Eubiotics for GI Dysfunction and some Autism

  

Today’s post is about some drugs/supplements that have already been discussed in earlier posts.  Rifaximin, used in cycles, is an effective part of our reader Maja’s therapy, while Sodium Butyrate was highlighted long ago by our reader in Switzerland, Alli.

I had a consultation with a gastroenterologist last week and came away with a prescription for Rifaximin, microencapsulated Sodium Butyrate and Lactobacillus Plantarum 299v. Where we live, these are all inexpensive. Rifaximin is an antibiotic with extra benefits and costs about 7 euros (9 dollars). 

A course of Rifaximin can cost $2,000 in the United States.

I was pleased to read that the private equity owners of a pharmaceutical company that raised the price of a common thyroid drug by 6000% have just been fined $140 million in the UK.

Advanz Pharma and former private equity owners were fined £100m by markets watchdog

Perhaps some of our US readers should query the crazy price of drugs in the US with their congressman? Very many cheap old drugs are ultra expensive in the US, even insulin is over-priced. Not a good model of a market economy. 

 

Eubiotics – a big business

You may very well never have come across the term eubiotic before, but it is already a multi-billion dollar business.  A eubiotic is something that changes the gut microbiome to improve health. The big business to date are additives to animal feed, rather than products for human health.

Eubiotics work for humans as well. Rifaximin is an antibiotic but it also has the additional properties of a eubiotic. 

“These include: modulation of the microflora of the gastrointestinal tract by promoting the growth of Lactobacilli and Bifidobacteria strains (the so-called “eubiotic” effect) as well as modulation of bacterial metabolism, including inhibition of the hydrocarbon-derived pathways.  This drug is also capable of reducing the virulence of enteropathogenic Escherichia coli strains by inhibiting the expression of enterotoxins or adhesive factors. Interestingly, Rifaximin is distinguished by several anti-inflammatory activities mainly exerted by the pregnane X receptor (PXR), expressed primarily in the gastrointestinal tract, the small intestine, and the colon. Due to the activity described above, Rifaximin is called a eubiotic, not an antibiotic.”

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497137/

Rifaximin, like vancomycin, is usually thought of as a GI antibiotic; it stays in your gut and almost none ends up in your blood.  Both drugs are used to kill off bacteria in your gut. This is all vancomycin does, so it is not classed as a eubiotic. Rifaximin, however, goes on to perform further functions as a eubiotic, so it models your gut flora in a beneficial way.

Rifaximin is almost a wonder drug for IBS-D (irritable bowel syndrome with diarrhea).  It is also a common therapy for SIBO (small intestinal bacterial overgrowth), but while it works well for some, it actually makes things worse for some others.

Rifaximin is used both as a therapy for an acute GI problem and preventatively. It can be used in cycles, like a few days every month.

Maja is in a good position, because where she lives Rifaximin costs a few euros/dollars.

People with IBS-D in the United States often cannot afford monthly cycles of Rifaximin.

Other kinds of eubiotics include prebiotics, other probiotics, all kinds of clever fiber, inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS) etc.  I did cover psychobiotics in an earlier post, these are probiotic bacteria that are used to reduce anxiety, ADHD and other psychiatric symptoms.

Psychobiotics (PS128) for Autism, Stereotypy and Sometimes Effective Therapies for what might be SIBO (Rifaximin and Herbal)

  

Sodium Butyrate

Sodium buyrate produces butyric acid when you swallow it.  Butyric acid is what gives rancid butter its smell.  Butyric acid is one of the big eubiotics used in the animal feed industry. I did cover the very old Japanese probiotic MIYAIRI 588 (full name is Clostridium butyricum MIYAIRI 588) a long time ago in this blog.  This probiotic, in use since the Second World War, produces butyric acid in your gut by fermentation.  In Japan this probiotic is used in humans and more recently as an additive to animal feed, to produce healthier, bigger, chickens and pigs. 

Our reader MG in Hong Kong recently reported that MIYAIRI 588 was beneficial in his case. 

