UA-45667900-1
Showing posts with label Biogaia. Show all posts
Showing posts with label Biogaia. Show all posts

Tuesday 15 December 2020

Fine tuning Social Behavior in Autism with an existing pediatric drug, Desmopressin?

 


There are two closely related hormones, vasopressin and oxytocin, that have been extensively researched in autism. 

With oxytocin you can modify social-bonding behavior. You can increase oxytocin in the brain either via a nasal spray containing oxytocin, or you can add a specific bacterium to your gut that triggers a signal to the brain to produce more of its own oxytocin.  The latter is my preferred method, because you can produce a mild long-lasting effect throughout the day.

Oxytocin has a very short life and it does not cross the blood brain barrier.

There is even a new study in the works that will compare these two methods of treating autism.

 

Probiotics and oxytocin nasal spray as neuro-social-behavioral interventions for patients with autism spectrum disorders: a pilot randomized controlled trial protocol

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication. Oxytocin (OXT), as a neuropeptide, plays a role in emotional and social behaviors. Lactobacillus reuteri (L. reuteri) supplementation led to an OXT-dependent behavioral improvement in ASD mouse models. Despite some promising results from animal studies, little is known about the efficacy of supplementation with L. reuteri, alone or with exogenous OXT therapy, on social-behavioral functions in ASD patients. This paper presents a protocol for a pilot randomized controlled trial to evaluate the feasibility of conducting a full trial comparing oral supplementation of L. reuteri probiotics and intranasal OXT spray to placebo on the effect of social and behavioral functions in ASD patients. The study will also capture preliminary estimates of the efficacy of the proposed interventions in ASD patients.

Methods

This pilot trial is a two-staged, randomized, double-blind, placebo-controlled, parallel-group study. Throughout the study (0–24 weeks), 60 patients with ASD will be randomly assigned to receive either oral L. reuteri probiotics or placebo. In the second study stage (13–24 weeks), all participants will receive intranasal OXT spray. As primary outcomes, serum OXT levels will be assayed and social behaviors will be assessed via the Autism Behavior Checklist and the Social Responsiveness Scale which are validated questionnaires, an objective emotional facial matching test, and a new video-based eye-tracking test. Secondary outcomes include the GI-severity-index and Bristol Stool Chart to assess GI function and gut microbiome/short-chain fatty acids. All the outcomes will be assessed at baseline and weeks 12 and 24.

Discussion

This pilot study will provide important information on the feasibility of recruitment, blinding and concealment, treatment administration, tolerability and adherence, specimen collection, outcome assessment, potential adverse effects, and the preliminary efficacy on both primary and secondary outcomes. If successful, this pilot study will inform a larger randomized controlled trial fully powered to examine the efficacies of oral L. reuteri probiotics and/or intranasal OXT spray on social-behavioral improvement in ASD patients. 

My conclusion was to add two drops of L.Reuteri DSM 17938 (Biogaia Protectis) into the liquid part of my son's Polypill therapy. That way there are no extra pills to swallow and in theory the bottle should last 50 days, so I am not forever looking to buy more.  If you want a bigger effect, just add more drops.  The producer suggests a daily dose of 5 drops for babies, to promote GI health - the original intended purpose.

When it comes to Vasopressin it looks like you cannot avoid a nasal inhaler, unless you want to try transcutaneous electrical acupoint stimulation (TEAS).  There is a debate as to whether Vasopressin and its analogs (man-made modified versions) can cross the blood brain barrier and to what extent. 

There are 4 previous posts that looked at Vasopressin. 

https://epiphanyasd.blogspot.com/search/label/Vasopressin 

The Vasopressin showing good results in the trials at Stanford is the injectable pharmaceutical version of the hormone made into a nasal spray.  This kind of spray could be made easily at a compounding pharmacy.

It turns out that a synthetic analog of vasopressin, called desmopressin, has been widely used for over 40 years to treat nocturnal enuresis (night-time bed-wetting) among other more serious conditions.

 

Desmopressin in Autism 

Nocturnal enuresis is common in individuals with but to our knowledge, there are no reports that desmopressin enhances social functioning in ASD (or in any other clinical population). This may be because desmopressin is typically administered at bedtime (so prosocial effects would be less evident) and orally (oral desmopressin does not cross the blood-brain barrier). The most likely explanation, however, is that desmopressin acts selectively on AVPR2, rather than on AVPR1A”

 

From:

A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism

 

Desmopressin N=1 example 

I was recently contacted by the father of a young boy with autism who has been prescribed Desmopressin nasal spray by his neurologist.

