Leukemia, IL-6 IL-10 and an Autism Flare-up

   

Leukemia/Leukaemia  is cancer that begins in the bone marrow and result in high numbers of abnormal white blood cells.

I received a comment on this blog a long time ago from a parent whose child had initially responded well to some of the autism therapies suggested on this blog. Later on all the therapies stopped working.  That child also has leukemia.

We now know this is a common event when you start treating autism, some comorbidity arises that blocks the effects of those therapies.  In my son’s case it is a simple pollen allergy, but it can be all kinds of inflammatory conditions such as colitis, IBS, IBD, GERD, celiac disease, juvenile arthritis, mastocytosis etc.  This list goes on, but now I know why it includes leukemia.

I do not consider epilepsy, or indeed cognitive dysfunction, as comorbidities.  Epilepsy is periodic extreme neuronal hyper-excitability, whereas in much autism there is chronic neuronal hyper-excitability.  Not surprisingly, chronic neuronal hyper-excitability can develop to periodic extreme neuronal hyper-excitability.  So I see epilepsy as a natural progression from childhood autism, but one that perhaps could and should be prevented.

Earlier on writing this blog I thought that genetics and cancer pathways would be beyond its scope, but in apparent absence of anyone much else publicizing the connections with autism I revised my view.

It has been known since 1930 that leukemia is comorbid with Down Syndrome (DS).  DS is caused by caused by the presence of all, or part of a third copy of chromosome 21 this leads to over expression of 300+ genes.  DS is usually easy to diagnose based on physical appearance .  The gene over-expression frequently leads to autistic behaviors and somewhat less frequently to various types of leukemia and in later years early onset Alzheimer’s.  The good news is that DS  children with acute myeloid leukemia (AML), and in particular the acute megakaryocytic leukemia (AMkL) subtype, have exceptionally high cure rates.

The particular gene that is over-expressed in DS and can cause leukemia is called HMGN1.

DS is increasingly rare in Europe, but quite common in the US due to differences in parental choice regarding the termination of pregnancies identified as high risk of Down Syndrome.

I think it only fair to consider leukemia as a possible comorbidity of autism, since may people with DS do indeed exhibit autistic behaviors.

There is no quality data to say how common leukemia is in non-DS autism.

 

Leukemia and Cytokines IL-6 and IL-10

I do consider the pro-inflammatory cytokine IL-6 to be public enemy number one of autism, while the anti-inflammatory cytokine is a potential friend.

There are different types of Leukemia, but it appears that IL-6 and IL-10 play a key role and at least in acute myeloid leukemia can predict the outcome.  Generally speaking leukemia is associated with elevated IL-6 and in particular when there is a relapse.

Acute myeloid leukemia (AML) blast cells frequently produce interleukin-6 (IL-6) 

“Serum levels of Interleukin-6 can be used as prognostic serum markers at diagnosis of adults acute myeloid leukemia and it could be used as follow up parameters for early detection of relapse stage”

Cytokine profiles in acute myeloid leukemia patients at diagnosis: survival is inversely correlated with IL-6 and directly correlated with IL-10 levels

An aberrant production of the pro-inflammatory cytokines IL-6 and TNF-α and the anti-inflammatory cytokine IL-10 is observed in AML patients. Low levels of IL-6 and high levels of IL-10 represent favorable prognostic factors for survival in AML patients. These results support the idea that cytokine deregulation may be useful as a marker for predicting clinical evolution in AML patients.

So we can infer that a leukemia relapse will likely lead to a worsening of autism driven by an elevation in the level of the pro-inflammatory cytokine IL-6.  This would account for why the autism drugs “stopped working” in the case of our reader.

We could then ponder that a therapy that reduces IL-6 and increases IL-10 might help keep some types of leukemia in remission.

This is altering the Th1/Th2 balance which was the target of our reader Alli from Switzerland who did decide to spend many hours reading the oncology research to understand all those cellular signaling pathways.

For those interested in why DS increases the risk of leukemia, scientists at the Dana-Farber Institute in Boston have figured this out, at least in the case of one common form of Leukemia.

Link between Down syndrome, leukemia uncovered

If only some more of the clever people studied autism.

Performances

Nearly all parents like to see their children performing on stage.  

This week I attended two very different performances.

The first was a play organized by my son Monty’s piano teacher; we came along to show support.  She organizes numerous events for children with special needs, she includes people with Asperger’s and all kinds of autism; some have an assistant on stage to support them and some do not.  One was in a wheelchair. She also includes some typical kids in the more demanding roles.  

As expected there were big smiles all around, happy performers and happy friends and family in the audience.  They have several repeat performances.

A couple of days later was another performance, this time Monty’s big brother was performing at the school poetry night.  Here again, the students were performing in front of the assembled parents.  As usual it was poems in a wide variety of languages, from Russian to Indonesian to Swedish.  Some students were showing off by reciting in their third or fourth language.

On the one hand the two performances were very different, because of the different level of ability, but in other ways it shows how everyone enjoys the chance to perform with their friends.

I don’t see Monty enjoying reciting poetry up on the stage, but he would happily play his piano.

Big brother clearly enjoyed reciting his poem in German and next year he will probably choose Russian. While little brother will likely always struggle with spoken language, big brother now speaks five languages.  But he probably would not enjoy having to play the piano up there on stage.

Each to his own and as the student presenter of the poetry night commented, “it beats sitting at home”.

Agenesis of the Corpus Callosum

Today’s post is about another supposedly rare cause of autism called Agenesis of the Corpus Callosum (ACC).

