Probiotics – Science and Pseudoscience

Once anyone starts to make claims that some autism is treatable, people respond in different ways.  Those applying what has always been taught in medical school, that autism is untreatable,  will either think you are making it all up, or worse, you are some evil person taking advantage of parents in emotional distress.

The very few people who read the research about things like metabolic errors and intracellular signaling may well take a different view. Also the oncology/cancer researchers who themselves think about sub-types of disease that are induced by specific signaling pathways (like RAS-induced cancers for example), may well see the sense in experimentation like that in this blog.

Medicine does indeed say that autism, Down Syndrome and ID/MR are untreatable; however current science does not support this.  Your local doctor applies medicine; he is likely totally out of his depth when it comes to where science is in 2016.

My posts are just my take on the science, I am well aware that some clever neurologists have looked at this blog and think it is all fantasy.  The doctors who have a child with autism and read this blog tend to look from a different perspective and with a much more open mind.  Once you find one therapy that is truly effective, bumetanide in our case, then there can be no turning back.

There are all kinds of diets, supplements and therapies promoted by various people, I wish them all well.

The problem any future science-based autism clinicians will have is that they inevitably get mixed up with other types.  In the US they already go to the same autism conferences, which surprises me. People then think, "Oh well if Professor X is here from Ivy League college Y, then everyone must be legit".  Big mistake. You need to be on really top form to separate out all the pseudoscience, and on occasion you may get it wrong. 

Probiotics

I used to be a skeptic of probiotic bacteria, that is until I was prescribed some little glass vials about a dozen years ago.  I had some side effect from an antibiotic prescribed for an ear infection.  I still recall the ENT doctor calling out (not in English) and asking what to prescribe for the GI side effects.  When I took his prescription to the pharmacy I received a pack of glass vials and a small saw blade.  You used the saw to cut the neck of the vial then you added water to the white fungus growing in the vial and poured into a glass of water, which you then drank.

It most definitely worked.

Even today when I tell my doctor relatives in the UK that probiotics work wonders for diarrhea, all I get is strange looks.

So I am already sold on the fact that probiotic bacteria can do great things for stomach problems.

I spoke to a friend in Denmark this week who has been ill much of the year and finally his problems have been diagnosed as stemming from Ulcerative Colitis.  His first symptom was actually a blood clot.  It turns out that inflammatory bowel diseases (IBD), like ulcerative colitis, increase your risk of blood clots.

So I told my friend to read up on VSL#3 and Viviomixx, which do seem to help IBD, and also to read up on melatonin in the IBD research.

Probiotics and Inflammatory Disease

Looking at immune health more generally we saw how the probiotic Miyairi 588 is used to produce butyric acid which can improve immune health.  This is why cost conscious farmers put it in their animal feed to produce healthier, faster growing animals.

We saw that an alternative is just to add sodium butyrate to the food.  This is done is both livestock and some humans.

Butyrate is an HDAC inhibitor and so is thought to have epigenetic effects.

Probiotics and the Brain

You might be able to convince your doctor that a probiotic bacterium can be good for your stomach, but would you convince him that it could be good for the brain?

I must admit I also would like to see some scientific evidence, beyond anecdotes - even my own anecdotes.

So finally today’s featured scientific study:-

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.

The study is interesting because it shows that a bacterium can modify GABA subunit expression in the brain, but when the vagus nerve is removed the effect is lost.  So it is pretty likely that in humans the vagus nerve is the conduit to the brain, as has many times been suggested, but here we have some pretty conclusive supporting evidence.

For a less science heavy explanation of the study:-

Belly bacteria boss the brain

Gutmicrobes can change neurochemistry and influence behavior

I did a post about the vagus nerve a while back and there is an easy to read article here:-

Viva vagus: Wandering nerve could lead to range of therapies

My old posts:-

The Vagus Nerve and Autism

Cytokine Theory of Disease & the Vagus Nerve

Conclusion

Individual GI bacteria have very specific effects.  In people with neurological dysfunctions the possibility genuinely exists to delivery therapies to brain via the gut.  This might have been seen as pseudoscience a decade ago, but now it is part of science, but not yet medicine.

