacteria) should improve autism. Correcting deficiencies in diet should improve autism.  Correcting GI inflammation should improve autism.

Dr Persico clearly would like there to be more testing of P-Cresol in urine, he sees it as a potential biomarker for autism.

Microbiota transplants are not widely on offer, but do appear to be a way to fix problems that you do not need to fully understand.  How many other nasties like P-cresol are there in the autistic person’s gut?  It is certainly conceivable that what therapy works for P-cresol will work for other nasties.

You would hope that all these Italian studies would lead up to a trial of oligofructose-enriched inulin or some probiotic bacteria to see if they can reduce both P-cresol in urine and the severity of autism (ADOS or CARS scales would be fine, Dr Persico).

You would hope that the in microbiota transplant trials in the US they are measuring what changes afterwards, hopefully they read Dr Persico’s research and measure P-Cresol and indeed the SCFAs propionic and butyric acid.

The UC Davis study again shows us that no single intervention is associated with the best outcomes in autism.  The best outcomes just seem to "happen".  They are not the result of any particular early intervention.  That does not mean do nothing, it just means that mainstream autism interventions are not as potent as their advocates keep telling us.  The billions of dollars spent on early intervention and ABA programs may not be the most effective allocation of resources.


  1. We have been in contact 9 days ago with someone who has Covid. My husband developed headaches yesterday and they gave continued today - unusual for him. A glass of red wine improved the headache for a time. This points towards vasoconstriction as cause. It could be the location of his endothelial Covid involvment. I am naturally panicking and thinking what I can do, to help him at first. So far my idea is that he should take NAC, azithromycin, aspirin and vitamin C. Does that make sense to you?

    1. tpes, unless your husband is overweight and with underlying health conditions, you do not have reason to get overly worried.

      My elder son has gone back to socializing with his friends and no surprise after a couple of weeks he picked up a virus. Now I have the same virus. Is it Covid or not? If it is not Covid, am I likely to get Covid anyway by going for a test? I thought I would send my son for the test, but it is not so simple.

      What I have done is wait until there are more symptoms suggestive of covid and then started hydroxychloroquine. I have faith in the Chinese and French researchers.

      If you are healthy you likely need no therapy. If you are a bit older, it makes sense to avoid any chance of even a moderate case, because you do not want any degree of permanent organ damage. That is why I opted to help my body reduce the viral load, which is what hydroxychloroquine and Azithromycin are suggested to do.

      I did not give my elder son any treatment. He still thinks it is OK to meet up with his friends and I am thinking that lockdown is a waste of time if young people are going act like young people always have.

      I am not attempting to lower my temperature, because the research shows your body's elevated temperature reduces the replication of a virus. This is assuming your temperature is not extremely high. Mine went to just 38 degrees.

      Interestingly, high cholesterol allows the virus to more easily enter cells. So having low cholesterol is protective. Statins do seem to reduce covid fatalities, but only in those already taking them.

      In at least half of Covid cases potassium level falls significantly and goes up when you get better. I did start taking my younger son's potassium supplement.

      I did find my old unused pulse oximeter and fitted some new batteries. This is a measure of how much oxygen you have in your blood, if it falls sharply you know there is a problem. Ideally you would know your baseline level. My elder son has 98% which is good and I have 94%. It has to be above 90%.

      I think you could buy one of these and it will put your find at rest, because your husband will likely have a normal reading.

      Of your list, Azithromycin would seem the most beneficial.

      If the disease was to progress to the second stage, that is when the anti-inflammatory drugs are needed.

    2. Well a very recent COVID-19 study here in the USA looking at a control group, Hydroxychloroquine only group, Azithromycin only group, and a Azithromycin plus Hydroxychloroquine group in mortality of hospitalized patients showed that the Hydroxychloroquine only group fared best with the Hydroxychloroquine plus Azithromycin group being second best and the Azithromycin only group being third best and the control group being last in terms of improved mortality. Of course if you pay attention to some news outlets, they try and point out severe heart damage from Hydroxychloroquine which in this particular study found zero heart damage in any of the patients.