As regular readers of this blog will have noted, extremely rare causes of autism, taken as a group are not so rare after all.  In fact it seems that autism is just a very large collection of somewhat rare biological conditions. 

Of the very few "Autism Dads" I have had a face to face conversation with, one has a child with ACC and another has a son with the even rarer Sotos syndrome. Sotos syndrome is characterized by gigantism, mild ID/MR and often autism. Mutations in the NSD1 gene cause Sotos syndrome

ACC is physical malformation of the brain that shows up clearly on MRI scans and potentially shows up on the mother’s regular ultrasound scans. 

The corpus callosum is a wide, flat bundle of fibers about 10 cm long that connects the left and right sides of the brain.  It facilitates communication between the two sides of the brain.

Agenesis of the corpus callosum (ACC) is a birth defect in which there is a complete or partial absence of the corpus callosum.

ACC leads to behaviors compatible with a diagnosis of autism or Asperger’s in about half of cases.

Symptoms of ACC  vary greatly among individuals, as they do in all types of autism.  Seizures are common, some people have poor motor coordination, and some people are non-verbal.

It is suggested by many that a diagnosis of ACC is not compatible with a diagnosis of autism; this just shows a lack of understanding.

Autism is just a description of behaviors, ACC is a biological diagnosis, like Fragile X syndrome or Down Syndrome.  So if a person has autistic behaviors caused by ACC, it is still autism, it is just autism with an explanation of its origin.

The most famous person with ACC was Kim Peek who was the inspiration for the character played by Dustin Hoffman in the well-known film Rain Man.

In addition to having the physical ACC malformation it has been suggested that the cause of ACC in his case was likely FG Syndrome.

Most mutations that cause FG syndrome can be found in the MED12 gene. However, mutations have also been found in FMR1, FLNA, UPF3B, CASK, MECP2, and ATRX genes. Mutations on these different genes lead to the different types of FG syndrome, all with similar characteristics.  Congenital heart defects are common and Peek died of a heart attack aged 58, outlived by his father.  

Agenesis of the Corpus Callosum and broader Autism

Undoubtedly there are people diagnosed with autism, who have undiagnosed ACC, since they never had an MRI scan.  Just like there are many people with autism who have an undiagnosed, but treatable, Chiari “brain hernia”.

It also appears that having a smaller corpus callosum, but falling short of what would be diagnosed as ACC by the MRI scan, is a feature of some people’s autism. You could consider it as partial ACC, like we had partial biotin/biotinidase deficiency.

A very recent paper from the 2016 Society for Neuroscience annual meeting suggested one reason why autism is more prevalent in males.  The study looked at infecting pregnant rats with group B streptococcus to activate the mothers immune system.  Inflammation was then triggered in the fetal side of the placenta, but only in male fetuses.

The males go on to develop brain and behavioral features reminiscent of autism.

Female fetuses were somehow protected and developed normally.  Hopefully Barons Cohen will read this and stop looking for undiagnosed females with autism. There are many good reasons why autism is less prevalent in females, and they are not just “better at hiding it”, as the so-called expert claims. 

 Placenta may hold clues to sex bias in autism

What is interesting is that in the male pups with “autism” they had an unusually thin corpus callosum. It turns out that such minor malformations occur in broader human autism. 

Lack of corpus callosum yields insights into autism

Autism May Involve A Lack Of Connections And Coordination In Separate Areas Of The Brain, Researchers Find

The largest of the white matter tracts is known as the corpus callosum, which allows communication between the two hemispheres (halves) of the brain.
"The size of the corpus callosum was smaller in the group with autism, suggesting that inter-regional brain cabling is disrupted in autism," Dr. Just said.

In essence, the extent to which the two key brain areas (prefrontal and parietal) of the autistic participants worked in synchrony was correlated with the size of the corpus callosum. The smaller the corpus callosum, the less likely the two areas were to function in synchrony. In the normal participants, however, the size of the corpus callosum did not appear to be correlated with the ability of the two areas to work in synchrony.

"This finding provides strong evidence that autism is a disorder involving the biological connections and the coordination of processing between brain areas," Dr. Just said.

Atypical development of white matter microstructure of the corpus callosum in males with autism: a longitudinal investigation.

CONCLUSIONS:

These longitudinal results suggest atypical early childhood development of the corpus callosum microstructure in autism that transitions into sustained group differences in adolescence and adulthood. This pattern of results provides longitudinal evidence consistent with a growing number of published studies and hypotheses regarding abnormal brain connectivity across the life span in autism.

Comments on this study

The study suggests that white matter abnormalities manifest early in autism, says Thomas Frazier, director of Center for Autism at the Cleveland Clinic in Ohio. “It also serves as a nice demonstration that brain abnormalities in autism will become clearest and most helpful for pointing to etiology when we look at them developmentally, longitudinally, rather than at a single age," he says.

The findings do not imply that corpus callosum abnormalities cause autism, cautions Ralph-Axel Müller, professor of psychology at San Diego State University, who was not involved with the work. Rather, any irregularities in the corpus callosum may stem from other abnormalities in the brain that have been associated with autism, Müller says.

Still, changes in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others, Travers says. "Is there some aspect of white matter micro-structure occurring early in the developmental pathology that locks in persistent autism across the lifespan? What are the mechanisms? Can they be unlocked?” she says. “These will be important questions for future research.”

  

Conclusion

It is estimated that at one in 4,000 individuals has a disorder of the corpus callosum. I suspect it is more, but you would need to routinely give MRI scans to people diagnosed with autism to find out.

It is clear that milder disorders of the corpus callosum may be a feature of many people’s autism and those changes over time in the corpus callosum may help to explain why autism symptoms worsen in some individuals and improve in others.

