TRH and Rifaximin – an alternative to intranasal TRH or oral Taltirelin/Ceredist?

I think this is going to be one of my smarter posts. It may be more for our doctor readers and our motivated home-based researchers. It does remain a hypothesis and while it looks plausible it is certainly not 100% proven – so typical Peter stuff.

Many parents with autism regularly treat their child with the antibiotic Rifaximin. This drug is also the go-to therapy for SIBO (small intestine bacterial overgrowth) and is a key part of the Nemechek autism protocol to increase butyric acid production in the gut (and reduce propionic acid).

Some parents report that their child with completely normal GI function responds well behaviorally to Rifaximin.

Rifaximin is taken orally and stays in the gut, it does not enter the blood stream.

Our long-time reader Maja mentioned that she still uses Rifaximin in her now adult daughter.

I then did a quick Google and was surprised to see Rifaximin linked to the hormone TRH.

And, most surprising, you can use Rifaximin to treat prostate inflammation, via its effect on TRH.

TRH was the subject of an experiment I did 12 years ago. I suggested that an existing Japanese drug, an orally available TRH super-agonist, could be repurposed at a low dose to treat autism.

 https://www.epiphanyasd.com/2014/05/the-peter-hypothesis-of-trh-induced.html

I then noted that a well-known, but a little controversial, doctor in the US used intranasal TRH to treat his patients with chronic fatigue syndrome.

Another doctor had grant funding from the US military to develop intranasal TRH to reduce suicides in veterans.

In my old post I started by wondering why my son and some others with severe autism respond so well to sensory stimulation like standing on the upper deck of a ferry boat in the open sea on a windy day, or sitting in an open-top bus, driving in a convertible car etc.

Without be able to do any testing I looked for “similar” situations that haven been studied. The closest I found was people jumping out of a plan (with a parachute) where one of the key changes was a surge in the level of the hormone prolactin.

How to replicate the open-top bus effect? One of my doctor relatives suggested sitting Monty in front of a fan. Over course I wanted better than that. I found that stimulating TRH receptors in the brain would release prolactin.  It was already known that TRH is disturbed in autism.

It seemed to me that a Japanese orphan drug developed to treat spinocerebellar degeneration (SCD) – a group of progressive neurodegenerative disorders characterized by ataxia (poor coordination, gait disturbance, speech difficulties) could be repurposed.

I did discuss with a Japanese doctor in Osaka and he prescribed it.

It is a very expensive drug, even when bought with a prescription, and it has a very short expiry date. The idea was to use a micro-dose, to avoid undesirable side effects and this would also make the price less scary. I thought it provided a benefit without side effects, but was impractical. At the full dose it is potent and is the only drug I have trialed that had a near immediate profound effect on myself. I suddenly had hyper-acute vision. The micro dose had no effect on me.

Since Ceredist (taltirelin) is a TRH analogue, it could in theory affect the hypothalamic–pituitary–thyroid (HPT) axis.

TRH normally stimulates TSH release from the pituitary, which then increases thyroid hormone (T4/T3) secretion. Taltirelin was designed for CNS activity rather than endocrine use. Its clinical development in Japan for spinocerebellar degeneration focused on neurological symptoms, not thyroid stimulation. Animal studies showed that taltirelin has much weaker TSH-releasing activity than native TRH, but much stronger central nervous system stimulant effects (improved motor coordination, wakefulness).

Human data at therapeutic doses for spinocerebellar degeneration, significant changes in thyroid hormone levels (TSH, T3, T4) have not been a common clinical issue. Monitoring thyroid function is not part of standard Ceredist treatment.

 

So what is TRH?

TRH (thyrotropin-releasing hormone) serves as a master regulator of energy metabolism, mood, arousal, cognition, and immune balance.

Core Endocrine Role

Produced in the hypothalamus (paraventricular nucleus), but also found in other brain regions and peripheral tissues.

Main function is to stimulate the anterior pituitary to release TSH (thyroid-stimulating hormone), this increases thyroid hormone (T3, T4) production in the thyroid gland.

A secondary effect promotes prolactin release from the pituitary. TRH is a significant stimulator, especially when dopamine inhibition is reduced.

 

Effects on Other Hormones

Growth hormone & insulin: Some modulatory effects reported in stress and metabolism, though less central.

ACTH/cortisol: Minor indirect effects; TRH can modulate stress responses via cross-talk with the HPA axis.

 

Mood and Behavior

Antidepressant effects - TRH has rapid mood-elevating and activating effects in both animals and humans, independent of thyroid hormones. Some clinical studies have tested TRH or TRH analogs as rapid-acting antidepressants.

Arousal & vigilance - it increases wakefulness, motivation, and locomotor activity.

Anxiety - can produce mild anxiogenic effects at high doses, but generally associated with improved mood and alertness.

 

Cognition

Neurotransmitter modulation - TRH interacts with cholinergic, dopaminergic, and glutamatergic systems.

Memory & learning - TRH and TRH-like peptides enhance memory consolidation and counteract cognitive decline in animal studies.

Neuroprotection - shown to reduce neuronal injury in models of ischemia and trauma.

 

Inflammation & Immunity

 Anti-inflammatory - TRH dampens pro-inflammatory cytokine production (e.g., TNF-α, IL-1β).

Microglia modulation - TRH reduces microglial over-activation, relevant in neuroinflammation.

Systemic effects: TRH analogs show protective roles in sepsis and multiple organ injury in animal studies, likely via immune regulation and mitochondrial support.

 

Here is the recent study that showed the common antibiotic Rifaximin increases TRH in the brain and in peripheral tissues. Rifaximin itself stays within the gut when taken by mouth, it does not enter the blood stream. It changes the gut microbiota which then sends a signal via vagus nerve to the brain (clever, isn’t it?).

Caveat – rats are not humans.

 

Rifaximin modulates TRH and TRH-like peptide expression throughout the brain and peripheral tissues of male rats

 

The TRH/TRH-R1 receptor signaling pathway within the neurons of the dorsal vagal complex is an important mediator of the brain-gut axis. Mental health and protection from a variety of neuropathologies, such as autism, Attention Deficit Hyperactivity Disorder, Alzheimer’s and Parkinson’s disease, major depression, migraine and epilepsy are influenced by the gut microbiome and is mediated by the vagus nerve. The antibiotic rifaximin (RF) does not cross the gut-blood barrier. It changes the composition of the gut microbiome resulting in therapeutic benefits for traveler’s diarrhea, hepatic encephalopathy, and prostatitis. TRH and TRH-like peptides, with the structure pGlu-X-Pro-NH₂, where “X” can be any amino acid residue, have reproduction-enhancing, caloric-restriction-like, anti-aging, pancreatic-β cell-, cardiovascular-, and neuroprotective effects. TRH and TRH-like peptides occur not only throughout the CNS but also in peripheral tissues. To elucidate the involvement of TRH-like peptides in brain-gut-reproductive system interactions 16 male Sprague–Dawley rats, 203 ± 6 g, were divided into 4 groups (n = 4/group): the control (CON) group remained on ad libitum Purina rodent chow and water for 10 days until decapitation, acute (AC) group receiving 150 mg RF/kg powdered rodent chow for 24 h providing 150 mg RF/kg body weight for 200 g rats, chronic (CHR) animals receiving RF for 10 days; withdrawal (WD) rats receiving RF for 8 days and then normal chow for 2 days.