      But considering there is a 0.04% mortality rate for those under age 70, you don't have much to worry about unless you are in a high-risk group. Of course cases in the United States are not surprisingly increasing a bunch in the last month due to relaxation of lockdown rules as well as 5% of the population admitting to being part of protests/riots in the last month, but deaths per day keep steadily going down in spite of the dramatic rise in cases. Why is this the case? Well simply put it is my opinion that early in the pandemic, many states actually had deadly policies that dramatically increased the death rate by forcing people to stay indoors with their loved ones, thereby increasing viral load, while at the same time egregiously putting elderly COVID-19 patients in nursing homes under the premise of getting them out of the hospital so that they would not infect others there. Whatever the intent was, it amazingly caused a huge spike in deaths in this group where you had greater than 50% of COVID-19 deaths coming from nursing homes (nationally I think the rate is 40% even though the nursing home deaths vary dramatically from state to state depending on the policies). The survivors of COVID-19 nursing home outbreaks now have immunity so many in the high-risk group either died or are largely immune while the young have been stuck at home playing video games and do not have immunity.

      That being said, since all of the highest risk people have been infected already due to very poor public health policy which employed with worst possible strategy, all of the younger low-risk people getting infected will not die of COVID-19 in sufficient numbers because they are by definition "low-risk". A handful of low-risk patients might feel they need to check themselves into a hospital, but very very few of them will actually die of COVID-19, even though there is a strong financial incentive for hospitals to label COVID-19 deaths from those who had COVID-19 when they died, rather than dying of COVID-19.

    3. In other words, in the USA we employed the reverse rational policy of trying to prevent rapidly building herd immunity among the very low-risk groups (children and young adults), while exposing the elderly in nursing homes to infected COVID-19 patients direct from the hospital, as well as infecting them with zero testing of staff who are often on prison work-release programs in some states and giving them zero PPE gear nor requiring it. Plus, while people can see what is going on with respect to PPE use in your local supermarket, due to social distancing rules, relatives could not check on the staff in nursing homes to see if they are even using good hygiene guidelines or else if those in the nursing home are being abused.

      As a result, we destroyed the economy, have no herd immunity, unnecessarily killed thousands of elderly people who needed protection while some governors were obsessed about policing children playing in their backyard, and now we leave the surviving elderly playing Russian Roulette with COVID-19 in public society indefinitely because herd immunity was never achieved.

      Fortunately, the one silver lining of the mass nationwide protests and riots is it destroyed social distancing so young people can finally get infected and build up herd immunity to protect those at high-risk. There is now a "second-wave" hysteria building by dishonestly presenting statistics that are irrelevant to public health policy such as focusing on "cases" rather than "deaths", but I am not so sure police will enforce that too much now that they have been unreasonably asked to be assaulted by rioters without fear of arrest while at the same time arresting otherwise law-abiding people who don't obey the edicts of their mayors and governors.

    4. Even though much mass media still says there is no evidence to show any benefit from Hydroxychloroquine, here is yet another research paper showing a substantial reduction in mortality.

      Outcomes of 3,737 COVID-19 patients treated with hydroxychloroquine/azithromycin and other regimens in Marseille, France: A retrospective analysis


      In our institute in Marseille, France, we initiated early and massive screening for coronavirus disease 2019 (COVID-19). Hospitalization and early treatment with hydroxychloroquine and azithromycin (HCQ-AZ) was proposed for the positive cases.


      We retrospectively report the clinical management of 3,737 screened patients, including 3,119 (83.5%) treated with HCQ-AZ (200 mg of oral HCQ, three times daily for ten days and 500 mg of oral AZ on day 1 followed by 250 mg daily for the next four days, respectively) for at least three days and 618 (16.5%) patients treated with other regimen (“others”). Outcomes were death, transfer to the intensive care unit (ICU), ≥10 days of hospitalization and viral shedding.


      The patients’ mean age was 45 (sd 17) years, 45% were male, and the case fatality rate was 0.9%. We performed 2,065 low-dose computed tomography (CT) scans highlighting lung lesions in 592 of the 991 (59.7%) patients with minimal clinical symptoms (NEWS score = 0). A discrepancy between spontaneous dyspnoea, hypoxemia and lung lesions was observed. Clinical factors (age, comorbidities, NEWS-2 score), biological factors (lymphocytopenia; eosinopenia; decrease in blood zinc; and increase in D-dimers, lactate dehydrogenase, creatinine phosphokinase, and C-reactive protein) and moderate and severe lesions detected in low-dose CT scans were associated with poor clinical outcome. Treatment with HCQ-AZ was associated with a decreased risk of transfer to ICU or death (Hazard ratio (HR) 0.18 0.11–0.27), decreased risk of hospitalization ≥10 days (odds ratios 95% CI 0.38 0.27–0.54) and shorter duration of viral shedding (time to negative PCR: HR 1.29 1.17–1.42). QTc prolongation (>60 ms) was observed in 25 patients (0.67%) leading to the cessation of treatment in 12 cases including 3 cases with QTc> 500 ms. No cases of torsade de pointe or sudden death were observed.