The father noted major positive behavioral changes from the first dose.

This is of course great news.

Desmopressin is a widely available drug, seen as safe, and that is why it is prescribed to children.

In the US the nasal spray version is no longer widely used for children and they use the oral version.

In some countries it is used for people with MS (Multiple Sclerosis) with nocturnal enuresis.

 

Desmopressin Shortage

Before readers get too excited, Ferring Pharmaceuticals, the big producer of Desmopressin nasal sprays did voluntarily withdraw its brands (Minirin, DDAVP Nasal Spray, Desmopressin Acetate Nasal Spray) from the market in August 2020 due to a quality problem. 


https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/ferring-us-issues-voluntary-nationwide-recall-ddavpr-nasal-spray-10-mcg01ml-desmopressin-acetate

  

There is now a shortage and so what was an easy to obtain drug, may be more difficult to get.  There is a Pfizer version called Presinex.  

From the above paper on vasopressin for autism:-

Vasopressin benefits 

“In conclusion, the present pilot study determined that 4-week intranasal AVP treatment compared to placebo enhanced social communication abilities, diminished anxiety symptoms, and reduced repetitive behaviors in children with ASD. On nearly all behavioral measures, participants with the highest pre-treatment blood AVP concentrations benefitted the most from AVP treatment, suggesting that pre-treatment blood AVP concentrations may be useful for setting dosing guidelines for this medication. Last, intranasal AVP treatment was well tolerated with minimal side effects in this pediatric study population. These preliminary findings suggest that intranasal AVP treatment has potential to enhance social abilities in an ASD patient population characterized by currently intractable social impairments” 

Transcutaneous electrical acupoint stimulation (TEAS) to raise vasopressin 

“there is evidence that nonpharmacological interventions may facilitate endogenous AVP release, for example, electroacupuncture stimulation increases brain AVP concentrations in rats. Transcutaneous electrical acupoint stimulation (TEAS) therapy improves social functioning and anxiety symptoms in children with ASD, particularly in those with the largest post-treatment increase in blood AVP concentrations. The authors of this prior report theorized that increased AVP signaling may be the mechanism by which the prosocial and anxiolytic benefits of TEAS treatment were achieved” 

 

Vasopressin with Bumetanide  - take great care

A while back, one reader did ask me about taking intranasal Vasopressin with Bumetanide.  His doctor in California thought this might not be wise since the two drugs have opposing effects.

·        Bumetanide (a diuretic) makes you pee more.

·        Vasopressin (the anti-diuretic hormone) makes you pee less.

The real problem is the risk of low sodium, hyponatremia.  This is always a risk with vasopressin and the risk might well increase if you took Bumetanide.  The risk is going to be dose dependent.

If you take Vasopressin and then drink large amounts of water this will disturb the volume of fluids in your body and in particular it will lower the level of sodium.  This may lead to seizures and ultimately worse.

Bumetanide does disturb the level of electrolytes, but nearly all the change usually occurs in Potassium, this is why you need to add back potassium via diet and add a supplement.  Sodium is not normally a problem, but always check all electrolytes when taking a blood draw.

If someone adds vasopressin to their existing bumetanide therapy, the doctor should definitely monitor the level of sodium.

In most people’s diet, sodium is one thing you are likely to have too much of and it is very easy to add a bit more sodium if the blood test suggests it is necessary.  In extreme cases of low sodium you need to use a special re-hydration drink, or an intravenous saline solution.  Monty has a relative who keeps going to hospital for the latter.

The diuretic action of Bumetanide is a side effect of the "autism effect" and so if you can reduce the diuresis of bumetanide that would be good thing.  Researchers are trying to find a better-bumetanide and their goal is to have no diuresis.

If combining vasopressin with Bumetanide is accompanied by both reduced diuresis and a matching reduction in fluid intake, this might actually work well.  Clearly, extra care needs to be taken and what might be perfectly safe in one person may not be safe in another person.

  

Conclusion

I do have to give a big thank-you to our reader who shared his experience with Desmopressin and to the neurologist for suggesting it.

Desmopressin looks like one of those autism therapies that needs only a very short trial to determine whether it is beneficial.  This is a big advantage.

You would hope the Stanford vasopressin researchers make a short trial of Desmopressin, just to compare the effect.  They probably will not.

All you have to decide is whether it is going to be the left nostril, or the right nostril.  With intranasal insulin there was a problem with irritation inside the nose, so alternating left and right sides might be best.  You hold your breath and then squirt the spray; the objective is not to breath the spray into your lungs.  An easy mistake to make.