Results

Significant changes in the levels of TRH and TRH-like peptides occurred throughout the brain and peripheral tissues in response to RF. The number of significant changes in TRH and TRH-like peptide levels in brain resulting from RF treatment, in descending order were: medulla (16), piriform cortex (8), nucleus accumbens (7), frontal cortex (5), striatum (3), amygdala (3), entorhinal cortex (3), anterior (2), and posterior cingulate (2), hippocampus (1), hypothalamus (0) and cerebellum (0). The corresponding ranking for peripheral tissues were: prostate (6), adrenals (4), pancreas (3), liver (2), testis (1), heart (0).

Conclusions

The sensitivity of TRH and TRH-like peptide expression to RF treatment, particularly in the medulla oblongata and prostate, is consistent with the participation of these peptides in the therapeutic effects of RF. 

 

It turns out that other researchers have looked at Rifaximin’s effects on the brain, but they never understood the mechanism.

 

Effects of Rifaximin on Central Responses to Social Stress—a Pilot Experiment

Probiotics that promote the gut microbiota have been reported to reduce stress responses, and improve memory and mood. Whether and how antibiotics that eliminate or inhibit pathogenic and commensal gut bacteria also affect central nervous system functions in humans is so far unknown. In a double-blinded randomized study, 16 healthy volunteers (27.00 ± 1.60 years; 9 males) received either rifaximin (600 mg/day) (a poorly absorbable antibiotic) or placebo for 7 days. Before and after the drug intervention, brain activities during rest and during a social stressor inducing feelings of exclusion (Cyberball game) were measured using magnetoencephalography. Social exclusion significantly affected (p < 0.001) mood and increased exclusion perception. Magnetoencephalography showed brain regions with higher activations during exclusion as compared to inclusion, in different frequency bands. Seven days of rifaximin increased prefrontal and right cingulate alpha power during resting state. Low beta power showed an interaction of intervention (rifaximin, placebo) × condition (inclusion, exclusion) during the Cyberball game in the bilateral prefrontal and left anterior cingulate cortex. Only in the rifaximin group, a decrease (p = 0.004) in power was seen comparing exclusion to inclusion; the reduced beta-1 power was negatively correlated with a change in the subjective exclusion perception score. Social stress affecting brain functioning in a specific manner is modulated by rifaximin. Contrary to our hypothesis that antibiotics have advert effects on mood, the antibiotic exhibited stress-reducing effects similar to reported effects of probiotic

 

Effects of the antibiotic rifaximin on cortical functional connectivity are mediated through insular cortex

It is well-known that antibiotics affect commensal gut bacteria; however, only recently evidence accumulated that gut microbiota (GM) can influence the central nervous system functions. Preclinical animal studies have repeatedly highlighted the effects of antibiotics on brain activity; however, translational studies in humans are still missing. Here, we present a randomized, double-blind, placebo-controlled study investigating the effects of 7 days intake of Rifaximin (non-absorbable antibiotic) on functional brain connectivity (fc) using magnetoencephalography. Sixteen healthy volunteers were tested before and after the treatment, during resting state (rs), and during a social stressor paradigm (Cyberball game—CBG), designed to elicit feelings of exclusion. Results confirm the hypothesis of an involvement of the insular cortex as a common node of different functional networks, thus suggesting its potential role as a central mediator of cortical fc alterations, following modifications of GM. Also, the Rifaximin group displayed lower connectivity in slow and fast beta bands (15 and 25 Hz) during rest, and higher connectivity in theta (7 Hz) during the inclusion condition of the CBG, compared with controls. Altogether these results indicate a modulation of Rifaximin on frequency-specific functional connectivity that could involve cognitive flexibility and memory processing.

  

Probing gut‐brain links in Alzheimer's disease with rifaximin

Gut‐microbiome‐inflammation interactions have been linked to neurodegeneration in Alzheimer's disease (AD) and other disorders. We hypothesized that treatment with rifaximin, a minimally absorbed gut‐specific antibiotic, may modify the neurodegenerative process by changing gut flora and reducing neurotoxic microbial drivers of inflammation. In a pilot, open‐label trial, we treated 10 subjects with mild to moderate probable AD dementia (Mini‐Mental Status Examination (MMSE) = 17 ± 3) with rifaximin for 3 months. Treatment was associated with a significant reduction in serum neurofilament‐light levels (P < .004) and a significant increase in fecal phylum Firmicutes microbiota. Serum phosphorylated tau (pTau)181 and glial fibrillary acidic protein (GFAP) levels were reduced (effect sizes of −0.41 and −0.48, respectively) but did not reach statistical significance. In addition, there was a nonsignificant downward trend in serum cytokine interleukin (IL)‐6 and IL‐13 levels. Cognition was unchanged. Increases in stool Erysipelatoclostridium were correlated significantly with reductions in serum pTau181 and serum GFAP. Insights from this pilot trial are being used to design a larger placebo‐controlled clinical trial to determine if specific microbial flora/products underlie neurodegeneration, and whether rifaximin is clinically efficacious as a therapeutic.

 

Rifaximin and the prostate

For some reason one of the main areas where Rifaximin triggers the production of TRH is in the prostate, in males. There are studies showing how Rifaximin can be used to treat prostatitis (prostate inflammation).

Symptom Severity Following Rifaximin and the Probiotic VSL#3 in Patients with Chronic Pelvic Pain Syndrome (Due to Inflammatory Prostatitis) Plus Irritable Bowel Syndrome

This study investigated the effects of long-term treatment with rifaximin and the probiotic VSL#3 on uro-genital and gastrointestinal symptoms in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) plus diarrhoea-predominant irritable bowel syndrome (D-IBS) compared with patients with D-IBS alone. Eighty-five patients with CP/CPPS (45 with subtype IIIa and 40 with IIIb) plus D-IBS according to the Rome III criteria and an aged-matched control-group of patients with D-IBS alone (n = 75) received rifaximin and VSL#3. The primary endpoints were the response rates of IBS and CP/CPPS symptoms, assessed respectively through Irritable Bowel Syndrome Severity Scoring System (IBS-SSS) and The National Institute of Health Chronic Prostatitis Symptom Index (NIH-CPSI), and performed at the start of therapy (V0) and three months after (V3). In IIIa prostatitis patients, the total NIH-CPSI scores significantly (p < 0.05) decreased from a baseline mean value of 21.2 to 14.5 at V3 , as did all subscales, and in the IIIb the total NIH-CPSI score also significantly decreased (from 17.4 to 15.1). Patients with IBS alone showed no significant differences in NIH-CPSI score. At V3, significantly greater improvement in the IBS-SSS and responder rate were found in IIIa patients. Our results were explained through a better individual response at V3 in IIIa prostatitis of urinary and gastrointestinal symptoms, while mean leukocyte counts on expressed prostate secretion (EPS) after prostate massage significantly lowered only in IIIa cases. 

Since SIBO is treated by rifaximin, some researchers linked SIBO with prostatitis: 

Chronic prostatitis and small intestinal bacterial overgrowth: is there a correlation?

Background: Clinical management of chronic inflammation of prostate and seminal vesicles is very complex. Among the causes of recurrent chronic prostatitis (CP), a possible malabsorption, such as lactose intolerance, in turn related to small intestinal bacterial overgrowth (SIBO), should be considered.

Methods: We have performed lactose and lactulose breath test (BT) in 42 patients with CP, in order to evaluate the prevalence of SIBO in this kind of patients and the concordance of the two tests.