My gastroenterologist prescribed me Microencapsulated Sodium Butyrate, which is covered in the research and has encouraging results. When you see the word microencapsulated, you might start feeling some pain developing in your wallet, rather than in your gut, but again, this product called Integra and made in Poland,  was not so pricey - about EUR 10 ($12) for 60 capsules. One capsule contains 150 mg of sodium butyrate in tiny particles covered in triglycerides.  I have no idea if it is going to do me any good, but the research suggests it is beneficial for certain types of GI dysfunction and will strengthen the intestinal gut barrier (the equivalent of the blood brain barrier). 

Butyric acid has several different modes of action, one is as an HDAC inhibitor, which was covered in earlier posts. HDAC inhibitors can change gene transcription, which is potentially very useful, including in the prevention and treatment of some cancers. The potent HDAC inhibitors from cancer therapy show effect in some types of single gene autism.

Autism-Like Social Deficits Reversed by Epigenetic Drug 

There are different classes of HDAC inhibitor and you would need to match the type of autism with the appropriate type of HDAC inhibitor.  Valproic acid is another common HDAC inhibitor sitting on the shelf of many people with autism plus epilepsy. 

Lactobacillus Plantarum 299v 

Lactobacillus plantarum 299v has been shown to improve symptoms of IBS (Irritable Bowel Syndrome).  It prevents Clostridium difficile-associated diarrhea among patients receiving antibiotic treatment.  It is also known to be immunomodulatory, shifting the balance away from pro-inflammatory cytokines.

The role of Lactobacillus plantarum 299v in supporting treatment of selected diseases 

Alterations in composition of human gut microbiome can lead to its dysbiosis. It is associated with gastrointestinal side effects during anti-cancer treatment, antibiotics administration, or infectious agents. There are studies confirming positive effect of consuming Lactobacillus plantarum 299v on intestinal microflora. This review summarizes the current knowledge about the role of L. plantarum 299v in supporting treatment of selected diseases, such as cancer, irritable bowel syndrome (IBS), and Clostridium difficile infection. The immunomodulating properties of L. plantarum 299v include an increase in the level of anti-inflammatory cytokines, which reduce the risk of cancer and improve the efficacy of regimens. The intake of L. plantarum 299v provides benefits for IBS patients, mainly due to normalization of stool and relief of abdominal pain, which significantly improves the quality of life of IBS patients. In addition, the intake of L. plantarum 299v prevents C. difficile-associated diarrhea among patients receiving antibiotic treatment. Due to the limited possibilities of treating these diseases and numerous complications of cancer treatment, there is a need for new therapeutic strategies. The administration of L. plantarum 299v seems to be useful in these cases. 

 

Bacteria could aid autistics

Might a daily dose of friendly bacteria help treat autism? UK researchers hope probiotics will soothe the gut problems linked to autism and may even ease psychological symptoms. They are planning a clinical trial to test the idea.

The proposed health benefits of probiotic bacteria are well known. The beneficial bugs are thought to out-compete other gut bacteria that can cause diarrhoea and ill health.

Children with autism are known to have higher levels of one group of 'bad' bacteria, Clostridia, in their guts, explains Glenn Gibson from the University of Reading. So he hopes probiotic food supplements that lower levels of Clostridia will allay some symptoms of autism.

He is not suggesting that the bad bacteria cause autism: genetic and environmental factors are both likely to contribute to the complex disorder, the cause of which is unknown. But toxic by-products of the bacteria may be absorbed into the blood and travel to the brain, where they may play a role in ill health.

At present, the researchers are honing their choice of bacteria. There are many different types of good bacteria, so it is important to choose one that can compete effectively against Clostridia.

One candidate, called Lactobacillus plantarum 299v, looks especially promising. The bacterium binds to the gut lining and stimulates its growth. As well as out-competing other bacteria, it also lowers gut pH, which helps the digestive tract to fight infection. It stays in the gut for days and has never been associated with any health problems.

 

Conclusion

I am always surprised how many common drugs that you come across have potential to be repurposed to benefit  some people with autism.

It really shows how effective therapy, for at least some people with autism, is already in the medicine cabinet at home, or more likely over at the grandparents’ house.

(statins, calcium channel blockers, asthma/COPD drugs, other blood pressure drugs, diuretics, type 2 diabetes drugs)

I thought my gastroenterologist’s therapy was quite enlightened. I hope his diagnosis is accurate; I am not entirely convinced, but time will tell.  The diagnosis from doctor number one was kidney stones and now I am on doctor number three. An accurate diagnosis is not always a simple matter, as autism parents know only too well.