Note that I am referring to the 10 mcg/0.1mL Desmopressin nasal spray.  The one used to treat kids that wet their bed at night.

There is also a much more potent 1.5 mg/mL version, called Stimate in the US.  This is used to treat von Willebrand’s Disease (Type I) and hemophilia/haemophilia.  You do not want that version.  This version is 15 times more potent than the anti bed-wetting variant. 

I have been suggesting to Aspies living in the US that they give Vasopressin a trial to counter the social deficits that some find troubling.  I think they are able to obtain this via a compounding pharmacy, with a helpful doctor’s prescription.

I think outside the US your doctor will think you are mad if you ask for a specially compounded vasopressin nasal spray, or indeed a compounded  oxytocin spray.

For people unable to get the intranasal vasopressin prescribed/compounded, Desmopressin is on option to discuss with your doctor. Maybe time to develop a bed wetting problem?

The Aspies in the Netherlands have the legal option of a tiny non-hallucinogenic dose of Psilocybin once a month, which seems an effective way to target Serotonin 5-HT2A receptor-mediated pathways and so improve social behavior. What caught my attention was that the effect of this tiny dose lasts a month and it can also be used to treat severe, otherwise untreatable, cluster headaches.

Psilocybin is the fancy name for magic mushrooms.

Psilocybin is also legal in Brazil and not surprisingly in Jamaica.  It looks like the US is moving in the same direction - medicinal magic mushrooms!


FDA grants Breakthrough Therapy Designation to Usona Institute's psilocybin program for major depressive disorder


The “medical” dose of Psilocybin is a tiny fraction of the “recreational” dose and is only taken when the effect of previous dose fades to zero.  It is not a crazy idea at all, just not currently a legal therapy in most countries.  More than half a century ago Lovaas was researching something very similar at UCLA, but using LSD.


All told, there are several potential ways to fine-tune social behavior in autism. Sulforaphane is yet another option.



 

Thursday 23 July 2020

How to increase Oxytocin (OT) effects in the autistic brain? OT nasal spray, L. reuteri DSM 17938, Magnesium, Estradiol, Nicotinamide riboside …



 Struggle to make friends? Consider Oxytocin



Today’s post was going to be about FMT super-donors, but instead we have a post about new insights into using oxytocin to treat autism.  From personal experience I can say that you really can target oxytocin receptors to affect mood/behavior; I have no personal experience of FMT (fecal microbiota transplants), but thousands of people use it for many conditions.  The FMT post will be next.

Oxytocin and vasopressin are two hormones, made in the hypothalamus, that are established targets for autism treatment. They are released into the bloodstream where they carry out their best-known functions, but they are also released from the hypothalamus directly into the brain where these hormones have entirely different functions.

Both oxytocin and vasopressin can be given as nasal sprays to enter the central nervous system (CNS) rather than just the blood stream.  This means you get the brain effects of the hormone, also known as the “central effects”.

As was discussed previously in this blog and is highlighted more recently in the article below, you can use certain bacteria in the gut to signal to the hypothalamus to produce more oxytocin.  This is really clever and it works in humans, not just research animals.  It also has the advantage of producing a more continuous effect than is found using the intranasal method to deliver oxytocin. 

When you sever the vagus nerve, the bacteria in the gut continues to produce the required chemicals, but the signal to the brain has been lost. The hypothalamus no longer produces increased oxytocin and so the behavioral/mood effect is lost. This has been proven in the research.

Gut microbes may treat social difficulties in autism mice


In science speak, “the results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals”.  It also appears that oxytocin improves wound healing. So perhaps old people with leg ulcers, which never seem to get better, might benefit from a daily dose of L. reuteri DSM 17938, it also might make them feel better due to those central effects.


Oxytocin in the brain acts via oxytocin receptors

As we learned years ago in this blog, you can increase the effect (turn up the volume) of receptors using a PAM (positive allosteric modulator).  Interestingly, magnesium is a PAM of the oxytocin receptor (OTR).  Many people with autism are supplementing magnesium, perhaps those using intranasal oxytocin should join them. 

A very recent paper has investigated in detail how oxytocin receptors function.


The peptide hormone oxytocin modulates socioemotional behavior and sexual reproduction via the centrally expressed oxytocin receptor (OTR) across several species. Here, we report the crystal structure of human OTR in complex with retosiban, a nonpeptidic antagonist developed as an oral drug for the prevention of preterm labor. Our structure reveals insights into the detailed interactions between the G protein–coupled receptor (GPCR) and an OTR-selective antagonist. The observation of an extrahelical cholesterol molecule, binding in an unexpected location between helices IV and V, provides a structural rationale for its allosteric effect and critical influence on OTR function. Furthermore, our structure in combination with experimental data allows the identification of a conserved neurohypophyseal receptor-specific coordination site for Mg2+ that acts as potent, positive allosteric modulator for agonist binding. Together, these results further our molecular understanding of the oxytocin/vasopressin receptor family and will facilitate structure-guided development of new therapeutics. 