Results: A positive lactulose BT was present in 33/42 patients and in 73% (24/33) was associated to lactose malabsorption. Five patients had positive response after lactulose, while only 4 had both negative tests.

Conclusions: Our data showed an association between lactose and lactulose BT positivity. They also indicated high prevalence of bacterial colonization of small bowel in patients with CP, possibly related to recurrence or chronicity of genitourinary tract inflammation. The research for these phenomena could be relevant in diagnostic route of infertile patients in whom slight gastro-enteric symptoms can be underestimated.

 

For those of you who still read books:

 

Betrayal by the Brain: The Neurologic Basis of Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural Network Disorders
This seminal work presents Dr. Goldstein's theory that CFS and fibromyalgia result from dysfunctions in neural networks. It integrates neuroscience research into the pathophysiology and treatment of these conditions.

A Companion Volume to Dr. Jay A. Goldstein's Betrayal by the Brain: A Guide for Patients and Their Physicians
Authored by Katie Courmel, this companion guide simplifies Dr. Goldstein's theories and treatment protocols for a broader audience, aiding patients and physicians in understanding and applying his methods.

 Tuning the Brain: Principles and Practice of Neurosomatic Medicine

In this book, Dr. Goldstein outlines the principles of neurosomatic medicine, a field he developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses.

In Tuning the Brain: Principles and Practice of Neurosomatic Medicine, Dr. Jay A. Goldstein discusses the use of thyrotropin-releasing hormone (TRH) in treating chronic fatigue syndrome (CFS) and related disorders. He describes TRH as a neuropeptide that can modulate neural network activity, particularly through the trigeminal nerve, which is involved in sensory processing. By stimulating this pathway, TRH may help "re-tune" the brain's response to sensory input, potentially alleviating symptoms associated with CFS and similar conditions.

The book outlines the principles of neurosomatic medicine, a field Dr. Goldstein developed that combines neurology, psychiatry, and pharmacology to treat chronic illnesses. It emphasizes the rapid modulation of neural networks through pharmacological means, aiming to restore normal sensory processing and alleviate symptoms.

 

Conclusion

It does look like Rifaximin has interesting effects beyond where it can reach itself.

Rifaximin → modifies gut microbiota → activates vagus nerve

Vagus nerve → signals to brainstem → hypothalamus → TRH release 

According to that rat study, TRH and TRH-like peptides are present in the prostate, and their levels change in response to rifaximin. The TRH (or TRH-like peptides) in the prostate is produced locally in the prostate tissue itself, not delivered there from the brain via the bloodstream. the level of production can be modulated by gut–brain signaling, such as after rifaximin treatment.

I have to say that this reminds me of using L-Reuteri probiotic bacteria to send a signal via the same vagus nerve to release oxytocin in the brain. Seems a better approach than intranasal oxytocin.

I think the study showing Rifaximin improves the response to social stress fits with Dr Goldstein’s use of intranasal TRH to “retune” the brain in the conditions he studied and the potential use to reduce suicide initiations. It is enough for me to see TRH as a possible common factor.

I think Goldstein and the US DoD scientists should have used the TRH super-agonist Taltirelin/Ceredist. It is 30x more potent and yet does not affect thyroid function. It also has a far longer half-life. The other alternative, we now see, would have been to use Rifaximin.

Goldstein has passed away and the US DoD gave upon TRH. Research indicates that intranasal esketamine can rapidly reduce suicidal thoughts. Esketamine was FDA approved in 2019.

Taltirelin was approved for use in humans in Japan in 2000 for spinocerebellar degeneration (SCD).

Note that spinocerebellar degeneration (SCD) has no drug therapy in the US/Europe, even though one has existed in Japan for 25 years. Looks pretty odd to me. In a perfect world low dose Taltirelin could be a useful add-on therapy for many neurological conditions and potentially even for prostatitis! Don’t hold your breath.

Taltirelin is now being researched in animal models of Parkinson’s and fatigue syndromes.

Unless you live in Japan and have a pal who is a doctor, I think autism parents are best off with Rifaximin.

As Maja just pointed out “Rifaximin is still very helpful. I repeat a ten-day course (2x400 mg) every two to three months”, in her adult daughter. We can never know for sure if increased TRH is mechanism, or reduced SIBO, or increased butyric acid, or something else. If it works, stay with it!

Doom Scrolling vs Taking Action - more Game Changers

 

Arnie (in the brown jacket) fixing a local pothole

Source: https://twitter.com/Schwarzenegger/status/1645886847342743552

  

Some actors can act and some cannot

I recently went to see Keanu Reeves in John Wick Chapter 4 with both of my sons. Big brother thought it was great, like a three-hour non-stop video game with Keanu Reeves laying waste to hundreds of villains. My view was that there was almost no dialogue. I have more dialogue with Monty, aged 19 with classic autism, than Reeves has in this film. It was rather like watching a film with Sylvester Stallone or indeed Arnold Schwarzenegger. For Monty I think the best part was probably the popcorn.

Big brother told me that Arnie can act, that is why he also made films like Kindergarten Cop.  That apparently is acting.

There is no doubt though that Arnie is a man of action, as well as being an action man.

I just got a link to him fixing a local pothole.  It is on his twitter feed. Not quite sure why I received it.

I forwarded the link to Monty’s Big Brother.

What does Dad have in common with Arnie?  We both go out and fix the pothole outside our house – the one that nobody wants to come and fix.

In our case I brought several bucket loads of steaming hot asphalt to fix the road. Arnie and his helpers used a few bags of cold repair asphalt – which looks a lot less bother.

When I went twice in search of asphalt, I explained to the road crews laying asphalt with a big machine that I just wanted a few bucket loads to repair an annoying hole in the road in front of our house. Both times the initial story was “you can’t do that ... you cannot fix the road yourself”. My approach, like Arnie’s, was “just watch me”.  The second time one of the road crew actually came to help.  Since then the whole road has been resurfaced, so my asphalting days are likely over.

 

Doom Scrolling

Even if you are not aware of the term "doom scrolling", if you have a smartphone you are probably already doing it.

 

Doom scrolling

The practice of obsessively checking online news for updates, especially on social media feeds, with the expectation that the news will be bad, such that the feeling of dread from this negative expectation fuels a compulsion to continue looking for updates in a self-perpetuating cycle.

 

It is similar to the echo chamber

In news media and social media, an echo chamber is an environment or ecosystem in which participants encounter beliefs that amplify or reinforce their pre-existing beliefs by communication and repetition inside a closed system and insulated from rebuttal.

 

These days many people have got hooked on reading about problems, rather than solving them. Severe autism being one such problem.

 

Taking action in Autism

I recently was contacted by a Dad who has been treating his child with autism for a few years.  He probably does not fix potholes like me and Arnie, but he does like to fix autism.  He is doing rather well.

He read my book and contacted me.  His very extensive investigation and trials resulted in his personalized therapy.  These were his game changers:-

 

SSRIs

Fluvoxamine         to treat OCD and improve cognition

(Luvox)

 

Antifungals

Fluconazole          The single most effective intervention. 

 (Diflucan)            It just lifted the fog.

Itraconazole 

          
Nystatin  

Antiviral

Valaciclovir (Valtrex)   

       

Antibiotics
Rifaximin               used extensively

 

Bumetanide             Improves cognition.

The antifungals and Rifaximin have the similar effect in terms of more situational awareness, “presence” and ability to interact.  Bumetanide improves cognition.