I did meet Dr Federico Balzola a while back. He is an Italian gastroenterologist with a keen interest in autism. He is an associate of Dr Arthur Krigsman, a US gastroenterologist heavily involved with autistic patients. In some countries the connection between GI problems and autism is still a taboo subject, seemingly because Dr Andrew Wakefield was a gastroenterologist.  

 

I am always surprised how many young Aspies have symptoms of IBS or IBD. I would actually like to know if this is mainly a problem in childhood and adolescence, which I suspect is the case. 

One of my most popular posts was another one about gastroenterology, which really surprised me.

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

 

FMT (Fecal Microbiota Transplantation) Super-donors and Abandoning the “One Stool Fits All” Approach

Not all stools were created equal

There was a comment recently left on this blog posing the question of what makes a good donor for FMT (Fecal Microbiota Transplantation), or a “poop transplant” in plain English.

FMT is actually an approved therapy for Clostridioides difficile infection (CDI). Research has shown  FMT to be more effective than the antibiotic vancomycin. To quote from the research, “The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin”.

FMT might not be for discussion at the dinner table, but it is highly effective in some instances.

FMT is actually far more widely used than you might imagine.  In one of today’s papers from China they had treated 1,387 people using 20 donors, for a wide variety of conditions.

In the US, autism researchers at Arizona State University showed a benefit that was maintained after a period of two years.

Autism symptoms reduced nearly 50 percent two years after fecal transplant

At two years post-treatment, most of the initial improvements in gut symptoms remained. In addition, parents reported a slow steady reduction of ASD symptoms during treatment and over the next two years. A professional evaluator found a 45% reduction in core ASD symptoms (language, social interaction and behavior) at two years post-treatment compared to before treatment began.

An earlier study with only vancomycin (an antibiotic) had found major temporary improvements in GI and autism symptoms, but the benefits were lost a few weeks after treatment stopped despite use of over-the-counter probiotics.

The obvious question to ask is whether FMT has a potential benefit to people with autism who do not have GI dysfunction.  I think this question is far from being answered.

We have seen in earlier posts that modifying the microbiome has great potential to fine-tune the function of the brain.  Researchers at UCLA showed that the high fat ketogenic diet controls epileptic seizures not through the action of ketones in the brain, but via the high fat intake changing the mix of bacteria in the gut.

The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet

FMT is just one way to modify the microbiome.  The UCLA researchers are developing a medical food to produce similar effects on the microbiome as the ketogenic diet.

Very likely a personalized bacteria transfer, customized to the symptoms of the person, might effectively treat many more conditions than just GI problems.  

It does look likely that for some conditions there may be super-donors, people whose microbiome is particularly effective, when transferred to others.

But the research cautions against what is called the “One Stool Fits All” Approach.  The donor and recipient need to be “compatible”.

The Super-Donor Phenomenon in Fecal Microbiota Transplantation

The microbial diversity of the donor is a good predictor of FMT success in the recipient. However, donor-recipient compatibility also plays an influential role in determining FMT success. Donor-recipient compatibility can stem from genetic factors such as differences in innate immune responses, or environmental factors including diet, xenobiotic exposure, and microbial interactions.

FMT for Inflammatory Bowel Disease (IBD): The Emergence of the FMT Super-Donor

IBD encompasses both Crohn's disease and ulcerative colitis; two debilitating disorders characterized by chronic relapsing inflammation of the intestinal. In contrast to CDI, there is no evidence that IBD results from an overgrowth of one specific pathogen. Rather, the disease is likely brought on by complex interactions involving the host's genetics, immune system, and gut microbiota. Both Crohn's disease and ulcerative colitis are broadly characterized by a reduced diversity of the gut microbiota with lower relative abundances of the Bacteroidetes and Firmicutes phyla and higher proportions of Proteobacteria. A specific reduction in the abundance of butyrate-producing bacterial species, particularly Faecalibacterium prausnitzii, has been observed for both Crohn's disease and ulcerative colitis. Meanwhile, for Crohn's disease, an increase in a pro-inflammatory form of Escherichia coli has also been reported.