      Although this is a retrospective analysis, results suggest that early diagnosis, early isolation and early treatment of COVID-19 patients, with at least 3 days of HCQ-AZ lead to a significantly better clinical outcome and a faster viral load reduction than other treatments.

  2. He literally only has a headache but two contacts who have covid who he met 9 days ago. My goal is to keep the covid really asymptomatic if possible. He is optimal weight, no health problems whatsoever. Glad to hear that you and yours are going through this well enough. I will add potassium to his stuff.

  3. Hello Peter and Tpes I want to share with you the channel I've been following, the videos are made by a doctor that attends coronavirus cases in the US and he explains how some treatments work against the virus, he recommends Dr. Seheult's Daily Regimen which is Vitamin D, C, Zinc, Quercetin, NAC. He also talks about the medications that are being used and how they work. I hope everything turns out ok.

    Here is the link:

    Have a nice day.

    1. Interesting. That is almost exactly the regimen I have for my mother as a preventative measure (keep the immune system responsive but excess runaway inflammation at bay).

  4. Hi Peter, hope you and your older son will be fine in these difficult times. Talking about this post is talking about what happens to my son and his kind of autism. We are still struggling with chronic constipation. The more constipated the more autistic (tics, anxiety,etc) he becomes. A new version of Yakult came out with no sugar, edulcorated with sucralose and maltitol. May be it could work to lower p-cresol and help with his chronic constipation.
    All best

    1. Valentina, did you talk to a good dietitian? I would think that constipation is a medical problem that can be solved. The opposite problem is also well known to make autism worse.

    2. Peter, I try to include more fiber, fruit and vegetables but it is difficult to follow a strict diet for life. Besides try to avoid soluble fiber that feeds bacterial overgrowth.

    3. Valentina,
      The balance of carbs and fats in the diet can affect constipation. (many/most?) carbs absorb water in the gut so eating more carbs can cause constipation until the gut adapts and produces more water. (Maybe takes a few days / a week or two) Obviously dehydration can cause problems here as well. Conversely, eating more fat and fewer carbs can produce diarrhea because of the excess water produced by the gut (again, until it adapts to the changed diet).

  5. Peter, do you believe that if Cresol was a problem, and reducing Cresol would help to build dendrites in a 21 year old? How do you know the microbial transplant has the good bacteria that particular person needs? Thanks, Mary

    1. Mary, measuring P-Cresol in urine is a standard lab test. If you are worried about it, you can do the test. If P-Cresol was elevated in a 21 year old, you would expect an improvement after correcting it.

      Using inulin would be simpler/safer than a microbiome transplant. The research showed that P-Cresol disturbed the microbiome and transplanting a "normal" microbiome solved the problem.

      In humans you would need to be sure of what you are are transplanting and I expect this will mean this remains a rare procedure. I think you would want the microbiome of a healthy neurotypical person who eats a varied Mediterranean-type diet; not someone who eats KFC, Mc Donalds and processed pizza.

  6. Peter, what about Ramadan as autism treatment? I'm partly kidding here, but it looks like there are good health reasons to this custom:


    1. Ling, fasting has come up several times before in this blog. Your body have evolved to expect periods of plenty and periods of famine. Fasting does trigger beneficial processes and, assuming you are not anorexic to start with, it is clearly a good thing.

      Modern diet, for many people, involves constant snacking.

      I think fasting would be hard to apply as an autism therapy for children, but it is important to avoid such children becoming obese, as they often are. Living in the US increases your risk of obesity - food is cheap and portions are huge.