 

Vitamins

B1 (Sulbutiamine)   high doses (800mg) quickly solved the longstanding feeding problems like chewing and swallowing, the stubbornness (e.g. refusing to go through a door)

Another form of B1 has been covered in this blog. Benfotiamine was proposed by our reader Seth in 2016 and he wrote a guest post about it.

Benfotiamine for Autism

A researcher/clinician called Derek Lonsdale wrote about the potential to treat autism with vitamin B1. 

B6  high doses (> 150 mg a day) are essential to avoid explosive rages. 

Vitamin B6 with magnesium is an old autism therapy that was made popular by the late Bernie Rimland. Rimland founded and directed two advocacy groups: the Autism Society of America (ASA) and the Autism Research Institute. He was the force behind Defeat Autism Now! (DAN). 

Bupropion is transformative, but the effect unfortunately fades in 5 days. 

 The mechanism of action of bupropion in the treatment of depression and for other indications is unclear. However, it is thought to be related to the fact that bupropion is a norepinephrine–dopamine reuptake inhibitor (NDRI) and antagonist of several nicotinic acetylcholine receptors. It is uncertain whether bupropion is a norepinephrine–dopamine releasing agent. 

L type calcium channel blockers helped but Nimodipine caused side effects with gum inflammation; this is a well-known possible side effect.

 * * *

Fluconazole and Rifaximin are quite popular therapies in autism and certainly tell that something is amiss in the intestines.  In the US Rifaximin is very expensive and so you will see Vancomycin used.

In Singapore one of the US-trained MAPS (autism) doctors recently got in trouble prescribing Fluconazole/ Diflucan and Vancomycin to young children with autism. The kids' pediatricians heard what he was prescribing and complained to the medical regulator. 

 

Doctor ordered to temporarily stop prescribing antibiotics, antifungal medication to children after specialists complain

Dr Erwin Kay Aih Boon, a general practitioner in private practice at Healthwerkz Medical Centre, had prescribed antibiotic Vancomycin and antifungal medication Fluconazole – trade name Diflucan – to children with autism.

It comes after four paediatricians in a hospital, which was unnamed in the grounds, complained to the Singapore Medical Council (SMC) about Dr Kay’s management of children with autism.

They said his management of the children were “not based on evidence”, the grounds read.

“Hospital A’s paediatricians were of the view the use of antibiotics and antifungal agents for the treatment of children with (autism spectrum disorders) was unnecessary and had the potential for harm,” said the committee in its grounds.

 

Conclusion

It is rather addictive reading the news that appears on your phone.

Making your own news, even if you choose not to share it with the wider world, looks like a better option.

I was asked by one person who reviewed a draft of my book, why do I not include a collection of autism treatment case studies. I explained that most people who have been successful do not want to publicly share their results.  That is a pity, but it is human nature – why take an unnecessary risk? Even Dr Kay in Singapore gets himself into trouble, just trying to help other people.

In spite of there being no autism treatment gazette with hundreds of detailed case histories for parents to look through, there are nonetheless many clues in the published research.

The key point is that therapy needs to be personalized. Antifungals, antibiotics and antivirals might do wonders for one person, but do absolutely nothing for your child.    

The worst problem of all can be aggression and self-injurious behavior; vitamin B6 clearly works for some, but most people will need one of the numerous other therapies.

 

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

 

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

By 品璉 江 - originally posted to Flickr as [1]This file has been extracted from another file: Taipei panorama.jpg, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=79310952

Taipei, home to Lactobacillus plantarum PS128, isolated from fu-tsai, which is a spontaneously fermented mustard product

Our reader Prada is a fan of the Biogaia Gastrus probiotic and did comment recently that her doctor does not believe in SIBO (Small Intestinal Bacterial Overgrowth).  We know that many doctors, particularly in English-speaking countries, believe that probiotics have no serious medical value. Many autism parents think their child has SIBO and give them probiotics, among other therapies.

Unless there is a consistently reliable diagnostic test that is affordable and widely available, you inevitably get the situation where patients are convinced that they have a condition (SIBO, PANS/PANDAS, Fibromyalgia etc) while their local doctor thinks it is all in their imagination.

When it comes to probiotic bacteria as a therapy, Italian doctors take them entirely seriously, while many English-speaking doctors regard them as little more than a placebo.  I discovered to my surprise 20 years ago that some really do work.

One reader of this blog in Italy was recommended the new Taiwanese-developed “Psychobiotic” Neuraxbio (Lactobacillus plantarum PS128) by her gastroenterologist and found it was beneficial for her child’s stereotypy. Anyway, her enthusiasm brought me back to Psychobiotics.

I did consider writing a post a while back on Psychobiotics, which are probiotic bacteria that can provide reliable modulation of something useful inside the brain and may have nothing to do with treating GI problems.  It is a nice idea, but the problem is the “reliable” part. In this blog we have already seen that in some people certain commercially available probiotics can have a benefit on behaviour. The problem is that in most people there was either no effect, or actually a negative effect.

There is a small probiotic company in Taiwan, called Bened, that is developing products specifically targeting neurological conditions, including: -

·        Depression

·        Autism

·        ADHD

·        Parkinson’s disease

In 2016 they patented their first product, Lactobacillus plantarum PS128 (isolated from fu-tsai) and started selling it in Asia, where it is widely available and now it is sold in Europe and the US.

In Hong Kong it is sold as “Smart Kids Probiotics” (智樂益生素), under the brand Boost & Guard (補健).

In France it is sold as Neurobiotique, in Italy as Neuraxbio and in the US as Solace.  The US vendor has an easy to read brochure

https://solaceprobiotic.com/pages/brochure

For readers in the Balkans, PS128 is also coming your way soon, Corona virus permitting.

http://www.benedbiomed.com/en/news/The%20world’s%20unique%20Psychobiotic%20PS128™%20will%20reach%20the%20Balkans.-103.html

In Bened’s view, the current opportunities are: -

·        Psychobiotics, that regulate both serotonin and dopamine and can treat anxiety and depression.  (Lactobacillus plantarum PS128)

“Chronic administration of Lactobacillus plantarum PS128 significantly ameliorates anxiety and depression-like behaviors, increases dopaminergic activity in the prefrontal cortex, and reduced stress-induced elevation of serum corticosterone and inflammatory cytokine levels in mice subjected to early maternal separation. Oral administration with Lactobacillus plantarum PS128 significantly decreases visceral hypersensitivity in a rat animal model. Lactobacillus plantarum PS128 shows potential for irritable bowel syndrome (IBS) treatment.”

·        Immunobiotics, that rebalance the production of Th1/Th2 cytokines (Lactococcus lactis A17)

“In vitro experiment reveals cytokines IFN-γ production by human peripheral blood mononuclear cells stimulated with Lactococcus lactis A17 is higher compared with those with other 17 Lactic acid bacteria strains, including Lactobacillus rhamnosus GG and Lactobacillus casei strain Shirota. The Ovalbumin (OVA)-sensitized BALB/c mouse model was further conducted to further examine the Immunomodulatory activities of A17. Repression of NOD-1, NOD-2, TLR-4 production”

·        Metabolicbiotics, that reduce weight, cholesterol and triglycerides in those with a high fat diet (Lactobacillus plantarum K21)

“Supplementation of Lactobacillus plantarum K21 appeared to alleviate body weight gain and epididymal fat mass accumulation, reduce plasma leptin levels, decrease cholesterol and triglyceride levels, and mitigate liver damage in diet-induced obese mice. In addition, Lactobacillus plantarum K21 supplementation strengthens intestinal permeability and modulates the amount of Lactobacillus spp., Bifidobacterium spp., and Clostridium perfringens in the cecal contents of diet-induced obese mice. Dietary intake of Lactobacillus plantarum K21 does protect against the onset of high-fat diet induced obesity through multiple mechanisms of action.”