Preventing Auto-Immune Disease and some Autism

Today’s post is another one filling in some gaps in this blog.

I think it is common sense to say that preventing a problem from developing is much wiser than trying to solve it later on.  This is a recurring issue in both life and medicine.

In the research we now see preventative measures developed to reduce the risk of cancer, we also see how some interventions are only effective when started very early.

In the case of autism we have seen than often it is caused by a myriad of factors that by themselves might have been harmless but when taken together are the multiples hits that caused the brain to develop differently.

Much research looks individually at these factors that increase the risk of autism.  In the wider media much disdain is directed to these findings as if each factor is THE cause of autism and how can so many things cause autism.  But by understanding these factors you can then set about countering them.

I did create my simplified schematic to explain classic autism a while back.  It is not perfect but it does illustrate much of what is going on.

I do get occasional questions about reducing the risk of autism.  For example, Monty now aged 13 with ASD, has a big brother and he wants to know.  Our reader, Kritika from India, has also raised this issue.  If you have autism in your family you may well decide you would like to minimize the risk of more cases.

In practical terms, you cannot change your genes or those inherited epigenetic markers.  Maybe this will change in future.  But there are things you can do.

We know that oxidative stress is a driver of much disease including autism.  This can be minimized by lifestyle changes and indeed with a little pharmacological help.

I was interested to see a study that used NAC to treat mothers who suffer unexplained pregnancy loss, the antioxidant showed a “significant increase in the take-home baby rate”.  I was really just looking for safety information.

N-acetyl cysteine for treatment of recurrent unexplained pregnancy loss 

Pregnancy could be associated with a state of oxidative stress that could initiate and propagate a cascade of changes that may lead to pregnancy wastage. This process of oxidative stress may be suppressed by the antioxidant effect of N-acetyl cysteine (NAC). The current study aimed to evaluate the effect of NAC therapy in patients diagnosed with unexplained recurrent pregnancy loss (RPL). The study was a prospective controlled study performed in the Women's Health Centre, Assiut University, Egypt. A group of 80 patients with history of recurrent unexplained pregnancy loss were treated with NAC 0.6 g + folic acid 500 microg/day and compared with an aged-matched group of 86 patients treated with folic acid 500 microg/day alone. NAC + folic acid compared with folic acid alone caused a significantly increased rate of continuation of a living pregnancy up to and beyond 20 weeks [P < 0.002, relative risk (RR) 2.9, 95% confidence interval (CI) 1.5-5.6]. NAC + folic acid was associated with a significant increase in the take-home baby rate as compared with folic acid alone (P < 0.047, RR 1.98, 95% CI 1.3-4.0). In conclusion, NAC is a well-tolerated drug that could be a potentially effective treatment in patients with unexplained RPL.

This then made be recall a US fertility clinic, that our reader Roger once mentioned in a comment.

http://www.preventmiscarriage.com/

http://www.preventautism.com/

“At Braverman Reproductive Immunology, we believe Autism Spectrum Disorder (ASD) and various pregnancy and infertility complications (listed below) appear to have the same cause. In fact, we have found that a large number of patients who present to our center with the below complications already have a child with ASD.

This discovery started us on the journey to see if ASD itself could be prevented while treating other associated conditions. We believe treatment for these common issues will not only prevent the pregnancy complications listed below, but may also prevent ASD in the group of patients that have already had a child with ASD.”

Dr Braverman does not mention oxidative stress, but perhaps he should.

So step one would be to reduce oxidative stress during pregnancy, via lifestyle changes and taking antioxidants.

Step two would be to avoid inflammation, Dr Braverman refers to the link to auto-immune disease and miscarriage/autism.

We know that maternal inflammation is one of the easiest ways to cause autism in mouse models (the MIA model - Maternal Immune Activation).

  

We have some research to show that the risk of auto-immune disease can indeed be reduced and indeed that the risk of progression from minor to more major auto-immune disease can also be minimized.

We even have a tiny study showing that immuno-modulatory therapy using a probiotic during pregnancy can reduce incidence of ADHD and autism. For me ADHD is just a case of autism-lite.

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

Background:

Recent experimental evidence suggests that gut microbiota may alter function within the nervous system providing new insight on the mechanism of neuropsychiatric disorders.

Methods:

Seventy-five infants who were randomized to receive Lactobacillus rhamnosus GG (ATCC 53103) or placebo during the first 6 mo of life were followed-up for 13 y. Gut microbiota was assessed at the age of 3 wk, 3, 6, 12, 18, 24 mo, and 13 y using fluorescein in situ hybridization (FISH) and qPCR, and indirectly by determining the blood group secretor type at the age of 13 y. The diagnoses of attention deficit hyperactivity disorder (ADHD) and Asperger syndrome (AS) by a child neurologist or psychiatrist were based on ICD-10 diagnostic criteria.

Results:

At the age of 13 y, ADHD or AS was diagnosed in 6/35 (17.1%) children in the placebo and none in the probiotic group (P = 0.008). The mean (SD) numbers of Bifidobacterium species bacteria in feces during the first 6 mo of life was lower in affected children 8.26 (1.24) log cells/g than in healthy children 9.12 (0.64) log cells/g; P = 0.03.

Conclusion:

Probiotic supplementation early in life may reduce the risk of neuropsychiatric disorder development later in childhood possible by mechanisms not limited to gut microbiota composition.

The issue, as with NAC during pregnancy, is whether immuno-modulatory therapy is safe.

The study on ADHD and autism was actually a study looking at whether a certain probiotic if given during pregnancy could reduce eczema later on in the child.

  

We also have the studied effect of having a pet dog at home.