Many other clever things going on in your gut.  The long awaited CM-AT pancreatic enzyme therapy, from a company called Curemark, is now entering its phase 3 trial (thanks Natasa). Click below. 

Blüm is the study of CM-AT, a biologic, for the treatment of Autism.

  

The Curemark lady, Joan Fallon, has collected numerous patents regarding various mixtures of pancreatic enzymes and even secretin.  Secretin was an autism therapy that was written off many years ago, but is still used by some DAN type doctors.

Some comments on this blog from parents of kids in the early CM-AT trials are supportive of its effect.

Pancreatic enzymes (e.g. Creon) are already used as a therapy for people who lack pancreatic enzymes and many people with autism have taken them.

Curemark have never published any of their trial data which annoys at least one of our medical researcher readers.  If you have so many patents, why not share your knowledge?

Improvement in core ASD symptoms after long-term treatment with probiotics

Another brief post today to draw your attention to a paper highlighted on the Questioning Answers blog.

There are two virtually identically probiotics one called VSL#3 and the other called Viviomixx.  As pointed out in a recent post there is an ongoing clinical trial of Vivomixx.

  

Ongoing Clinical Trial of Vivomixx Probiotic in Children with Autism

Some readers of this blog are trialing VSL#3 or Viviomixx.

The new paper is a case study of a 12 year old boy with severe autism who was given VSL#3 at his residential care home.

He has celiac disease, but his doctors were surprised that when the reduction in severity of abdominal symptoms was accompanied by an improvement in his autism.

This should not come as a surprise to regular readers.  Just recall Kanner’s subject #1, Donald Triplett, who was later diagnosed with juvenile arthritis. When his arthritis was treated his autism improved.  This is exactly what should be expected.

Treat your comorbidities, particularly those of an inflammatory/auto immune nature, and very likely you will improve behavior and even cognition.

Unexpected improvement in core autism spectrum disorder symptoms after long-term treatment with probiotics

Abstract

Objectives: Autism spectrum disorder is a neurodevelopmental condition that typically displays socio-communicative impairment as well as restricted stereotyped interests and activities, in which gastrointestinal disturbances are commonly reported. We report the case of a boy with Autism Spectrum Disorder (ASD) diagnosis, severe cognitive disability and celiac disease in which an unexpected improvement of autistic core symptoms was observed after four months of probiotic treatment.

Method: The case study refers to a 12 years old boy with ASD and severe cognitive disability attending the Villa Santa Maria Institute in resident care since 2009. Diagnosis of ASDs according to DSM-V criteria was confirmed by ADOS-2 assessment (Autism Diagnostic Observation Schedule).

The medication used was VSL#3, a multi-strain mixture of ten probiotics. The treatment lasted 4 weeks followed by a four month follow-up.

The rehabilitation program and the diet was maintained stable in the treatment period and in the follow up. ADOS-2 was assessed six times: two times before starting treatment; two times during the treatment and two times after interruption of the treatment.

Results: The probiotic treatment reduced the severity of abdominal symptoms as expected but an improvement in Autistic core symptoms was unexpectedly clinically evident already after few weeks from probiotic treatment start. The score of Social Affect domain of ADOS improved changing from 20 to 18 after two month’s treatment with a further reduction of 1 point in the following two months. The level 17 of severity remained stable in the follow up period. It is well known that ADOS score does not fluctuate spontaneously along time in ASD and is absolutely stable.

Conclusions: The appropriate use of probiotics deserves further research, which hopefully will open new avenues in the fight against ASD.

GERD/Reflux, Autism, Head Banging and mGlu5

This brief post addresses one further issue as to why people with autism can often suffer from various nasty gastrointestinal (GI) problems. 