  

What does Lactobacillus PS128 do?

The research suggests that PS128 affects serotonin and dopamine while also being anti-inflammatory by reducing the expression of the inflammatory cytokine IL-6 and increasing the expression of the anti-inflammatory cytokine IL-10.  In the jargon, it shifts the Th1/Th2 balance.

Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice. 

 Highlights

·        We found a Lactobacillus plantarum strain PS128 changed emotional behaviors.

·        PS128 reduced depression-like behavior in ELS mice.

·        PS128 reduced anxiety-like behavior in normal adult mice.

·        PS128 modulated prefrontal cortical serotonergic and dopaminergic systems.

  

Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms.

Alteration of behavior and monoamine levels attributable to Lactobacillus plantarum PS128 in germ-free mice.

 

Probiotics, defined as live bacteria or bacterial products, confer a significant health benefit to the host, including amelioration of anxiety-like behavior and psychiatric illnesses. Here we administered Lactobacillus plantarum PS128 (PS128) to a germ-free (GF) mouse model to investigate the impact of the gut-brain axis on emotional behaviors. First, we demonstrated that chronic administration of live PS128 showed no adverse effects on physical health. Then, we found that administration of live PS128 significantly increased the total distance travelled in the open field test and decreased the time spent in the closed arm in the elevated plus maze test, whereas the administration of PS128 had no significant effects in the depression-like behaviors of GF mice. Also, chronic live PS128 ingestion significantly increased the levels of both serotonin and dopamine in the striatum, but not in the prefrontal cortex or hippocampus. These results suggest that the chronic administration of PS128 is safe and could induce changes in emotional behaviors. The behavioral changes are correlated with the increase in the monoamine neurotransmitters in the striatum. These findings suggest that daily intake of the L. plantarum strain PS128 could improve anxiety-like behaviors and may be helpful in ameliorating neuropsychiatric disorders.

New perspectives of Lactobacillus plantarum as a probiotic: The gut-heart-brain axis

Lactobacillus plantarum is a non-gas-producing lactic acid bacterium that is generally regarded as safe (GRAS) with Qualified Presumption of Safety (QPS) status. Although traditionally used for dairy, meat and vegetable fermentation, L. plantarum is gaining increasing significance as a probiotic. With the newly acclaimed gut-heart-brain axis, strains of L. plantarum have proven to be a valuable species for the development of probiotics, with various beneficial effects on gut health, metabolic disorders and brain health. In this review, the classification and taxonomy, and the relation of these with safety aspects are introduced. Characteristics of L. plantarum to fulfil the criteria as a probiotic are discussed. Emphasis are also given to the beneficial functions of L. plantarum in gut disorders such as inflammatory bowel diseases, metabolic syndromes, dyslipidemia, hypercholesteromia, obesity, and diabetes, and brain health aspects involving psychological disorders.

Psychobiotics

According to the definition by WHO, mental health is an integral and essential component of health, a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity. Furthermore, mental health is more than just the absence of mental disorders or disabilities (WHO, 2016). Major depressive disorder and anxiety disorders are debilitating illnesses that are rising as a global burden of disease (Whiteford et al., 2015; Logan et al., 2016). Dr. Dinan and colleagues defined a new group of bacteria, termed psychobiotics, as ‘live organisms that produce health benefits in patients suffering from psychiatric illness when ingested in adequate amounts’ and the ingestion of psychobiotics may induce psychotropic effects on behavior and additional neurochemicals in the brain (Dinan et al., 2013). This concept has shed light on microbe-based psychopharmacology. The human intestine has a large surface area, ranging from 30 to 400 cubic meters (Perez-Lopez et al., 2016), and is inhabited by 1013 to 1014 microorganisms. The number of microorganisms is 10 times greater than that of human cells, and the encapsulated genetic material exceeds the human genome content by 150-fold (de Vos and de Vos, 2012; Lozupone et al., 2012; Dinan et al., 2013). Because the large number of microorganisms live with human, it is logical to infer that associated microorganisms may play roles in human health and even in mental health. Considering that the gut-brain axis is a new concept and the applications of probiotics to enhance mental health is at its infancy, only few strains of L. plantarum have been investigated for this purpose. One of the more prominent strains of L. plantarum investigated as a psychobiotic is L. plantarum PS128 (Liu et al., 2016a, 2016b). The psychotropic effects of L. plantarum PS128 were investigated in an early life stress (ELS) mouse model. ELS negatively impacts brain development and results in behavioral changes in adulthood (Lupien et al., 2009). Maternal separation triggers ELS in rodents (O’Mahony et al., 2011). Mice that experience maternal separation exhibit lasting behavioral abnormalities, enhanced stress responses, increased anxiety-like and depression-like behaviors, elevated HPA reactivity, and altered neurochemical expression (Cryan and Holmes, 2005). Several behavior tests were employed to evaluate the effects of L. plantarum PS128 on abnormal behaviors, namely the sucrose preference test (SPT) and forced swimming test (FST). L. plantarum PS128 at a daily dose of 109 CFU/mouse reduced ELS-induced depression-like behaviors (Liu et al., 2016b). Maternal separation-triggered stress responses are evidenced by elevated levels of corticosterone before and after FST stress treatment. L. plantarum PS128 significantly reduced corticosterone levels at baseline and after FST, indicating that PS128 normalizes the HPA axis. Elevated serum levels of IL-6 are often observed in people experiencing childhood stress (Coelho et al., 2014). Modulation of IL-6 expression also potentiates the beneficial effects of L. plantarum PS128 on depression. Reduced levels of dopamine (DA) and serotonin (5-HT) and increased turnover rates of DA and 5-HT have been observed in the prefrontal cortex (PFC) of ELS mice. L. plantarum PS128 reversed these changes to a status similar to normal control mice, demonstrating the potential of PS128 as a psychobiotic to improve mental health. L. plantarum C29 was reported to protect memory deficit induced by scopolamine (Jung et al., 2012), D-galactose (Woo et al., 2014), aging (Jeong et al., 2015), and IBD (Lee et al., 2018). Increased expression of derived neurotrophic factor (BNDF) was observed in the above studies. BDNF protein is widely distributed throughout the adult brain in almost all cortical areas and was believed to be necessary for the continued survival and phenotypic maintenance of mature, fully developed neurons. In review of Zuccato and Cattaneo (2009), the levels of BDNF in brain were decreased in neurodegenerative diseases, Alzheimer disease, Parkinson disease, and Huntington disease (Zuccato and Cattaneo, 2009). The protective effects of L. plantarum C29 on memory deficit may attribute to the ability to elevate BDNF in brain

Does Lactobacillus PS128 work for “autism”?

People understandably assume a product should do what it says.  Probiotics to treat GI problems from diarrhea to IBS to IBD are pretty well researched and though some are expensive (e.g. VSL#3, Vivomixx) they do work for many people.

Some people use Biogaia Gastrus as a Pyschobiotic with success and our reader Prada has joined that group.  The only way to find out is to try it, but in the case of Biogaia Gastrus it actually makes some people much worse.

There actually is a published study investigating the effect of Lactobacillus plantarum PS128 on Children with Autism.

The study suggests that our reader in Italy and the people with the testimonials in US version of PS128 are not just exceptions.