Magnesium and mood disorders: systematic review and meta-analysis



Another consequence of ERβ under-expression in autism

Also interesting to those following autism research, is the role of ERβ (estrogen receptor beta).  It is well known that in the brains of those with autism, there is a lack of ERβ.  A lack of ERβ is likely to lead to lower oxytocin in the brain and CSF (spinal fluid).  In many types of autism, we know that the level of oxytocin in CSF is reduced.

If you activate ERβ you both increase expression of oxytocin receptor (OTR) and also increase the level of oxytocin measured in the CSF.  You can activate ERβ with estrogens, like estradiol or even phytoestrogens like soy.  The ideal therapy to use would be DHED.


The cheap diuretic spironolactone may very well indirectly increase the level of oxytocin in CSF.

Oxytocin and Estrogen Receptor β in the Brain: An Overview

Oxytocin (OT) is a neuropeptide synthesized primarily by neurons of the paraventricular and supraoptic nuclei of the hypothalamus. These neurons have axons that project into the posterior pituitary and release OT into the bloodstream to promote labor and lactation; however, OT neurons also project to other brain areas where it plays a role in numerous brain functions. OT binds to the widely expressed OT receptor (OTR), and, in doing so, it regulates homeostatic processes, social recognition, and fear conditioning. In addition to these functions, OT decreases neuroendocrine stress signaling and anxiety-related and depression-like behaviors. Steroid hormones differentially modulate stress responses and alter OTR expression. In particular, estrogen receptor β activation has been found to both reduce anxiety-related behaviors and increase OT peptide transcription, suggesting a role for OT in this estrogen receptor β-mediated anxiolytic effect. Further research is needed to identify modulators of OT signaling and the pathways utilized and to elucidate molecular mechanisms controlling OT expression to allow better therapeutic manipulations of this system in patient populations.






NAD and Nicotinamide Riboside to boost Oxytocin

Today we see that recent research from Japan shows that in those people with autism who have reduced NAD, they may well be able to improve behavior/mood by increasing the level of their oxytocin using Nicotinamide Riboside (NR).

Nicotinamide riboside (NR) is a special form of vitamin B3, sold as an expensive supplement.  The FDA say it is safe for use in humans.


Nicotinamide riboside supplementation corrects deficits in oxytocin, sociability and anxiety of CD157 mutants in a mouse model of autism spectrum disorder


Oxytocin (OT) is a critical molecule for social recognition and memory that mediates social and emotional behaviours. In addition, OT acts as an anxiolytic factor and is released during stress. Based on the activity of CD38 as an enzyme that produces the calcium-mobilizing second messenger cyclic ADP-ribose (cADPR), CD157, a sister protein of CD38, has been considered a candidate mediator for the production and release of OT and its social engagement and anti-anxiety functions. However, the limited expression of CD157 in the adult mouse brain undermined confidence that CD157 is an authentic and/or actionable molecular participant in OT-dependent social behaviour. Here, we show that CD157 knockout mice have low levels of circulating OT in cerebrospinal fluid, which can be corrected by the oral administration of nicotinamide riboside, a recently discovered vitamin precursor of nicotinamide adenine dinucleotide (NAD). NAD is the substrate for the CD157- and CD38-dependent production of cADPR. Nicotinamide riboside corrects social deficits and fearful and anxiety-like behaviours in CD157 knockout males. These results suggest that elevating NAD levels with nicotinamide riboside may allow animals with cADPR- and OT-forming deficits to overcome these deficits and function more normally.

NR elevates brain NAD+ and cerebrospinal OT

Social preference deficit and anxiety of CD157KO males are best corrected at a relatively low dose of NR

The results demonstrated that the daily oral administration of NR rescued the social behavioural impairments observed in male CD157KO mice. NR had essentially no effects on social behaviour in wild-type male mice. The beneficial effects of NR appear to depend on restoration of CSF OT levels because the NR-induced OT elevation was only detected in CD157KO mice, which have a CSF OT deficit.