The first successful case report of an FMT for the treatment of IBD was published in 1989 when a male with refractory ulcerative colitis achieved clinical remission for 6 months following a retention enema with healthy donor stool. Subsequently, a large number of FMT studies have been conducted on IBD patients with variable clinical outcomes, remission rates, and longevity of effect. Recently, Paramsothy et al. performed a systematic review and meta-analysis of 53 studies (four RCT, 30 cohort, 19 case studies) of FMT in IBD patients. Avoiding publication bias, their analysis of cohort studies revealed FMT was more effective at inducing remission in Crohn's disease patients when compared to patients with ulcerative colitis (52 vs. 33%, respectively). With regard to ulcerative colitis, a larger number of FMT infusions and a lower gastrointestinal tract administration were associated with improved rates of remission.

In contrast to studies of CDI, FMT studies conducted on IBD patients have frequently identified differential recipient responses that have been associated with variability in the donor stool. Currently, the stool used for FMT is not standardized in terms of donor selection (related vs. unrelated), preparation (fresh vs. frozen, aerobic vs. anaerobic), or the dose that is administered (single vs. multiple doses). While inconsistencies in FMT protocols make it difficult to compare different studies, there is a large degree of variability in clinical responses to FMT between recipients who have been subjected to the same study design. It is unfortunate that information on a recipient's genetic background or dietary intake is not yet routinely assessed, particularly given that some instances of IBD have an underlying genetic component. Due to the lack of genetic information, investigators have instead focused on the donor-dependent effect and proposed the existence of so called super-donors to explain the variation in recipient responses.

The first study to record the super-donor effect was a randomized control trial that was investigating the efficacy of FMT for inducing clinical remission in patients with ulcerative colitis. Moayyedi et al. assigned 75 patients with active disease to weekly enemas containing either fecal material or water (placebo) for a period of 6 weeks. FMT was shown to be superior to the placebo, resulting in significantly higher rates of endoscopic and clinical remission, albeit of modest effect (24 vs. 5%, respectively), after 7 weeks. Of the nine patients who entered remission, seven had received FMT from the same donor. Thus, it was argued that FMT success was donor-dependent.

Currently, it is not possible to predict the clinical efficacy of a donor before FMT in IBD patients. It has been suggested that remission rates could be improved by pooling donor's stool together, limiting the chances a patient will receive only ineffective stool. This stool pooling approach was recently investigated on an Australian cohort of 85 mild to moderate ulcerative colitis patients, in the largest randomized control trial of FMT for IBD to date. Rather than receiving FMT from just one donor, patients in the treatment arm were administered a stool mixture that contained contributions from up to seven different donors with the hope that donor-dependent effects could be homogenized. In addition to this, a far more intensive dosing program was adopted with an initial FMT delivered by colonoscopy that was followed by fecal enemas, five times a week for 8 weeks. Despite the multi-donor and intensive dosing approach, Paramsothy et al. achieved post-FMT remission rates (FMT, 27% vs. placebo, 8%, p = 0.02) that were similar to those reported previously. Notably, however, both clinical and endoscopic remission were required for primary outcome achievement in this study, whereas previous studies have mostly focused on either endoscopic or clinical remission rates alone. The pooled stool mixture was demonstrated to have higher microbial diversity than individual stool alone based on OTU count and phylogenetic diversity measures. Subsequent analysis of the different stool batches discovered that one donor appeared to exhibit a super-donor effect. Specifically, patients that received FMT batches that contained stool from this one donor exhibited a higher remission rate than those whose FMT batches did not include the super-donor (37 vs. 18%, respectively).

FMT for Other Disorders: Is There Also a Super-Donor Effect?

Evidence of FMT super-donors in other disorders outside of IBD is currently lacking. Case series and reports limit the capacity to identify super-donor effects because of limited sample sizes. However, despite the lack of large cohort studies, several studies have hinted at the possibility of a donor-dependent effect on FMT outcome. For example, in a short-term FMT pilot trial on 18 middle-aged men with metabolic syndrome, FMTs from lean donors (allogenic FMT) were found to correspond with a 75% increase in insulin sensitivity and a greater diversity of intestinal bacteria in the recipient compared to autologous FMTs (recipient-derived). It was later noted that the patients who experienced a more robust improvement of insulin sensitivity post-FMT had all been in receipt of the same donor. In a subsequent study on 38 Caucasian men with metabolic syndrome, lean donor FMT also resulted in a significant improvement in peripheral insulin sensitivity at 6 weeks. However, this effect was lost by the 18 week follow up. For the allogenic FMT, 11 lean donors were used, seven of which were used for more than one recipient. Whilst donor-dependent effects were not reported, the authors noted that the “multiple fecal donors might explain the transient and variable effects seen in the allogenic group.” As FMT research in this field progresses from small-scale case series to larger-scale randomized placebo controlled clinical trials, it remains to be seen whether the super-donor phenomenon generalizes to other conditions outside of IBD.

