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

 

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

There are many comorbidities associated with autism.  I have long held the view that these comorbidities hold the key to understanding each particular case of autism.  In many cases this may be far more useful than genetic testing, which only seems to help in a minority of cases.

“Ringed esophagus” aka “Corrugated esophagus”


This then allows you to put people into sub-groups that may well respond to the same therapy.  This may all sound like common sense, but apparently is not.

Eosinophilic esophagitis (EoE) is a relatively new diagnosis and it is applies to a certain type of reflux/GERD/GORD that might be associated with a difficulty in swallowing and may not respond well to the standard stomach acid lowering therapies.

It is likely that most people with Eosinophilic esophagitis have never been correctly diagnosed. Many people have taken several years to get the correct diagnosis.

It is known that Eosinophilic esophagitis is much more common in autism than the general population. One study showed that EoE is four time more likely to be diagnosed in someone with autism. I suspect many people with autism never have their GI problems fully diagnosed.

We now have to add some new science to this blog

Granulocytes

There is a great deal already in this blog about mast cells.  Many readers have children who have allergies, mast cell activation, or even mastocytosis.  Mast cells are the ones (but not the only ones) that release histamine.

Mast cells are just one type of a class of cells called Granulocytes, that are produced in your bone marrow.

Granulocytes are a category of white blood cells characterized by the presence of granules, which release their contents when they degranulate.

The four types of granulocytes are:- 

·        mast cells

These have been well covered in the past. These are what cause problems for people with pollen allergy.

·        eosinophils

Eosinophils play a crucial part in the killing of parasites because their granules contain a unique, toxic basic protein and cationic protein. Eosinophils regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils), they are involved in the destruction of tumor cells, and they promote the repair of damaged tissue. Interleukin-5 interacts with eosinophils and causes them to grow and differentiate; IL-5 is produced by basophils.

Note that some people with autism find that the TSO helminth parasites modify their immune system and improve their autism. This may relate to what is contained in the granules of eosinophils.  

·        basophils 

Basophils are similar to mast cells, in that they contain prestored histamine within their granules. Unlike mast cells they circulate in your blood . Basophils are the least common of the granulocytes, representing about 0.5 to 1% of circulating white blood cells. However, they are the largest type of granulocyte. They are responsible for inflammatory reactions during immune response, as well as in the formation of acute and chronic allergic diseases, including anaphylaxis, asthma, atopic dermatitis and hay fever. They can produce histamine and serotonin that induce inflammation, and heparin that prevents blood clotting.

There is research underway to try to develop basophil stabilizers.

·        neutrophils

Neutrophils are normally found in the bloodstream. During the beginning phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation.

Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cells.

Neutrophils also release an assortment of proteins in three types of granules by a process called degranulation. The contents of these granules have antimicrobial properties, and help combat infection.

An obvious question would be, if you know you have a problem with mast cells are you likely to have an issue with the other types of granulocytes?

One role of eosinophils is to regulate other immune cell functions (e.g., CD4+ T cells, dendritic cells, B cells, mast cells, neutrophils, and basophils).

The subject is highly complex and again not fully understood, but it is clear that granulocytes are all interrelated and so a problem with one may well be associated with a problem with others.

In the case of Eosinophilic esophagitis (EoE), both eosinophils and mast cell are directly involved.

Basophils, like mast cells, release histamine among other things when they degranulate.

Mast cells usually do not circulate in the blood stream, but instead are located in connective tissue.  Circulating granulocytes, like basophils can be recruited out of the blood into a tissue when needed.

So in addition to mast cell stabilizers perhaps, we might benefit from basophil and eosinophil stabilizers.

Surprisingly, the antihistamine cetirizine has Eosinophil-stabilizing properties, as does the asthma drug Montelukast. Both drugs are widely used in children.

Another substance, curine, also inhibits eosinophil influx and activation and is seen as a potential new treatment for asthma.  Interestingly the drug curine, is an alkaloid, that blocks L-type Ca²⁺ channels.

Regular readers may recall that I proposed the L-type calcium channel blocker Verapamil to control my son’s mast cell degranulation. Mast cells degranulate in a very complex fashion that involves the flow of Ca²⁺.

This may or may not be a coincidence. 

Fullerene nanomaterials are being developed as both mast cell and peripheral blood basophil stabilizers.

L-type calcium channels and GI disorders in Autism

There are many types of GI disorder in autism, however I suggest that a large group can be categorized as being broadly Granulocyte Disorders, which may well all respond to L-type calcium channel blockers, to some extent.