Effects of Lactobacillus plantarum PS128 on Children with Autism Spectrum Disorder in Taiwan: A Randomized,Double-Blind, Placebo-Controlled Trial

This four-week, randomized, double-blind, placebo-controlled study investigated the effects of Lactobacillus plantarum PS128 (PS128) on boys with autism spectrum disorder (ASD) aged 7–15 in Taiwan. All subjects fulfilled the criteria for ASD diagnosis of DSM-V and the Autism Diagnostic Interview-Revised (ADI-R). Questionnaires used for the primary outcome measure include the Autism Behavior Checklist-Taiwan version (ABC-T), the Social Responsiveness Scale (SRS) and the Child Behavior Checklist (CBCL). The Swanson, Nolan, and Pelham-IV-Taiwan version (SNAP-IV) and the Clinical Global Impression-improvement (CGI-I) were used for the secondary outcome measure. The results showed that PS128 ameliorated opposition/defiance behaviors, and that the total score of SNAP-IV for younger children (aged 7−12) improved significantly compared with the placebo group. Additionally, several elements were also notably improved in the PS128 group after 28-day consumption of PS128. Further studies are needed to better clarify the effects of PS128 for younger children with ASD on broader symptoms.

I think the following study is relevant to our Italian reader, for whom NAC did not benefit stereotypy, but PS128 did.

I did mention to her the Tourette’s type autism, that was studied in Siena. In these people a dopamine disorder causes the repetitive behavior, so the behaviors are really better described as tics than stereotypy.  Note that a serotonin agonist can cause a dopamine driven tic.

  

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

Lactobacillus plantarum PS128 ameliorates2,5-Dimethoxy-4-iodoamphetamine-induced tic-like behaviors via its influenceson the microbiota–gut-brain-axis

Highlights

Serotonin receptor agonist DOI causes tic-like behaviors and gut dysbiosis in rat.

DOI triggers hyperactive signaling in mesocortical and nigrostriatal pathways.

PS128 alleviates DOI-induced behavior and hyperactive signaling.

PS128 modulates enteric serotonergic system and stabilizes gut microbiota.

PS128 strengthens the microbiota–gut–brain axis function of the host.

 

Abstract

We previously reported a novel psychobiotic strain of Lactobacillus plantarum PS128 (PS128) which could ameliorate anxiety-like& depression-like behaviors and modulate cerebral dopamine (DA) and serotonin (5-HT) in mice. Here, we examine the possibility of using PS128 administration to improve tic-like behaviors by using a 5-HT_2A and 5-HT_2C receptor agonist 2,5-Dimethoxy-4-iodoamphetamine (DOI). PS128 was orally administered to male Wistar rat for 2 weeks before two daily DOI injections. We recorded the behaviors immediately after the second DOI injection and compared the results with control and haloperidol treatment groups. PS128 significantly reduced tic-like behaviors and pre-pulse inhibition deficit in a threshold-dose of 10⁹ CFU per day. Brain tissue analysis showed that DOI induced abnormal DA efflux in the striatum and prefrontal cortex, while PS128 ingestion improved DA metabolism and increased norepinephrine (NE) levels in these two regions. In addition, PS128 ingestion increased DA transporter and β-arrestin expressions and decreased DOI-induced phosphorylation of DA and cAMP regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) at Thr34 and extracellular regulated protein kinases (ERK). PS128 ingestion also modulated peripheral 5-HT levels and shaped the cecal microbiota composition, which helps to alleviate DOI-induced dysbiosis. These results suggested that PS128 ameliorated DOI-induced tic-like hyper-active behaviors via stabilizing cerebral dopaminergic pathways through its modulation of host’s microbiota–gut–brain axis. Thus, we believe there are potentials for utilizing psychobiotics to improve syndromes caused by DA dysregulation in DA-related neurological disorders and movement disorders such as Tourette syndrome.

Lactobacillus PS128 clearly does benefit some people. It does have an effect on GI problems, but it may well benefit some people who have no GI problems.  It is specifically targeted at the brain, not the gut.

If available locally it is worth a trial.

Is it going to make some people “worse”?  It affects serotonin and dopamine and it is “anti-inflammatory” (raises IL-10 and lowers 1L-6), so some people undoubtedly will not be compatible.

It is not a cheap product, but is sold to be refrigerated and contains 30 billion colony forming units (CFU).  It looks like a serious probiotic like VSL#3, Vivomixx and Biogaia.

People are making home-made yogurt with Biogaia Protectis and Biogaia Gastrus, so if Lactobacillus PS128 is effective but looks pricey, you can make your own. Lactobacillus bacteria grow well in milk

Some yoghurts have Lactobacillus rhamnosus added.

Making fermented milk products is actually very easy, this how you can grow your own Lactobacillus PS128.

I can envisage adding Lactobacillus PS128 fermented in milk to Monty’s breakfast yoghurt.

The other possible reason that Lactobacillus PS128 helped our Italian reader’s daughter is its effect on serotonin.

Some people find that SSRI drugs like Prozac reduce stereotypy along with anxiety.  SSRI drugs can have side effects and may not be an ideal therapy for stereotypy.

Research in apes supports the fact that some people find inositol reduces stereotypy.  Inositol is a naturally occurring sugar found in the brain that acts both as a messenger and a precursor to other neurotransmitters. The inositol trisphosphate receptor (IP3R) is a Ca²⁺ channel activated by inositol trisphosphate (IP3).  IP3R appears to be a downstream nexus where many different types of autism converge.

Inositol is used to treat PCOS due to its metabolic effects.

Inositol appears to indirectly have an effect on serotonin, but it gets very complicated.

Source: Potential role and therapeuticinterests of myo-inositol in metabolic diseases

As you would expect, the serotine-type stereotypy is the result of one specific receptor.  It appears to be 5-HT₇ or 5-HT_1A.

An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-HT7 and 5-HT1A Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models

Stereotypy (e.g., repetitive hand waving) is a key phenotype of autism spectrum disorder, Fragile X and Rett syndromes, and other neuropsychiatric disorders, and its severity correlates with cognitive and attention deficits. There are no effective treatments, however, for stereotypy. Perturbation of serotonin (5-HT) neurotransmission contributes to stereotypy, suggesting that distinct 5-HT receptors may be pharmacotherapeutic targets to treat stereotypy and related neuropsychiatric symptoms. For example, preclinical studies indicate that 5-HT₇ receptor activation corrects deficits in mouse models of Fragile X and Rett syndromes, and clinical trials for autism are underway with buspirone, a 5-HT_1A partial agonist with relevant affinity at 5-HT₇ receptors. Herein, we report the synthesis, in vitro molecular pharmacology, behavioral pharmacology, and pharmacokinetic parameters in mice after subcutaneous and oral administration of (+)-5-(2′-fluorophenyl)-N,N-dimethyl-1,2,3,4-tetrahydronaphthalen-2-amine ((+)-5-FPT), a new, dual partial agonist targeting both 5-HT₇ (K_i = 5.8 nM, EC₅₀ = 34 nM) and 5-HT_1A (K_i = 22 nM, EC₅₀ = 40 nM) receptors. Three unique, heterogeneous mouse models were used to assess the efficacy of (+)-5-FPT to reduce stereotypy: idiopathic jumping in C58/J mice, repetitive body rotations in C57BL/6J mice treated with the NMDA antagonist, MK-801, and repetitive head twitching in C57BL/6J mice treated with the 5-HT₂ agonist, DOI. Systemic (+)-5-FPT potently and efficaciously reduced or eliminated stereotypy in each of the mouse models without altering locomotor behavior on its own, and additional tests showed that (+)-5-FPT, at the highest behaviorally active dose tested, enhanced social interaction and did not cause behaviors indicative of serotonin syndrome. These data suggest that (+)-5-FPT is a promising medication for treating stereotypy in psychiatric disorders