In the course of identifying a nutritional intervention for CD157KO mice, we reproduced the anxiety-like and social-avoidance-like deficits reported previously. Reproducibly lower levels of CSF OT in male CD157KO mice make these mice an attractive model of autism, anxiety disorder, or social avoidance in neurodegenerative diseases. Significantly, this model responds to both OT and NR as a treatment.
The challenge of polygenic diseases of incomplete penetrance is that they are difficult to understand mechanistically. Multiple genetic and environmental (biochemical) factors may converge to dysregulate pathways that are altered in common conditions such as ASD. We note that one potentially hopeful point when studying polygenetic diseases is that brain systems are redundant, and thus, it may be possible to increase normal functions that are only partially encoded by genetically damaged circuitry.
NAD+ is consumed by CD38 in formation of cyclic ADP-ribose. It then participates in OT release in the hypothalamus. In our study, ADP-ribosyl cyclase activity was maintained at a similar range as that in wild-type animals (data not shown). A recent study suggested that NR supplementation did not change CD38 expression. However, in vitro studies have shown that NAD+ applied to the mouse hypothalamus leads to OT release. It is reasonable to assume that an elevation in NAD+ levels by NR in the hypothalamus is responsible for repair of the OT release.

Future work will probe CD38 dependence and the cell-type dependence of the beneficial effects of NR on CD157KO behaviour, the potential benefits of NR in other ASD models, and the potential of NR to become a safe nutritional intervention, in addition to OT, for at least some types of ASD in human populations.



NAD+ is reduced in older people

There is a lot of research into combating the effects of aging.  It is agreed that the older you get, the less NAD+ you have and so research has looked at numerous ways to raise it.

The CD157KO mice model of autism does feature reduced NAD+, but nobody knows how common reduced NAD+ is in autism.

If you have low levels of NAD+ there will be negative consequences.

I think you can consider NAD+ depletion in a similar way to oxidative stress, both are inevitable and damaging features of aging.

Most healthy younger people are likely wasting their time and money worrying about oxidative stress and NAD+.  These are the people with “detox” diets and juices.

However, most old people and some young people with autism really stand to benefit from correcting oxidative stress and any reduced NAD+.
  

Therapeutic potential of NAD-boosting molecules: the in vivo evidence





Hallmarks of NAD homeostasis
NAD+ is not merely a redox co-factor, it is also a key signaling molecule that controls cell function and survival in response to environmental changes such as nutrient intake and cellular damage. Fluctuations in NAD impact mitochondrial function and metabolism, redox reactions, circadian rhythm, immune response and inflammation, DNA repair, cell division, protein-protein signaling, chromatin and epigenetics.
There are many ways to boost NAD+.

NAD+ Precursors              
Niacin/ nicotinic acid (NA), Nicotinamide riboside (NR) Nicotinamide (NAM) etc.

CD38 Inhibitors                 
Flavonoids (Quercetin, Luteolin, Apigenin, fisetin, rutin and naringin)             
Luteolinidin.  Kuromanin/ Chrysanthemin, an anthocyanin (food pigment)    

PARP Inhibitors    
BGB-290, Olaparib, Rucaparib, Veliparib, CEP-9722, E7016, Talazoparib, Iniparib, Niraparib, PJ34, DPQ, 3-aminobenzamide
                       
SARM Inhibitors
XAV939                    

NAMPT Activators
P7C3 



Conclusion

Some readers of this blog do give intranasal oxytocin as a therapy.  There have been numerous studies on children with autism, some discussed in earlier posts.  Oxytocin needs to be kept chilled, not to lose its potency.

Eleven previous posts in this blog refer to Oxytocin.


As to whether stimulating oxytocin receptors is going to be worthwhile in your case of autism, you will just have to try it and see.
I found that the Biogaia Protectis probiotic (L. reuteri DSM 17938) had very clear effects, which were very much hallmark effects of oxytocin.  This is easy and inexpensive to try.
Some readers of this blog do use Nicotinamide Riboside (NR), which we saw today can increase oxytocin by increasing NAD+.
There are very many reasons why you do not want to be lacking in NAD+, other than oxytocin, but if you already have plenty NAD+ you will unlikely see a benefit from yet more.
Magnesium is a very common autism supplement; it is often given with vitamin B6; both can be used to treat stress.

Superiority of magnesium and vitamin B6 over magnesium alone on severe stress in healthy adults with low magnesemia: A randomized, single-blind clinical trial







Wednesday 6 May 2020

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




By 品璉 - 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


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


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-HT2A and 5-HT2C 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.









As you would expect, the serotine-type stereotypy is the result of one specific receptor.  It appears to be 5-HT7 or 5-HT1A.


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-HT1A 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 (Ki = 5.8 nM, EC50 = 34 nM) and 5-HT1A (Ki = 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: -


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.