Indeed this may be a better solution than the widely used cromolyn sodium.

Perhaps people with autism, and their family members have certain calcium channels that are either overexpressed, or do not close fast enough, leading to a higher level of intracellular calcium.  This of course ties back in with Professor Gargus and his theories about IP3R and the calcium store inside the “endoplasmic reticulum”.

This all gets extremely complex.

My rather simple suggestion would be that if you have autism and any GI problem from the esophagus downwards, a three day trial of verapamil just might change your life.  As is almost always the case, there are some people who do not tolerate verapamil.

Interleukin 5

Interleukin 5 (IL-5) is an inflammatory cytokine produced by type-2 T helper cells  (Th2), mast cells, basophils and eosinophils.

IL-5 interacts with eosinophils and causes them to grow and differentiate.

IL-5 has long been associated with the cause of several allergic diseases including allergic rhinitis and asthma, where a large increase in the number of circulating, airway tissue, and induced sputum eosinophils have been observed.

You might expect high levels of IL-5 in people with Eosinophilic esophagitis (EoE)

Anti–IL-5 (mepolizumab) therapy for eosinophilic esophagitis 

Anti–IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3⁺ blood cells) in patients with EE and improved clinical outcomes.

Not surprisingly the same anti-IL-5 therapy has been approved to treat severe asthma.

NICE recommends first-of-its kind asthma treatment mepolizumab  

Patients are given mepolizumab by injection every four weeks. It costs £840 per dose.

Mepolizumab for autism?

It is very expensive, so I doubt many people will think of Mepolizumab for autism.  If you have EoE, or severe asthma, you may be able to access this IL-5 therapy, my guess is that it would also reduce the severity of any comorbid autism.

Back to Eosinophilic Esophagitis

I was writing a while ago about food allergy in my book and came across the opinion that food allergy is no more common in autism than in typical people, but what is more common is Eosinophilic Esophagitis.

Eosinophilic esophagitis is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of digestive system (gastrointestinal) illness.  In many cases it likely remains undiagnosed. If it continues, after a few years swallowing becomes difficult, in part because a “ringed esophagus” develops that impedes the passage of food.

As seems to be often the case there are plenty of contradictions in the diagnosis and treatment, as you will find as you read on.

The symptoms are broadly what would normally be diagnosed as reflux/GERD/GORD. This is very often found in people with autism and I expect in their relatives.

It is relevant to autism because it will be yet another comorbidity that when treated should improve autism, but it is also another marker of a particular sub-group of autism.

There are numerous other GI conditions comorbid with autism - colitis, IBD, IBS etc.  In the end I imagine that the molecular basis of some of these diagnoses is actually the same, so you will find the same therapies may be effective.

It looks like that one common factor is the mast cell and, just as in pollen allergy and asthma, stabilizing mast cells yields great benefit. Stabilizing mast cells is complex but involves the flow of calcium ions, Ca²⁺.  By modifying the flow of Ca²⁺ you can prevent mast cells degranulating.  This was one of my earlier discoveries, but there is now research showing the L type calcium channels “open” mast cells.  Keeping these channels closed is actually quite simple.

It would seem logical that the same approach could be therapeutic to other conditions that are, at least in part, mediated by mast cells.

According to the Mayo Clinic these are symptoms of eosinophilic-esophagitis

Adults:

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         Chest pain that is often centrally located and does not respond to antacids

·         Persistent heartburn

·         Upper abdominal pain

·         No response to gastroesophageal reflux disease (GERD) medication

·         Backflow of undigested food (regurgitation)

Children:

·         Difficulty feeding

·         Vomiting

·         Abdominal pain

·         Difficulty swallowing (dysphagia)

·         Food impaction

·         No response to GERD medication

·         Failure to thrive (poor growth, malnutrition and weight loss)

The diagnosis of EoE is typically made on the combination of symptoms and findings of diagnostic testing.


Prior to the development of the EE Diagnostic Panel, EoE could only be diagnosed if gastroesophageal reflux did not respond to a six-week trial of twice-a-day high-dose proton-pump inhibitors (PPIs) or if a negative ambulatory pH study ruled out gastroesophageal reflux disease (GERD).

Treatment strategies include dietary modification to exclude food allergens, medical therapy, and mechanical dilatation of the esophagus.