  7. Thanks Peter will check on the P-Cresol lab test.If it an issue, he will feel better, but like you have suggested before, the critical time was to recognize this earlier. He def. had gut issues as a youngster and obviously he cognitively would have been better if this were caught earlier. It is about marginal improvement at this stage, which is better than no improvement, not return to full potential.

  8. Fasting makes your body produce stem cells and send them places to repair stuff. which means (and they really do) that stem cells help in autism. Peter, Enrique B from the Autism research coalition is taking his kids for Embrel tomorrow, will let you know how that went.

  9. Hello Peter, I hope you and your family are doing well. My son's GI problem is mostly diarrhea, and other days of constipation but he has been better with verapamil though I believe his gut problems have not been resolved, I committed several mistakes with his food trying to make him healthy meals, when he was 1.8 years I gave him a barley tortillas and he couldn't sleep for days because of the stomach ache, he had many nights like that before he started taking verapamil, he also received antibiotics and paracetamol from a young age. I'd give him yakult almost every day, but I never saw a difference. I came across a study about agave inulin and they found out that only agave inulin makes a certain bacteria that helps diminish inflammation to be more scarce so chicory inulin or other type of might be better. I found also an article about a study with Rifaximin, and it reminded me about your post on Psychobiotics, the effect is very similar to the probiotic PS-128 on social stress, I don't know if the study comes from a reliable source, but I've been thinking about it, and I wanted to ask you what do you think, is there a possibility it could be used low dose long term? or maybe intermittently? I haven't even tried it but it seems very interesting.

    This is the study on Rifaximin:

  10. considering that you don’t write all that much about stem cells and that I have spent a long time researching them, here are my conclusions on them for all readers here: 1. there are several types of stem cells. they all have different ways they act in the body. your best pick is to throw a coin since nobody in the world could tell you what will work for your child. from many hundreds if not thousands of experiences it seems that alternating cord blood with cord tissue is the best. both in the us and in europe there is a lot of availability of cord tissue therapy and very little of cord blood. however, i believe everybody should try it, especially considering that it doesn’t cost the world. 2. if you have gains, they will appear anytime from day one until 6-8 months after. they can really come on quite suddenly after several months when you think nothing happened. there is no telling what the gains would be 3. all stem cell therapies lead to immune suppression which leads to pans like issues and herpes virus reactivation. best is to do some antiviral antibacterial antifungal prophylaxis the first 2 weeks after receiving cells. 4. Duke, which has done so much with stem cells so far in autism, has derived some strange conclusions which are not at all what the community of parents who have used them have noticed. I have naturally read a lot of papers on stem cells and also, due to events surrounding my daughters cord blood, I have talked personally to most of the top researchers in stem cells in the world including dr Kurtzberg. If you have around 2-3 thousands euro/dollars, I would give a commercially available stem cell product like Corecyte, Predictive in the US or stem cell therapy in private clinics in Poland a try.

  11. Dear Peter, I can't thank you enough for your generosity in taking the time to share your knowledge. My son is 11 and is ASD. Just as a background, our approach all these years has been mainly a balanced, very nutritious diet (Weston A Price) limiting gluten/refined carbs, and complementary therapies such as homeopathy and osteopathy. They helped very much in our case and he has been mainstreamed for many years. He still has challenges, particularly socially. I have been researching gut related issues for years (SIBO etc..) as although he has regular BMs (well formed), he must have gut fermentation issues as eating a high glycemic meal causes behaviour changes (the usual silliness commonly associated by lay people with yeast, giggling, etc.). He develops breath that smells of alcohol and does behave like someone who is tipsy. We tried inulin in the past (while trying the Nemechek protocol) for 3 months and ended up stopping because he became slightly rude and antagonistic. I have read many of your articles/searched the site, but if you could please kindly point me to another of your posts about this or if you know anything that could help us help our son and steer in that direction, it would be amazing. GP was absolutely of no help of course. Thank you so much.

    1. Julie, the posts below look at dietary autism and SIBO.

      The wonder therapy for some people is Rifaximin. It is a prescription drug normally given to adults, but it is the standard therapy for SIBO. You could try asking your GP.

      If you are in the UK, you may be able to obtain it from a legitimate online pharmacy, if you complain about traveller’s diarrhea in an adult. Just google “buy rifamixin uk” and you will see several options.

      You just take one course of Rifamixin and see if behaviours improve. You do not need to take it all the time.


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