First a recap.

Mast Cell Activation

We have already seen that some people’s GI problems are caused by mast cell activation/degranulation.  These cells are activated by allergens (certain foods in this case) and then they release histamine and other pro-inflammatory agents like IL-6.  Degranulation of mast cells can itself cause pain, but the main problem is the resulting damage/inflammation caused by the IL-6 and histamine.

The effective therapy is a mast cell stabilizer.  These include Verapamil (better known as a calcium channel blocker), Cromolyn Sodium, Ketotifen, Azelastine and to a lesser extent most anti-histamines like Claritin, Zyrtec etc.  Quercetin, the flavonoid, also has an effect.

Pancreatic Dysfunction

We also saw that L-type calcium channel (Cav1.2) dysfunction in the pancreas may disrupt the production of certain digestive enzymes.  The lack of these enzymes will disrupt the digestive process and likely affects other processes elsewhere in the body.  Verapamil blocks the Cav1.2 channel.

Ulcerative Colitis

We saw that inflammation and colitis, as diagnosed by an endoscopy, is another comorbidity of autism; this may be in part caused by the mast cell degranulation, but it does fit with the broader hypothesis of the over-activated immune system.  We saw how the potassium ion channel Kv1.3 was the mechanism behind some useful immuno-suppressive therapies, including those TSO parasites.  For those who are skeptical, here is another recent study, I just found:-

Expression of T-cell KV1.3 potassium channel correlates with pro-inflammatory cytokines and diseaseactivity in ulcerative colitis.

  

Kv1.3 should then be a target to treat ulcerative colitis and, I believe, autism itself. Some Kv1.3 blockers exist today; one is Verapamil, another is Curcumin, for those who prefer supplements to drugs.

Curcumin Serves as a Human Kv1.3 Blocker to Inhibit Effector Memory T Lymphocyte Activities

Before I forget to write this down somewhere, it appears that Kv1.3 can also be modulated by PKA and PKC, which decrease its activity. 

Dual Regulation of the n Type K+ Channel in Jurkat T  lymphocytes by Protein Kinases A and C*

We have already come across protein kinase B (PKB) and there will be a post soon of PKA, PKB and PKC.  This all links back to oxidative stress, neuroinflammation and even those dendritic spines.

  

Reflux

Today’s post is about reflux, sometimes known as gastroesophageal reflux disease (GERD) or gastro-oesophageal reflux disease (GORD).  Reflux is when the acid from the stomach rises through the esophagus/oesophagus to the mouth.

Many adults suffer from reflux from time to time and there are many OTC and prescription drug treatments. It can cause pain and discomfort, and would be particularly troubling if you could neither verbalize, nor understand your symptoms.

Why this post?

You may wonder why I have jumped from broccoli (the previous post) to reflux.  There is a reason.

I was recently listening to a conversation between doctors about a head-banging child and then came “it’s not autism; he’s got reflux, that is why he was banging his head.”

That sounded very odd to me.

It turns out many people with autism suffer from reflux, so you could say it is a comorbidity.  But why might that be?

mGlu5 receptors and disease

In an earlier, rather complicated, post I introduced the glutamate receptor, mGlu5.  This receptor is at the centre of research into Fragile X at MIT.  Fragile X is the most common single gene cause of autism.  It has been shown that mGlu5 dysfunction appears in many types of autism and indeed schizophrenia (adult-onset autism).

   

I then chanced upon a recent paper on mGLu5 and came across this section:-

Through contributions to synaptic plasticity, mGlu5 receptors have been implicated in neuronal processes such as learning and memory as well as disorders including Fragile X Syndrome (FXS), tuberous sclerosis, autism, epilepsy, schizophrenia, anxiety, neuropathic pain, addiction, Alzheimer’s disease, Parkinson’s disease, L-DOPA-induced dyskinesias, and gastroesophageal reflux disease

That was quite a surprise, but yet another good lesson of why the comorbidities should all be carefully researched.