Efficacy of Low-Dose Buspirone for Restricted and Repetitive Behavior in Young Children with Autism Spectrum Disorder: A  Randomized Trial 

Children 2-6 years of age with ASD (N = 166) were randomized to receive placebo or 2.5 or 5.0 mg of buspirone twice daily. The primary objective was to evaluate the effects of 24 weeks of buspirone on the Autism Diagnostic Observation Schedule (ADOS) Composite Total Score. Secondary objectives included evaluating the effects of buspirone on social competence, repetitive behaviors, language, sensory dysfunction, and anxiety and to assess side effects. Positron emission tomography measures of tryptophan metabolism and blood serotonin concentrations were assessed as predictors of buspirone efficacy.

Results

There was no difference in the ADOS Composite Total Score between baseline and 24 weeks among the 3 treatment groups (P = .400); however, the ADOS Restricted and Repetitive Behavior score showed a time-by-treatment effect (P = .006); the 2.5-mg buspirone group showed significant improvement (P = .003), whereas placebo and 5.0-mg buspirone groups showed no change. Children in the 2.5-mg buspirone group were more likely to improve if they had fewer foci of increased brain tryptophan metabolism on positron emission tomography (P = .018) or if they showed normal levels of blood serotonin (P = .044). Adverse events did not differ significantly among treatment groups.

Conclusions

Treatment with 2.5 mg of buspirone in young children with ASD might be a useful adjunct therapy to target restrictive and repetitive behaviors in conjunction with behavioral interventions.

  

Stereotypies in Captive Primates and the Use of Inositol: Lessons from Obsessive–Compulsive Disorder in Humans

Animal stereotypies have long been used in the study of obsessive–compulsive disorder (OCD) in humans. These studies have led to the understanding of some of the molecular pathways in the disorder and the use of selective serotonin reuptake inhibitors and myo-inositol in the treatment of these conditions. If animal models, especially nonhuman primate models, were used to study human disorders and if the resulting treatments were successful, then conversely one should be able to treat nonhuman primate stereotypies with similar methods. We here summarize animal models of OCD (including nonhuman primate models) and human OCD treatments, and using successful human treatment by myo-inositol as models, recommend the use of myo-inositol in good captive management practice and the treatment of nonhuman primate stereotypies. We believe that this would be particularly useful in the treatment of stereotypies in nonhuman primates because they are physiologically so similar to humans.

Inositol holds much promise in the treatment and prevention of stereotypic behavior, and although much research is required to understand the molecular mechanisms behind its mode of action and the reason for failure in 30 % of human cases, its use does mean the possibility of treatment and prevention in 60–70 % of cases that would otherwise be untreatable.

Back to SIBO

Many people think their child with autism has SIBO (Small intestinal bacterial overgrowth). Most likely some do and some do not.

To diagnose SIBO you need a breath test

Here is what Johns Hopkins have to say about SIBO: -

https://www.hopkinsmedicine.org/gastroenterology_hepatology/diseases_conditions/small_large_intestine/small-intestinal-bacterial-overgrowth.html

Our gastroenterologists (doctors who specialize in the digestive system) diagnose SIBO with a lactulose breath test. For the test, you will swallow a drink containing the sugar lactulose. Next, you will breathe into a balloon approximately every 15 minutes over the course of three hours. Each time, we remove the breath sample from the balloon and test it. SIBO may be present if your breath sample contains hydrogen or methane shortly after drinking the solution.

Treatment

·         hydrogen-predominant SIBO: The primary treatment is the antibiotic rifaximin.

·         methane-predominant SIBO This type of SIBO is harder to treat, and it may take longer to respond to treatment. We use rifaximin plus neomycin for these cases.

·         recurrent SIBO: We closely monitor you for a recurrence of SIBO. If it happens, you will benefit from our experience treating the disease. We have experience with formulations of antimicrobial herbs, which can be used to treat recurrences and as an alternative for initial treatment of hydrogen- or methane-predominant SIBO.

As part of your treatment, we recommend following a FODMAP (low fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diet and consulting with a nutritionist.

The symptoms of SIBO are not unique to SIBO

SIBO is an abnormal number of bacteria in the small intestine that can lead to:

·         bloating and increased passing of gas (flatulence)

·         diarrhea or constipation

·         abdominal pain

·         nausea

·         fatigue

What are SIBO risk factors?

Structural or anatomic abnormalities may affect normal movement of the small intestine (motility). Stasis, or lack of movement, can lead to bacterial imbalance. This can occur if you:

·         Have diverticulosis — tiny bulging pouches (diverticula) in the small intestine

·         Had surgery that changed the small intestine’s structure, such as Roux-en-Y gastric bypass surgery, or surgery on the right colon with removal of the ileocecal valve, or surgery on the last part of the small bowel.

·         Have adhesions (scar tissue) that developed after radiation therapy or after multiple abdominal surgeries

·         Have amyloidosis (a buildup of amyloid protein deposits) — deposits can accumulate in the small intestine and change its structure

Use of certain medications could be linked to SIBO. These include:

·         Narcotic medications

·         Anti-spasm medications for irritable bowel syndrome (IBS), such as hyoscyamine or dicyclomine

·         Long-term use of proton pump inhibitors (PPIs) — medications that decrease acid in the stomach to control heartburn

·         Frequent use of antibiotics, which may alter the bacteria in the small bowel

Chronic systemic conditions can cause motility issues. If you have these conditions, you may be at a higher risk for SIBO:

·         Diabetes

·         Lupus

·         Scleroderma or connective tissue disorders

What is the problem with rifaximin?

Rifaximin is a generic antibiotic used to treat traveler’s diarrhea, irritable bowel syndrome and SIBO.

In much of the world Rifaximin is very cheap, it costs a few dollars/euros where I live, but in the US it costs thousands of dollars a year.

So, the land of the free is where big pharma is free to make obscene profit margins, as they do even with life-saving drugs like insulin.  In developed countries Type-1 diabetic people get their insulin free and there is universal healthcare.

There are many other drug options other than Rifaximin and in the study below they found some herbal treatments as effective as Rifaximin.

Herbal Therapy Is Equivalent to Rifaximin for the Treatment of Small Intestinal Bacterial Overgrowth

Objective:

Patients with small intestine bacterial overgrowth (SIBO) have chronic intestinal and extraintestinal symptomatology which adversely affects their quality of life. Present treatment of SIBO is limited to oral antibiotics with variable success. A growing number of patients are interested in using complementary and alternative therapies for their gastrointestinal health. The objective was to determine the remission rate of SIBO using either the antibiotic rifaximin or herbals in a tertiary care referral gastroenterology practice.

Design:

One hundred and four patients who tested positive for newly diagnosed SIBO by lactulose breath testing (LBT) were offered either rifaximin 1200 mg daily vs herbal therapy for 4 weeks with repeat LBT post-treatment.