Abandoning the “One Stool Fits All” Approach

Microbial dysbiosis is a blanket term for an unhealthy or imbalanced gut community. As such, the population structure that is considered to represent microbial dysbiosis is variable between different disorders. Moreover, the microbiome deficit of one individual may not necessarily mirror that of another individual and therefore it is not surprising that patients respond differently to FMT. As more FMT-related clinical and microbial data are generated, it is becoming clear that “one stool does not fit all” in the context of treating chronic diseases with microbial dysbiosis. Equally so, the selection of donors based solely on clinical screening guidelines provides no guarantee of FMT success. It appears a patient's response to FMT predominantly depends on the capability of the donor's microbiota to restore the specific metabolic disturbances associated with their particular disease phenotype. If this is true, a donor-recipient matching approach, where a patient is screened to identify the functional perturbations specific to their microbiome, may be the best way forward. The patient could then be matched to a specific FMT donor known to be enriched in taxa associated with the metabolic pathway that needs to be restored. Immune tolerance screening would also be beneficial for reducing the impact of donor-recipient incompatibilities stemming from underlying differences in innate immune responses.

Framework for rational donor selection in fecal microbiota transplant clinical trials

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact.

Association Between the Clinical Efficacy of Fecal Microbiota Transplantation in Recipients and the Choice of Donor

Objective: To examine the association between the clinical efficacy of fecal microbiota transplantation (FMT) in recipients and the choice of donor, and to observe the characteristics of intestinal flora and metabolites among different donors. 

Methods: A retrospective case-control study was conducted. Donor whose feces was administrated for more than 30 recipients was enrolled. Data of 20 FMT donors and corresponding recipients at Intestinal Microecology Diagnosis and Treatment Center of the Tenth People's Hospital from October 2018 to December 2019 were collected retrospectively.

During follow-up, the efficacy of each recipient 8-week after FMT treatment was recorded and analyzed. Based on the efficacy of each donor, the donors were divided into three groups.Association of the efficacy of each donor group with the morbidity of complications, and association of efficacy of recipients with donors were analyzed. The evaluation indicators of FMT efficacy included objective clinical effectiveness and/or subjective effectiveness. Objective effectiveness indicated clinical cure plus clinical improvement, and subjective effectiveness indicated marked effectiveness plus medium effectiveness through questionnaire during follow-up. 

Results: A total of 1387 recipients were treated by 20 donors, including 749 cases of chronic constipation, 141 cases of chronic diarrhea, 107 cases of inflammatory bowel disease (IBD), 121 cases of irritable bowel syndrome (IBS), 83 cases of autism, and 186 cases of other diseases, such as radiation bowel injury, intestinal pseudo-obstruction, paralytic intestinal obstruction, functional bloating and allergic diseases. There were 829 cases, 403 cases, and 155 cases in high efficacy group, moderate efficacy group and low efficacy group respectively. Baseline data among 3 groups were not significantly different (all P> 0.05).