House dust exposure mediates gut microbiome Lactobacillus enrichmentand airway immune defense against allergens and virus infection

 

Early-life exposure to dogs is protective against allergic disease development, and dog ownership is associated with a distinct milieu of house dust microbial exposures. Here, we show that mice exposed to dog-associated house dust are protected against airway allergen challenge. These animals exhibit reduced Th2 cytokine production, fewer activated T cells, and a distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii, which itself can confer airway protection when orally supplemented as a single species. This study supports the possibility that host–environment interactions that govern allergic or infectious airway disease may be mediated, at least in part, by the impact of environmental exposures on the gastrointestinal microbiome composition and, by extension, its impact on the host immune response.

One of my views is that by early treatment of autism you may indeed reduce the risk of epilepsy.  The key here is “reduce the risk”, it does not mean there is no risk.  There are likely hundreds of causes of epilepsy, but if you can reduce the incidence by 30+% that would look like a big success to me.

I recall another study that looked at treating people with eczema to see if you could reduce the chance of progression to asthma.  Using Ketotifen the trial showed that it was indeed possible.

Prevention of asthma by ketotifen in infants with atopic dermatitis. 

To evaluate the prophylactic effect of ketotifen against the onset of asthma we selected 121 infants with atopic dermatitis, without any history suggestive of asthma (cough and/or wheezing). Sixty-one children received ketotifen twice daily. Those who weighed less than 14 kg received 0.8 mg; 14 kg or more, 1.2 mg. Sixty children, a placebo syrup indistinguishable from the active syrup. Both groups were followed for 1 year, with bimonthly evaluations. The criteria for onset of asthma were two different episodes of wheezing treated with bronchodilator drugs. Both groups were comparable regarding age, sex, weight, onset, and duration of atopic dermatitis and age at the onset of asthma. During the 1 year study, asthma was observed in eight children of the ketotifen group (13.1%) and in 25 children of the placebo group (41.6%) (P less than .001). Side effects were negligible and routine laboratory tests disclosed no significant alterations. Ketotifen is a very useful drug for prevention of asthma in children with atopic dermatitis and total IgE more than 50 IU/mL.

Somali Autism Clusters

This then takes me back to that issue I looked at long ago, which was the reason for the Somali immigrants to Sweden and US having so many children with autism.  This even got termed the Swedish Disease by the migrants, they claimed to have never seen autism back home in Somalia.

Then we have the hygiene hypothesis which in effect says that, within limits, a little dirt is good for you.

Hormonal Dysfunction

We know that gestational diabetes increases the risk of autism and we also known that the mother being hypothyroid increases the risk.  In some cases the hormone dysfunction is a consequence of the auto-immune dysfunction.

We also know the female hormone progesterone is extremely neuro-protective.  The level of this hormone is supposed to rise during pregnancy.

  

In past times hormones were given to some pregnant mothers, but this went out of fashion.  Perhaps this should be revisited?

Then we have the surge of the hormone oxytocin that the baby is supposed to receive at birth.  This surge may be relevant to the GABA switch when shortly after birth this neurotransmitter is supposed to switch from excitatory to inhibitory as the neurons mature. If the baby is born by Caesarian there will be no oxytocin surge for the baby.   

Preventing Regressive Autism Secondary to Mitochondrial Disease (AMD)

It is on open secret that doctors at Johns Hopkins have identified a variant of regressive autism called Autism secondary to Mitochondrial Disease (AMD).

It remains unclear how rare this is and absolutely nobody serious is going to research this, if they ever want to receive a research grant in the future.

We saw that in people with a genetic predisposition to mitochondrial dysfunction, an immune over-reaction to an insult like multiple vaccinations can trigger mitochondrial disease.  This will present itself as autism and quite possibly severe autism in a previously unaffected child.

Those doctors treating AMD use mild immuno-suppressing drugs before any future vaccinations.

How do you minimize the chance of AMD? 

The first thing is to never use paracetamol/acetaminophen in a baby or child, particularly just after vaccination.  This drug may kill the pain but it depletes GSH the body’s main antioxidant, just when it needs it most.   Use something like Ibuprofen.

Vaccines are given in multiples so as to save time and money and I suppose improve compliance. You might expect giving them one-by-one would actually make them more effective as well minimizing any collateral damage to a small percentage of kids.

Conclusion

As I keep reminding readers, I am not a doctor, but it would be nice if a few more doctors other than Braverman took preventing autism seriously.

I would like to know if progesterone is an effective therapy in the MIA model of autism.  In this model they trigger the mother’s immune system during pregnancy which leads to offspring with autism.  What would be the effect of giving progesterone?  Would it protect the pups?

Are progesterone levels reduced in mice that will become autistic?

So I suppose I would trial NAC and progesterone in the mother mouse.

For everyone else it is case of choosing whether or not to make lifestyle changes to reduce oxidative stress.  Improving gut bacteria can be done via probiotics, eating more (slightly dirty) fruit and vegetables, having a pet dog, spending some time in the nature.  

As for vaccine risk, however small it might indeed be, there will never be a serious investigation of this, for understandable reasons. 

Broccoli Powder without the Taste

In this blog I make a point of not promoting non-generic products, except when they have some special features.  This was the case with sustained release NAC, which does seem to be a much better product than the gelatin capsules.

In the case of broccoli powder and Sulforaphane, there was some testing done that showed most products sold in the US do not actually produce any Sulforaphane.  Small doses of broccoli powder do indeed seem to have a positive effect in some people’s autism and even on insulin sensitivity in people with diabetes.  We assume this is down to sulforaphane, but even that is not certain, there are other interesting substances in broccoli

In the Johns Hopkins research on sulforaphane they use a deep frozen product made in the lab that is not commercially available.  The research was initially in cancer, but does now extend to autism.