The current recommendation for first line treatment is PPI in lieu of diet as a significant portion of EOE cases respond to this, and it is a low risk, low cost treatment.

The second and third line therapies are an elimination diet of either the 6 or 4 most common triggers, or topical corticosteroids, including both fluticasone, and topical viscous budesonide.

Elimination diets would be followed by re-introduction of foods under supervision if the first diet is successful. Allergy evaluation has not been found to be an effective means to determine what foods to eliminate.

  

Eosinophilic esophagitis in adults: An update

MAST CELL STABILIZERS

In a small case series, Cromolyn sodium failed to show any clinical or histologic improvement in EoE patients

LEUKOTRIENE INHIBITORS

Montelukast is an eosinophil stabilizing agent. It improved clinical symptoms in EoE but there was no histological improvement

PROGNOSIS

As mentioned earlier, EoE is a chronic inflammatory disease of the esophagus. The inflammation leads to remodeling, fibrosis and stricture. Fortunately, no case of esophageal malignancy has been reported in EoE. Patients are generally diagnosed after several years of their symptoms. Although symptomatic improvement occurs after treatment, recurrence is common after discontinuation of treatment. So maintenance therapy is needed to prevent recurrences. At the present time there is no head to head study to suggest the best maintenance treatment. Continuation of swallowed corticosteroid and/or dietary therapy should be done in all EoE patients particularly in those with history of food impaction, dysphagia, esophageal stricture, and in those with rapid symptomatic and histologic relapse following initial treatment

Eosinophilic esophagitis and Mast Cells

Eosinophilic esophagitis is called Eosinophilic because it is mediated by Eosinophils, however it has been established that mast cells also play a role. 

Involvement of mast cells in eosinophilic esophagitis

Whereas prior studies have primarily focused on the role of eosinophils in disease diagnosis and pathogenesis, this study investigates the involvement of mast cells.

Herein we have identified local mastocytosis and mast cell degranulation in the esophagus of EE patients; identified an esophageal mast cell associated transcriptome that is significantly divergent from the eosinophil-associated transcriptome with CPA3 mRNA levels serving as the best mast cell surrogate marker; and provide evidence for the involvement of KIT ligand in the pathogenesis of EE.

One possible explanation for eosinophilic esophagitis:

Expanding the paradigm of eosinophilic esophagitis: mast cells and IL-9

A potential immunological mechanism involved in the pathogenesis of EoE. An uncontrolled TH2 immune response initiated by an allergic insult results in the transition of the esophagus from a normal (NL) to EoE phenotype through enhanced IL-13 production that induces highly elevated CCL26 (eotaxin-3) expression by esophageal epithelium. Dysregulated TH2 immune response and enhanced CCL26 secretion together promote the infiltration of CD4⁺TH2 cells, eosinophils, and mast cells, and potentially, type-2 innate lymphoid cells (ILC2) and CD4⁺TH9 cells; into the esophagus. TGF-β and IL-4 produced by the activated mast cells and CD4⁺TH2 cells may induce eosinophils, ILC2, and/or CD4⁺TH9 cells to produce IL-9, which in turn, promotes esophageal mastocytosis that contributes to the development of EoE pathophysiology.

Possible Eosinophil stabilizers

An Open Label Add-On Trial of Cetirizine for Neuromyelitis Optica (P4.003)

CONCLUSIONS Eosinophil-stabilizing properties and favorable safety profile make cetirizine an attractive add-on therapy for NMO. Thus far it has been well-tolerated in our patient population, with incoming data about efficacy expected over the coming months

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

·        Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum.

·        Curine inhibits eosinophil influx and activation and airway hyper-responsiveness.

·        Curine mechanisms involve inhibition of Ca²⁺ influx, and IL-13 and eotaxin secretion.

·        No significant toxicity was observed in mice orally treated with curine for 7 days.

·         Curine has the potential for the development of anti-asthmatic drugs.

  

Conclusion

Non conventional therapies for eosinophilic esophagitis might include:-

·        Cetirizine

·        Verapamil

·        Montelukast

·        Curine

The very expensive therapy is Mepolizumab.

If you have one type granulocyte causing a disorder, is seems almost inevitable that the other types of granulocyte are also involved.

Treating granulocyte disorders should improve autism and left untreated they may mask the effect of otherwise useful autism therapies. 

One reader did previously suggest a bone marrow transplant for autism. A rather radical solution, but if someone with autism was given donor bone marrow as part of another therapy, you might well see their autism improve.