In comparison of bacterial abundance (operational taxonomic unit, OTU) among different effective donor groups, the high efficacy group was the highest (330.68±57.28), the moderate efficacy group was the second (237.79±41.89), and the low efficacy group was the lowest (160.60±49.61), whose difference was statistically significant. 
In comparison of butyric acid content among three groups, the high efficacy group had the highest [(59.20±9.00) μmol/g], followed by middle efficacy group [(46.92±9.48) μmol/g], and the low efficacy group had the lowest [(37.23±5.03) μmol/g], whose difference was statistically significant (F=10.383, P=0.001). The differences of acetic acid and propionic acid among three groups were not statistically significant (all P>0.05). A total of 418 cases developed complications (30.1%). Morbidity of complication in low efficacy group, moderate efficacy group and high efficacy group was 40.6% (63/155), 30.0% (121/403) and 28.2% (243/829) respectively, and the difference was statistically significant (χ(2)=9.568, P=0.008). The incidence of diarrhea in low efficacy group, moderate efficacy group and high efficacy group was 7.1% (11/155), 4.0% (16/403) and 2.8% (23/829) respectively, and the difference was statistically significant (χ(2)=7.239, P=0.027). Comparing the incidences of other types of complications, no statistically significant differences were found (all P>0.05). Follow up began 8 weeks after the FMT treatment. The total follow-up rate was 83.6% (1160/1387). The overall effective rate 58.3% (676/1160). Effective rates of various diseases were as follows: chronic constipation 54.3% (328/604), chronic diarrhea 88.5% (115/130), IBD 56.1% (55/98), IBS 55.1% (59/107), autism 61.6% (45/73), and other diseases 50.0% (74/148). Comparing the effective rate of three groups of donors for different diseases, there was no statistically significant difference in chronic diarrhea (P>0.05); there was a positive correlation trend in IBD, IBS and autism, but the differences were not statistically significant (all P>0.05). For chronic constipation and other diseases, high efficacy group had the highest effective rate [65.0% (243/374) and 63.2% (55/87)], followed by moderate efficacy group [49.4% (86/174) and 38.1% (16/42)], and low efficacy group had the lowest [16.1% (9/56) and 15.8% (3/19)], whose differences were significant (all P

Conclusions: Different donors have different efficacy in different diseases. Chronic constipation, radiation bowel injury, etc. need to choose donors with high efficacy. IBD, IBS and autism may also be related to the effectiveness of donors, while chronic diarrhea is not associated to the donor. The efficiency of the donor is negatively correlated to the morbidity of complications. The abundance and diversity of intestinal flora and the content of butyric acid may affect the efficacy of the donor.

Conclusion

FMT in practice today does look rather primitive, but seems to be beneficial more than half of the time, even in autism in the Chinese study.

As expected, different donors have different efficacy in different diseases.  As FMT becomes more popular you would expect that more super-donors will be stumbled upon and then clinicians will have a better chance to match the donor to the recipient.

For certain GI conditions that do not respond well to current drug therapy, FMT does look a good option to investigate.  The level of success is likely to vary depending on the availability and selection of the donor.

It does seem that orally ingested bacteria in the form of probiotics often do not colonize the gut as hoped for, and just past straight through, with only a limited and transient effect.  The fact that FMT can have a very long-lasting effect is remarkable and likely due to the fact that these bacteria are direct from another human.

Modifying the microbiome is only now emerging as a treatment idea and it will take many decades to fully develop it.

Ingesting a mix of another human’s bacteria is not without risk.  

Massachusetts General Hospital oversaw trial that led to the first death from a fecal transplant, a new paper shows

This spring, a 73-year-old man with a rare blood condition became the first person to die from drug-resistant bacteria found in a fecal transplant. New details about that unprecedented incident emerged on Wednesday.

The man was a participant in a clinical trial run at Massachusetts General Hospital and received fecal transplant capsules made in November with fecal material from one stool donor, according to a paper published Wednesday in the New England Journal of Medicine. Tests after the man’s death revealed that material contained a rare type of E. coli bacteria.

FMT seems to be becoming fashionable, with all kinds of people offering it.  The American Journal of Gastroenterology even published a study on Do-it-Yourself FMT. "Almost all indicated that they would perform DIY FMT again, though many would have preferred to have FMT in a clinical setting."  I would vote for the clinical setting and a carefully selected/screened donor. 

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

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-020-00626-0/figures/1

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

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

Gut microbial metabolite p-Cresol promotes autistic-like behaviors in mice through remodeling of the gut microbiota 

Background 

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.

Methods 

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.

Results 

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.

Conclusions 

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.

Urinary p-cresol in autism spectrum disorder.

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.

Urinary p-cresol is elevated in small children with severe autism spectrum disorder.

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.

Slow intestinal transit contributes to elevate urinary p-cresol level in Italian autistic children.

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”.

Trajectories of Autism Symptom Severity Change During Early Childhood

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.

Conclusion

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.