We saw in earlier posts that that some broccoli powders have retained the necessary enzymes needed to produce Sulforaphane in your body. You can always add back the enzyme that got destroyed in processing, using Daikon radish, which is similar to what happens in Johns Hopkins lab process.

One producer, whose product I have not used, has come out with a new product that will be interesting to people whose child does not swallow pills and hates the taste of broccoli.

The producer keeps writing to me to tell me that their product produces the most sulforaphane.  What would be nice would be independent testing of several products currently on the market.

EnduraCell  PomGenex 300g Powder

·            “Delicious tasting, all natural blend of three of Nature’s most highly-prized plant foods; Pomegranate Juice, Coconut Water and 100% Whole Nutraceutical Grade Broccoli Sprouts”

Their broccoli powder is called EnduraCell and the more child friendly drink is called PomGenex.

You can buy their products in Australia and from their US distributor.

Anyone trying it is very welcome to leave their feedback here.

Other interesting Probiotic Bacteria for Cholesterol, Osteoporosis, Diabetes, Eczema, Asthma, Cancer and perhaps some Autism

  

In the next 30 to 50 years I think many common diseases will be, in part, treated by bacteria.  There is already a great deal of research to show that gut bacteria play a key role in both some diseases and the effectiveness of some therapies.

I was surprised to read that the effectiveness of some common existing cancer drugs appears to depend on the presence, or not, of specific gut bacteria.

Many gut bacteria have very specific, but different, effects on the immune system.  There may be no one-size-fits-all options and it is not a case of good bacteria and bad bacteria.  Too much of some “good” bacteria and they becomes “bad” bacteria.

Taking a pragmatic approach you can look at the effects of widely available probiotic bacteria and see if any might have a beneficial effect on a specific person’s autism.

We already saw in the trials that people made following Alli from Switzerland’s revelation about the two L.reuteri bacteria found in Biogaia Gastrus, that what is good for one person might not be effective in the next person.

In my case one of the L.reuteri bacteria in Biogaia Gastrus has a profound positive effect on allergy, and hence autism, while the second bacteria has negative behavioral effects.  Fortunately, the L.reuteri protectis bacteria in Biogaia Gastrus can be purchased separately.

Not surprisingly, companies are patenting the bacteria with research-proven therapeutic effects.  Many supplement companies are using the non-patented bacteria because they are cheaper.  Very often they do not specify exactly which sub-type of bacteria they use and you have no means of knowing whether they change the bacteria over time depending on pricing and availability.

Nonetheless if you skim through the probiotic bacteria research and anecdotal evidence there are some interesting options.

 

First a quick recap

So far in this blog we have seen some particularly interesting individual probiotic bacteria:-

Miyairi 588 from Japan produces butyric acid in the gut.  Butyric acid has been shown to have several interesting effects.  It improves immune health and for this reason is included in animal feed.  It has been shown to improve the integrity of gut to avoid “leaky gut”.  It is an HDAC inhibitor which means it may well have epigenetic effects.  It is an alternative to using butyrate supplements.

 Lactobacillus reuteri 17938 (Lactobacillus reuteri Protectis)

This bacteria is the one we are using and it has potent effects on my son’s summertime allergy that makes his autism much worse.

Lactobacillus reuteri ATCC PTA 6475

This is a potent anti-inflammatory bacteria, but its mode of action does not agree with my son, but it seems to do great things for many others.

Viviomixx and VSL#3

We saw that many people with IBS/IBD and some with autism find these two combination bacteria helpful.  Being a mixture of bacteria means that it may be only certain ingredients that have a helpful effect in a specific person with autism.

Many people with types of IBD/IBS do seem to respond well to the combined bacteria found in Viviomixx and VSL#3.

Some other interesting, commercially available, bacteria

I came across several interesting products. 

Lactobacillus reuteri NCIMB 30242

This bacteria is very well researched and has effects on some of comorbidities that effect some people with autism, such as vitamin D metabolism and calcium homeostasis.

As is often the case the benefits mainly relate to the immune system.  This particular bacteria reduces C-reactive protein (CRP) which is a commonly used marked for inflammation.  It reduces “bad” cholesterol and it has an odd effect on vitamin D making it interesting for people with reduced bone density.

I have no idea if it will help some people with autism, but it is very easy to find out since this patented bacteria is available in several products, targeted at your heart, GI or bones but also lightening your wallet.

Given how quick the L.reuteri protectis showed effect (1 day) I only intend to trial NCIMB 30242 for a few days.

Lactobacillus reuteri NCIMB 30242 research

L. reuteri NCIMB 30242: A Probiotic with Benefits

 Objectives

 The objective of this study was to evaluate the effects of probiotic bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 on cholesterol lowering, mechanism of action and gastrointestinal (GI) symptomatology in hypercholesterolemic adults.

Methods 127 subjects consumed either L. reuteri NCIMB 30242 or placebo capsules over a 9-week intervention period in a randomized controlled trial.

Results L. reuteri NCIMB 30242 capsules reduced LDL-cholesterol by 11.6% (P=0.001), total cholesterol by 9.1%, 

Conclusions L. reuteri NCIMB 30242 capsules should be considered as an adjunctive therapy for hypercholesterolemia and may be useful for promoting GI health.

  

Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial.

L. reuteri NCIMB 30242 increased serum 25-hydroxyvitamin D by 14.9 nmol/L, or 25.5%, over the intervention period, which was a significant mean change relative to placebo of 17.1 nmol/L, or 22.4%, respectively (P = .003).