Results:

Three hundred ninety-six patients underwent LBT for suspected SIBO, of which 251 (63.4%) were positive 165 underwent treatment and 104 had a follow-up LBT. Of the 37 patients who received herbal therapy, 17 (46%) had a negative follow-up LBT compared to 23/67 (34%) of rifaximin users (P=.24). The odds ratio of having a negative LBT after taking herbal therapy as compared to rifaximin was 1.85 (CI=0.77-4.41, P=.17) once adjusted for age, gender, SIBO risk factors and IBS status. Fourteen of the 44 (31.8%) rifaximin non-responders were offered herbal rescue therapy, with 8 of the 14 (57.1%) having a negative LBT after completing the rescue herbal therapy, while 10 non-responders were offered triple antibiotics with 6 responding (60%, P=.89). Adverse effects were reported among the rifaximin treated arm including 1 case of anaphylaxis, 2 cases of hives, 2 cases of diarrhea and 1 case of Clostridium difficile. Only one case of diarrhea was reported in the herbal therapy arm, which did not reach statistical significance (P=.22).

Conclusion:

SIBO is widely prevalent in a tertiary referral gastroenterology practice. Herbal therapies are at least as effective as rifaximin for resolution of SIBO by LBT. Herbals also appear to be as effective as triple antibiotic therapy for SIBO rescue therapy for rifaximin non-responders. Further, prospective studies are needed to validate these findings and explore additional alternative therapies in patients with refractory SIBO

Table 1

Conditions That Predispose Toward the Development of Small Intestine Bacterial Overgrowth

Achlorhydria (surgical, iatrogenic, autoimmune)

Motor abnormalities

Scleroderma

Intestinal pseudo-obstruction

Diabetic enteropathy

Vagotomy

Abnormal communication between colon and small bowel

Fistulas between colon and small bowel

Resection of ileocecal valve

Structural abnormalities

Systemic and intestinal immune deficiency states

Surgical loops (Billroth II, entero-entero anastomosis, Rou-en-Y)

Duodenal or jejunal diverticula

Partial obstruction of small bowel (stricture, adhesions, tumors)

Large small Intestine diverticulosis

Systemic diseases (celiac disease, cirrhosis, pancreatic exocrine insufficiency, non-alcoholic fatty liver disease)

Alcoholism

Table 2

Protective Factors That Protect Against the Development of Small Intestine Bacterial Overgrowth

• Gastric acid

• Pancreatic enzymes

• Bile acids

• Cholecystectomy

• Motility

• Migrating motor complex

• Biofilm

• Secretory immunoglobulin A

Table 3

Extrinsic Factors That Alter the Gut Microbiome and May Influence the Development of Small Intestine Bacterial Overgrowth

FODMAPsa (fructose, lactose, galactans, fructans, sugar alcohols)

Proton pump inhibitors

Anti-motility agents

Fiber

Prebiotics

Probiotics

Antibiotics

Table 4

Antibiotic Regimens Used for Small Intestine Bacterial Overgrowth

Agent                                        Dose                Frequency

Amoxicillin-clavulanate               500 mg             3 times/day

Cephalexin                                250 mg             4 times/day

Chloramphenicol                       250 mg             4 times/day

Ciprofloxacin                            500 mg             twice daily

Doxycycline                              100 mg             twice daily

Metronidazole                           250 mg             3 times/day

Neomycin                                 500 mg             twice daily

Norfloxacin                               400 mg             twice daily

Rifaximin                                  400 mg             3 times/day

Tetracycline                               250 mg             4 times/day

Trimethoprim-                            1 double-          twice daily

Sulfamethoxazole                      strength tablet

Conclusion

I think PS-128 is very likely to be a winner for many people diagnosed with Tourette’s syndrome.

Repetitive behaviors in autism that are caused by a dopamine anomaly may well respond to PS-128. Note that a serotonin anomaly can cause a dopamine anomaly.

Undoubtedly, some people with autism are going to develop a motor/verbal tic when they take PS-128.  They should stop taking it and the tic should fade away, just like the negative reaction to Biogaia Gastrus fades away in those so affected. 

Anxiety is a common feature in autism, but has numerous underlying mechanisms, so I think PS-128 will help some and not others.  It is certainly worth trying.

Tics and stereotypy get confused and the causes may indeed overlap.  Dopamine anomalies can lead to tics and movement disorders.  Serotonin anomalies can lead to repetitive behaviors and of course anxiety.  Oxidative stress can lead to stereotypy and even compulsive behavior like Trichotillomania (pulling out your own hair).  

Autoimmune encephalopathy can give symptoms of tics, OCD and/or stereotypy, and even schizophrenia depending on which receptors in the brain are affected - PANS/PANDAS is a subtype of autoimmune encephalopathy.

·        Low dose Buspirone. It is not an SSRI, but this anxiety medicine at very low doses (2.5 to 5 mg) looks interesting for serotonin-type stereotypy

·        Inositol (it’s cheap and OTC)

·        Prednisone for Autoimmune encephalopathy

You might think the supplement 5HTP would help with the serotin type of stereotypy; 5HTP is a precursor of serotonin that is sold widely for anxiety etc.  Long term use may cause you problems.

5-HTP efficacy and contraindications

The most significant side effects and adverse reactions may occur with long-term use (many months or longer). Administration of 5-HTP alone depletes catecholamines (dopamine, norepinephrine, and epinephrine). When dopamine depletion is great enough, 5-HTP will no longer function.  If other centrally acting monoamine-related disease processes involving catecholamines are present, administration of 5-HTP alone may deplete dopamine, norepinephrine and epinephrine thereby exacerbating these conditions

Some doctors and indeed autism self-advocates think that stereotypy is a healthy calming behavior.  These autism self-advocates tend to be the ones that had a terrible time during their school years, because they were not accepted and now feel that qualifies them to give advice to others.  I not so sure they are right, I would rather take autism advice from happy/successful Aspies, rather than bitter ones.

I think that uncontrollable stereotypy gets in the way of normal life and learning in particular; if its origin is biological, it can be treated.  Since there are multiple possible mechanisms at work, it can take time to find your effective therapy.  As usual, perseverance yields results in most cases.

Back to the SIBO part of this post

I think most people with intestinal dysbiosis do not have SIBO.  If you live in the US, it looks quite easy to get a breath test for SIBO.

Rifaximin seems to benefit many people with autism and GI problems; they may well not have SIBO.  For people outside the US, Rifaximin looks a good choice, for recurring use.  Our reader Maja is a big fan of Rifaximin for her daughter.

If you have to pay thousands of dollars a year for Rifaximin, you may want to look at both the drug and herbal alternatives.

For SIBO caused by long term use of PPIs (acid reducing drugs) you can try alternate day dosing, or the old remedy of drinking diluted apple cider vinegar.  Both methods should increase acidity in the small intestine making it hostile to unwanted bacteria, the way nature intended.  If you drink apple cider vinegar you have to rinse your mouth out afterwards or you will damage your teeth.

Probiotics have been in widespread use to treat GI problems in some countries for half a century.  That is plenty time to judge their effectiveness, if people care to look.

Probiotics have been shown to have far reaching effects beyond the gut and this causes many people to have serious doubts.  How can your gut affect your brain, your eczema or your asthma?

When it comes to the brain, the research has proved that there is bidirectional communication between the brain and the gut via the vagus nerve.  Sever the vagus nerve (which used to be a medical procedure for IBS) and the effect is lost.

Many probiotics sold lack potency either because they were not stored correctly, and the bacteria died or because the producer has included too few bacteria to start with.

The users of Biogaia Gastrus for autism are taking 5 tablets a day, because one tablet contains only 100 million CFU.