 

The full paper, for anyone with time on their hands is:- 

Location-dependent signaling of the Group 1 metabotropic glutamate receptor, mGlu5.

Conclusion

If you have autism, you may have an mGlu5 dysfunction.  This will become treatable once the needed PAMs (Positive Allosteric Modulators) and NAMs (Negative Allosteric Modulators) have been brought to market.  A great deal of research is ongoing.

In the meantime, mGlu5 dysfunction is quite possible elsewhere in the body.  mGlu5 dysfunction is associated with some very rare disorders, but the common ones are diabetes and reflux.

The head-banging boy very possibly had both autism and reflux; he did develop diabetes.

For more on autism and diabetes, a short, thought provoking, but technical, paper:-

Insulin signaling and autism

Interestingly, we saw earlier that Verapamil seems to offer protection against type 1 and 2 diabetes. This time it is its calcium channel blocking role that is the mechanism.

Verapamil drug may reverse diabetes related death of pancreatic beta cells

No big surprise that Verapamil is an ingredient of the autism Polypill.

Verapamil drug may reverse diabetes-related death of pancreatic beta cells

Verapamil for a Broader sub-group of Autism and even Diabetes?

This blog is about science rather than medicine, and believe me there is a much bigger difference than you might hope for.

Many aspects of the research literature indicate the potential of certain calcium channel blockers, like Verapamil, to be useful in treating autism.  As we have seen, there are many different causes of autism and what treatment works in one type may be totally ineffective in another type.

For almost a year Monty, now age 11 with ASD, has taken Verapamil to control the behavioural effects of allergy that are driven by so called “mast cell degranulation”.  His pollen allergy makes his summertime behaviour dramatically worse; a reaction that is almost entirely reversed by Verapamil.

In my page in this blog on Allergies and Autism I raised the question as to whether Verapamil would be effective in treating the many people with autism who have food allergies leading to gastrointestinal (GI) problems.  Many people with autism have symptoms like Irritable Bowel Syndrome (IBS) or Inflammatory Bowel Disease (IBD) and these are widely associated with worsening autistic behaviours.  Monty has no GI issues or food intolerance.  I was very interested to receive some lengthy comments from a mother with a son who does have autism plus GI problems.  She found Verapamil highly effective in treating both his GI problems and the autism.  This is rather significant, since while I do receive the odd comment that H1 antihistamines have an unexpected beneficial effect on autism, which supports some of my own findings and theories, the issue of GI problems is very common in autism.  Could a pill called Verapamil be the little wonder for them as well?  The science does indeed support this, even if current medicine does not.

 

How can medicine be so disconnected from science?  It does seem to happen far more often than it should.

I did wonder if I was missing something about Verapamil.  It is an L-type calcium channel blocker and in autism there is a known genetic dysfunction (CACNA1C) that affects the calcium channel (Cav1.2) blocked by Verapamil.  It also turns out that Verapamil has been shown to be a highly effective mast cell stabilizer.  I did a little more digging and found something very surprising, the effect of Verapamil on the pancreas.  The pancreas makes all kinds of enzymes as well as insulin.  In some people with an auto-immune dysfunction the body destroys its own insulin producing cells and diabetes results.  In some people with autism (also an auto-immune condition) the pancreas seems not produce some of the other enzymes and there are various DAN-type treatments for this; and the new CUREMARK drug CM-AT seems to target this dysfunction.

Science has remarkably shown that Verapamil had the potential to reverse diabetes, if intervention is early.  Given that type 1 and type 2 diabetes are becoming increasingly common and account for a substantial part of national healthcare costs, it seem odd that medicine has not taken full note.

Preventing β-Cell Loss and Diabetes With Calcium Channel Blockers

It appears that older people on Verapamil for hypertension, strangely do not develop type 2 diabetes, which supports the claim for Verapamil.