CONCLUSIONS:

To our knowledge, this is the first report of increased circulating 25-hydroxyvitamin D in response to oral probiotic supplementation.

  

Building healthy bones takes guts

Probioticboosts bone density in mice, could point way to new, natural treatments for osteoporosis

  

"We know that inflammation in the gut can cause bone loss, though it's unclear exactly why," said lead author Laura McCabe, a professor in MSU's departments of Physiology and Radiology. "The neat thing we found is that a probiotic can enhance bone density."

In the study, the male mice showed a significant increase in bone density after four weeks of treatment. There was no such effect when the researchers repeated the experiment with female mice, an anomaly they're now investigating.

Lactobacillus Reuteri NCIMB 30350

One reader of this blog is already a fan of Lactobacillus Reuteri NCIMB 30350 which comes from BioAmicus in Canada.

BioAmicus have had feedback from other customers who tried it having read the press reports on Lactobacillus Reuteri and autism.

 They told me:-

“The parents who have seen improvement with BioAmicus Reuteri note eye contact, social activity, language use, as well as improved instruction comprehension.”

They plan to make their own autism clinical trial.

                     https://bioamicus.com/autism-research/

Lactobacillus Johnsonii NCIMB 30351

The next interesting bacteria I came across is Lactobacillus Johnsonii.  There numerous strains.

This bacteria has been shown to be behind why children who live in a house with pet dog are protected from asthma.  Numerous studies like the auto immune disease asthma with increased incidence of autism.

The bacteria is protective against development of another auto immune disease, Type 1 diabetes.

Lactobacillus Johnsonii appears to mediate the effectiveness of some common cancer drugs.

BioAmicus have a Lactobacillus Johnsonii bacteria called NCIMB 30351 usually given to babies.

  

As some readers have already highlighted Lactobacillus bacteria can be used to make all kinds of yoghurt, kefir etc.  So you can grow your own at home to keep the cost down.

Lactobacillus johnsonii research

House dust exposure mediates gut microbiome Lactobacillus enrichment and airway immune defense against allergens and virus infection

Early-life exposure to dogs is protective against allergic disease development, and dog ownership is associated with a distinct milieu of house dust microbial exposures. Here, we show that mice exposed to dog-associated house dust are protected against airway allergen challenge. These animals exhibit reduced Th2 cytokine production, fewer activated T cells, and a distinct gut microbiome composition, highly enriched for Lactobacillus johnsonii, which itself can confer airway protection when orally supplemented as a single species. This study supports the possibility that host–environment interactions that govern allergic or infectious airway disease may be mediated, at least in part, by the impact of environmental exposures on the gastrointestinal microbiome composition and, by extension, its impact on the host immune response.

Research Shows How Household Dogs Protect Against Asthma, Infection

UCLA research suggests that gut bacteria could help prevent cancer

  

The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide

 Cyclophosphamide is one of several clinically important cancer drugs whose therapeutic efficacy is due in part to their ability to stimulate antitumor immune responses. Studying mouse models, we demonstrate that cyclophosphamide alters the composition of microbiota in the small intestine and induces the translocation of selected species of Gram-positive bacteria into secondary lymphoid organs. There, these bacteria stimulate the generation of a specific subset of “pathogenic” T helper 17 (pT_H17) cells and memory T_H1 immune responses. Tumor-bearing mice that were germ-free or that had been treated with antibiotics to kill Gram-positive bacteria showed a reduction in pT_H17 responses, and their tumors were resistant to cyclophosphamide. Adoptive transfer of pT_H17 cells partially restored the antitumor efficacy of cyclophosphamide. These results suggest that the gut microbiota help shape the anticancer immune response.

Lactobacillus Johnsonii N6.2 Mitigates the Development of Type 1 Diabetes in BB-DP Rat

Inhibition of Type 1 Diabetes Correlated to a Lactobacillus johnsonii N6.2-Mediated Th17 Bias

Although it is known that resident gut flora contribute to immune system function and homeostasis, their role in the progression of the autoimmune disease type 1 diabetes (T1D) is poorly understood. Comparison of stool samples isolated from Bio-Breeding rats, a classic model of T1D, shows that distinct bacterial populations reside in spontaneous Bio-Breeding diabetes-prone (BBDP) and Bio-Breeding diabetes-resistant animals. We have previously shown that the oral transfer of Lactobacillus johnsonii strain N6.2 (LjN6.2) from Bio-Breeding diabetes-resistant to BBDP rodents conferred T1D resistance to BBDP rodents, whereas Lactobacillus reuteri strain TD1 did not. In this study, we show that diabetes resistance in LjN6.2-fed BBDP rodents was correlated to a Th17 cell bias within the mesenteric lymph nodes. The Th17 bias was not observed in the non-gut–draining axillary lymph nodes, suggesting that the Th17 bias was because of immune system interactions with LjN6.2 within the mesenteric lymph node. LjN6.2 interactions with the immune system were observed in the spleens of diabetes-resistant, LjN6.2-fed BBDP rats, as they also possessed a Th17 bias in comparison with control or Lactobacillus reuteri strain TD1–fed rats. Using C57BL/6 mouse in vitro assays, we show that LjN6.2 directly mediated enhanced Th17 differentiation of lymphocytes in the presence of TCR stimulation, which required APCs. Finally, we show that footpad vaccination of NOD mice with LjN6.2-pulsed dendritic cells was sufficient to mediate a Th17 bias in vivo. Together, these data suggest an interesting paradigm whereby T1D induction can be circumvented by gut flora-mediated Th17 differentiation.