There is no mystery as to why this is happening.  Calcium channels are widely expressed in pancreas, just as they are in the heart and the brain.  The effect of aberrant calcium channel signalling does no good for the brain in autism and in some other people, with a tendency to auto-immune problems, it would appear to be the pancreas that suffers.

You will recall that autism is amongst, other things, an auto-immune condition.  If you look at the extended family you will likely notice other auto-immune conditions like diabetes, thyroid problems, and arthritis.  (I would myself add fibromyalgia and even some types of chronic headaches to this list)

Recall that several drugs that help autism have a beneficial effect in diabetes and that the key type 2 drug for diabetes seems to have a positive effect on autism.

PPAR alpha, beta and gamma in Autism, Heart Disease and Diabetes

In the above post we saw that PPAR gamma (PPARγ) is a nuclear hormone receptor which modulates insulin sensitivity.  The following autism study looked at the effect of a common diabetes drug, pioglitazone (Actos), an FDA-approved PPARγ agonist used to treat type 2 diabetes, with a good safety profile. 
 

Effect of pioglitazone treatment on behavioral symptoms in autistic children

Pioglitazone is currently in Phase 2 trials for autism.

Another comorbidity of autism that is an auto-immune condition is asthma.  Here again, Verapamil was shown many years ago to hold promise.

Verapamil in the prophylaxis of bronchial asthma

A single oral dose of verapamil 80 mg was shown significantly to inhibit histamine-induced bronchoconstriction in 8 out of 16 asthmatic subjects (maximum increase in PD_20FEVHi 416%). There was still significant protection (Δ PD_20FEV1Hi>100%) in the responders 5 h after the oral dose.

I also noted in earlier posts that anti-oxidants seem to reduce the insulin required by diabetics and also improves one of the big problems that occurs along with diabetes that is peripheral neuropathy.  These antioxidants, like ALA, NAC, Thioctacid etc are also chelators of heavy metals.  While the planned study of chelators in autism in the US was effectively “banned”, a large study was carried out on heart patients.  Chelation was shown to be remarkably beneficial, but chelation is really just a shock dose of antioxidants.

Effect of Disodium EDTA Chelation Regimen on Cardiovascular Events in Patients With Previous Myocardial Infarction The TACT Randomized Trial

My take on this is that in many medical conditions, oxidative stress is present and therefore any antioxidant will be beneficial, but some more so than others.  In the well-researched world of asthma they concluded that the most potent, safe antioxidant was NAC (N-acetylcysteine).  NAC is my choice for autism.

Conclusion

If you have autism and suffer from chronic GI problems, Verapamil might well offer significant relief.

If you have unexplained autism flare-ups, like aggression, in summer this may well be driven by a pollen allergy, Verapamil is likely to help.

If your older relative has hypertension already and looks likely to be heading towards type 2 diabetes, maybe suggest they talk to their doctor about Verapamil;  it may well treat both.

Incidentally, if you have a child with autism and suffer yourself from chronic headaches or fibromyalgia, you might want to try some Verapamil yourself.

Verapamil is a very cheap generic drug; one tablet cost a couple of cents/pence. 

Opinion

I continue to be surprised how far medicine is behind science.

In the case of autism there is now a great deal of “actionable” research that is available for anyone to read.  This blog is about autism, but it seems that in many other areas of medicine the same is true, for example diabetes and types of cancer.   

The idea is that you should wait for clinical trials.  But who do you think is going to do them? There is no financial incentive for drug firms to do trials on old generic drugs for new uses.  Prepare for a long wait.

The medical practitioners involved with autism, mainly psychiatrists if anyone, show little interest in any novel treatment that has not yet been approved.  With such little interest from clinicians, novel treatments will remain well kept secrets for decades to come.

The “alternative” practitioners dealing with autism, like DAN doctors, are mainly in the US; but they are not fully grounded in science and seem overly interested in unorthodox expensive lab tests and costly supplements.

So you really do have to figure out autism for yourself, if you want to control it.