The effect of Lactobacillus johnsonii Ncc533 (La1) on the balance of Th1/Th2 cells in BALB/c mice

  

 Lactobacillus rhamnosus GG

  
This bacteria has numerous scientifically researched beneficial effects. Most recently it was shown to affect the expression of GABA receptors.  For some people with autism this might be beneficial. In particular it may reduce anxiety, since this was the effect noted in mouse research.

Lactobacillus rhamnosus GG (ATCC 53103) is a strain of L. rhamnosus that was isolated in 1983 from the intestinal tract of a healthy human being; filed for patent on 17 April 1985, by Sherwood Gorbach and Barry Goldin, and the 'GG' derives from the first letters of their surnames. 

The patent refers to a strain of "L. acidophilus GG" with American Type Culture Collection (ATCC) accession number 53103; later reclassified as a strain of L. rhamnosus. The patent claims the L. rhamnosus GG (ATCC 53103) strain is acid- and bile-stable, has a great avidity for human intestinal mucosal cells, and produces lactic acid. Since the discovery of the L. rhamnosus GG (ATCC 53103) strain, it has been studied extensively on its various health benefits and currently L. rhamnosus GG (ATCC 53103) strain is the world's most studied probiotic bacterium with more than 800 scientific studies.

The genome sequence of Lactobacillus rhamnosus GG (ATCC 53103) has been decoded.

Medical research and use

While Lactobacillus rhamnosus GG (ATCC 53103) is able to survive the acid and bile of the stomach and intestine, is claimed to colonize the digestive tract, and to balance intestinal microflora, evidence suggests that Lactobacillus rhamnosus is likely a transient inhabitant, and not autochthonous. Regardless, it is considered a probiotic useful for treatment of various maladies, as it works on many levels. Most of the molecular mechanisms are not known, however.

Peanut allergy

Research is showing that L. rhamnosus as a probiotic could stop allergic reactions to peanuts in 80% of children.

Diarrhea

Lactobacillus rhamnosus GG has been shown beneficial in the prevention of rotavirus diarrhea in children. The prevention and treatment of various types of diarrhea has been shown both in children and in adults.

Respiratory tract infections

L. rhamnosus GG may reduce the risk of obtaining respiratory tract infections in children that attend daycare.

Atopic dermatitis, eczema

Lactobacillus rhamnosus GG also has shown potential in treatment and primary prevention of atopic dermatitis, but the results of intervention trials have been mixed. A clinical trial with seven-year follow-up shows L. rhamnosus GG is useful in the prevention of atopic dermatitis in children at high risk of allergy.

Urogenital tract

The clinical health effects of L. rhamnosus GG have been widely studied. Both L. rhamnosus GG and L. rhamnosus GR-1 appear to protect the urogenital tract by excreting biosurfactants to inhibit the adhesion of vaginal and urinary pathogens.

Intestinal tract permeability

L. rhamnosus has been found to reduce intestinal permeability in children who suffer from irritable bowel syndrome, and it also has been found to counter alcohol-related intestinal permeability.

Gastrointestinal carriage of VRE

In 2005, L. rhamnosus GG was first used successfully to treat gastrointestinal carriage of vancomycin-resistant Enterococcus (VRE) in renal patients.

Anxiety

Research published in the Proceedings of the National Academy of Sciences on August 29, 2011 reported this bacterium may have an effect on GABA neurotransmitter receptors. Mice who were fed L. rhamnosus JB-1 had less anxiety and had different levels of a brain-chemical sensor and stress hormones.

This paper was mentioned previously in this blog

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

There is increasing, but largely indirect, evidence pointing to an effect of commensal gut microbiota on the central nervous system (CNS). However, it is unknown whether lactic acid bacteria such as Lactobacillus rhamnosus could have a direct effect on neurotransmitter receptors in the CNS in normal, healthy animals. GABA is the main CNS inhibitory neurotransmitter and is significantly involved in regulating many physiological and psychological processes. Alterations in central GABA receptor expression are implicated in the pathogenesis of anxiety and depression, which are highly comorbid with functional bowel disorders. In this work, we show that chronic treatment with L. rhamnosus (JB-1) induced region-dependent alterations in GABA_B1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA_Aα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABA_Aα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior. Moreover, the neurochemical and behavioral effects were not found in vagotomized mice, identifying the vagus as a major modulatory constitutive communication pathway between the bacteria exposed to the gut and the brain. Together, these findings highlight the important role of bacteria in the bidirectional communication of the gut–brain axis and suggest that certain organisms may prove to be useful therapeutic adjuncts in stress-related disorders such as anxiety and depression.

Weight loss

Research published in the British Journal of Nutrition in 2013 suggests that Lactobacillus rhamnosus CGMCC 1.3724 may increase weight loss in women who are dieting. The research was initiated after several studies showed that the gut bacteria in obese individuals differs significantly from those in thin people. Women in the study lost nearly twice the weight that the placebo group lost. No difference was observed in men, however.

Risks

The use of L. rhamnosus GG for probiotic therapy has been linked with very rare cases of sepsis in certain risk groups, primarily those with a weakened immune system and infants. Ingestion of L. rhamnosus GG is, nevertheless, considered to be safe, and data from Finland show a significant growth in the consumption of L. rhamnosus GG at the population level has not led to an increase in the number of Lactobacillus bacteraemia cases.

Probiotic Lactobacillus Probiotic rhamnosus downregulates FCER1 and HRH4 expressionin human mast cells

Abstract

AIM: To investigate the effects of four probiotic bacteria and their combination on human mast cell gene expression using microarray analysis.

METHODS: Human peripheral-blood-derived mast cells were stimulated with Lactobacillus rhamnosus (L. rhamnosus) GG (LGG^®), L. rhamnosus Lc705 (Lc705), Propionibacterium freudenreichii ssp. shermanii JS (PJS) and Bifidobacterium animalis ssp. lactis Bb12 (Bb12) and their combination for 3 or 24 h, and were subjected to global microarray analysis using an Affymetrix GeneChip^® Human Genome U133 Plus 2.0 Array. The gene expression differences between unstimulated and bacteria-stimulated samples were further analyzed with GOrilla Gene Enrichment Analysis and Visualization Tool and MeV Multiexperiment Viewer-tool.

RESULTS: LGG and Lc705 were observed to suppress genes that encoded allergy-related high-affinity IgE receptor subunits α and γ (FCER1A and FCER1G, respectively) and histamine H4 receptor. LGG, Lc705 and the combination of four probiotics had the strongest effect on the expression of genes involved in mast cell immune system regulation, and on several genes that encoded proteins with a pro-inflammatory impact, such as interleukin (IL)-8 and tumour necrosis factor alpha. Also genes that encoded proteins with anti-inflammatory functions, such as IL-10, were upregulated.

CONCLUSION: Certain probiotic bacteria might diminish mast cell allergy-related activation by downregulation of the expression of high-affinity IgE and histamine receptor genes, and by inducing a pro-inflammatory response.

Bifidobacterium Infantis 35624 

Bifidobacterium infantis 35624  is marketed in the US by Proctor & Gamble, while in Europe it is sold by the Irish developer.

It is well researched and does have effects beyond the gut.

Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut

Certain therapeutic microbes, including Bifidobacteria infantis (B. infantis) 35624 exert beneficial immunoregulatory effects by mimicking commensal-immune interactions; however, the value of these effects in patients with non-gastrointestinal inflammatory conditions remains unclear. In this study, we assessed the impact of oral administration of B. infantis 35624, for 6‒8 weeks on inflammatory biomarker and plasma cytokine levels in patients with ulcerative colitis (UC) (n = 22), chronic fatigue syndrome (CFS) (n = 48) and psoriasis (n = 26) in three separate randomized, double-blind, placebo-controlled interventions. Additionally, the effect of B. infantis 35624 on immunological biomarkers in healthy subjects (n = 22) was assessed. At baseline, both gastrointestinal (UC) and non-gastrointestinal (CFS and psoriasis) patients had significantly increased plasma levels of C-reactive protein (CRP) and the pro-inflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) compared with healthy volunteers. B. infantis 35624 feeding resulted in reduced plasma CRP levels in all three inflammatory disorders compared with placebo. Interestingly, plasma TNF-α was reduced in CFS and psoriasis while IL-6 was reduced in UC and CFS. Furthermore, in healthy subjects, LPS-stimulated TNF-α and IL-6 secretion by peripheral blood mononuclear cells (PBMCs) was significantly reduced in the B. infantis 35624-treated groups compared with placebo following eight weeks of feeding. These results demonstrate the ability of this microbe to reduce systemic pro-inflammatory biomarkers in both gastrointestinal and non-gastrointestinal conditions. In conclusion, these data show that the immunomodulatory effects of the microbiota in humans are not limited to the mucosal immune system but extend to the systemic immune system.

The research highlighted by Proctor & Gamble is here:-

http://www.bifantis.com/probiotic-scientific-data.php

The product is sold as Alflorex in Europe and Align in the US.

               http://www.alimentaryhealth.ie/products/Alflorex

Conclusion

One big issue with all probiotics is just how potent they are when you actually consume them, rather than when they are manufactured.

Most people are taking probiotics for very general reasons, but people with IBS/IBD are a group who have very specific problems.  VSL#3 and Viviomixx do seem to be the probiotics of choice among those with IBS/IBD.

For allergy and atopic dermatitis some people clearly benefit from specific probiotics such as Bifidobacterium lactis BB-12 and Lactobacillus GG, but not all people respond.

Lowering cholesterol by probiotic is very easy to verify, so I presume it really must work in some cases.

Generally reducing colic, reflux, gas etc. in babies is a claim made for numerous probiotics.

You could spend a vast amount of money on probiotics for autism and it really is only worth using one(s) that have a genuine impact.

It would be useful to collect some data on what dosage is required when somebody actually does respond behaviourally to a probiotic.  Thanks to Alli and other readers I think we have the data on Biogaia products.

So far only one reader has given feedback on Lactobacillus Reuteri NCIMB 30350 (Bioamicus), but it was positive. The people at BioAmicus in Canada are very interested to know if their products are effective in some autism.

There are many people in the US using Culturelle for kids with autism, but I did not see any rave reviews.  Probably it is used for GI problems rather than to improve autism itself.

It does depend a lot where you live, how easy it is to access specific probiotics at a reasonable price.  Some are much cheaper in the US and some cheaper in Europe.

My current list of potentially interesting probiotics is:-

I really never expected to be writing about the merits of probiotics. It was a big surprise to learn that Miyiari 588 is put in animal feed to improve immune health via increasing the SCFA (short chained fatty acid) butyric acid.  Butyric acid is relevant to autism.  It was a bigger surprise to see L.reuteri Protectis reduce my son’s troublesome pollen allergy and changed the colour of his nose.

It is worthwhile doing some experimentation to see what, if anything, actually is helpful.

There are sound reasons why some people with autism may respond to one of the above bacteria.  As of now though, Biogaia is the probiotic of choice to try first, since many people with autism respond well.

All positive and negative feedback on these, or any other probiotic bacteria is very welcome.