Metyrosine, Intranasal Suramin and Visbiome/Viviomixx for Autism?

 

Our reader Natasa brought to my attention various things recently; this included the fact that intranasal delivery of Suramin for autism is being developed and the repurposing of an old drug called Metyrosine for autism.

I also noted a recent study that used a popular probiotic formerly called VSL#3, now called Visbiome/Viviomixx. This is interesting because it found that autistic people without GI dysfunction benefited.  The study had a high drop out rate and the improvement was not huge. Visbiome/Viviomixx is pricey for a probiotic, but not the price of two Ferraris like Metyrosine.

 

Suramin Nasal Spray -  PAX 102

Suramin is Dr Naviaux’s idea to treat autism and indeed several other conditions. Suramin is an existing drug approved outside the USA and made by Bayer.  Clearly Dr Naviaux’s new partner Paxmedica was not able to make a deal with Bayer, so they have to figure out themselves how to manufacture Suramin, which loses more time.  The good news is that they are working on intranasal delivery, the traditional way to delivery Suramin is by injection.

Research showed that the effect of Suramin is lost after a few weeks, so quite frequent injections would be needed.  Intranasal delivery has the advantage of avoiding injections and hopefully reduces the side effects of Suramin.

 

https://www.paxmedica.com/pipeline

 

  Metyrosine

  

 Metyrosine looks very interesting, until you see the price.

Metyrosine is yet another old generic drug, from 40 years ago, that can be used to lower blood pressure.  It inhibits the enzyme tyrosine hydroxylase and, therefore, catecholamine synthesis, which, as a consequence, depletes the levels of the catecholamines dopamine, adrenaline and noradrenaline in the body.

Metyrosine seems to have been forgotten about as a cheap hypertensive drug, but was repositioned as an ultra-expensive drug for a rare condition called Pheochromocytoma (PHEO).  PHEO is a rare tumor of the adrenal gland; these tumors are capable of producing and releasing massive amounts of catecholamines, metanephrines, or methoxytyramine, which result in the most common symptoms, high blood pressure, fast heart rate, and sweating.

Unfortunately, Metyrosine (brand name Demser) has become one of the world’s most expensive drugs, costing up to $30,000 a month.

Old posts on catecholamines:-

Secondary Monoamine Neurotransmitter Disorders in Autism – Treatment with 5-HTP and levodopa/carbidopa?

Catecholamines and Autism

Metyrosine for Autism

The proposed mechanism of action for the treatment of ASD is consistent with the assumption that an imbalance exists between catecholaminergic systems and the modulators of aminergic systems in the CNS and periphery.  Excess levels of nerve growth factor (NGF) and brain-derived NGF (BNGF), which are released into the catecholamine synaptic cleft, can cause branching and arborization of synaptic terminals, thus increasing the strength of catecholaminergic neurotransmission. Because growth factors are a component in these synapses, elevated levels of NGF and BNGF become chronic, along with elevated levels of dopamine and other catecholamines from these hypertrophic nerve terminals. The result may be a hypertrophy of the synaptic architecture, resulting in a persistent imbalance between aminergic systems and their offsets, which can lead to overstimulation of some CNS tracts and depletion of others. Consequently, increased dopamine activity within the CNS and the gut is associated with ASD, repetitive stereotyped behaviors, and defiant and anxiety disorders.  By reducing presynaptic catecholamine synthesis, storage, and release, Metyrosine/L1-79 may reduce the associated release of NGF and BNGF, rebalancing catecholaminergic mechanisms in the brain, gut, mesentery, and elsewhere. These effects are not mimicked by receptor-blocking agents that reduce postsynaptic depolarization without addressing the underlying hypertrophic dendritic architecture.  If this proposed mechanism of action in ASD is correct, reduced catecholamine synthesis, storage, and release should improve ASD symptoms. In the long term, reducing catecholamine release may enable the hypertrophic sympathetic nervous system to regress to a homeostatic configuration.

 

I suppose to get a unique patent, the developer has decided to use a different version of Metyrosine.

Their version, L1-79, is slightly different to Metyrosine

Metyrosine is the L-isomer of amethylparatyrosine.

L1-79 is a mixture of the L-isomer of amethylparatyrosine and the D-isomer amethylparatyrosine.

Metyrosine is already an approved agent, and the US Food and Drug Administration  guidance states that any stereoisomer of an approved agent can be considered to be the same agent, so the developer can treat their drug L1-79 as being an FDA approved drug (but not yet approved for autism as the use).

 

Effect of L1-79 on Core Symptoms of Autism Spectrum Disorder: A Case Series

Purpose:

This study examines the effects of the tyrosine hydroxylase inhibitor L1-79, a racemic formulation of a-methylparatyrosine, in patients with autism spectrum disorder (ASD) in a prospective case series. The L-isomer formulation of amethylparatyrosine, metyrosine, is approved for the management of patients with pheochromocytoma.

Methods:

Six male and 2 female patients aged 2.75 to 24 years with ASD were treated for 8 weeks at L1- 79 doses ranging from 90 to 400 mg thrice daily. Assessments at weekly intervals included the Aberrant Behavior Checklist eCommunity (ABC-C), Connor's Parent Rating Scale (CPRS), and Clinical Global Impressions (CGI) scale. The Autism Diagnostic Observation Schedule (ADOS) was administered at baseline and week 10. Findings: The ABC-C and CPRS scores improved between baseline and end of study for 7 of 8 participants; most participants' assessment scores decreased. At week 8, the CGI efficacy index was 05 for 6 of 8 participants, indicating modest improvement with at least partial resolution of symptoms and no medication adverse effects, and 09 for 2 participants, indicating minimal improvement and no change in status or care needs, without adverse effects. The mean ADOS scores improved by 31% for 4 of the 6 participants tested, with 1 patient experiencing a 47% improvement. Seven of the 8 participants previously taking psychotropic medications were stable without their legacy medications while receiving L1-79, and 1 patient resumed a single legacy medication at a lower dose. Three adverse events were reported; symptoms were mild and resolved without change in therapy.

Implications:

These results suggest L1-79 may be a tolerable and effective treatment for the core symptoms of ASD, which must be confirmed with double-blind studies.

 

The trial was very small, but if you look at the results, half of the participants were big-time responders.

If Metyrosine was still a cheap antihypertensive drug it would be very interesting.

Unfortunately, there is a clear trend to withdraw cheap generic drugs that can be repurposed and then bring them back as ultra expensive drugs for the new use.

Sadly, autism will need polytherapy, so you may need 5 drugs.  Nobody can afford 5 ultra-expensive drugs.

 

Viviomixx/ Visbiome for those without GI dysfunction 

Italians like probiotics and the study below is from Italy.  It uses the De Simone Formulation (DSF) which became well known as VSL#3, but following legal disputes is now marketed as Vivomixx in EU, Visbiome in USA.

The study does suggest that those without any GI dysfunction may benefit from this product. These people are in the “NGI group”, in the paper below.

We already know that some people with autism and GI dysfunction do benefit from this product, which is widely used by people with all kinds of GI dysfunction.  Clearly if you reduce GI dysfunction, behavior is likely to improve.

It is more potent than many probiotics.

Each packet contains 450 billions bacteria from eight probiotic strains:

·        Streptococcus thermophilus DSM24731

·        Bifidobacterium breve DSM24732

·        Bifidobacterium longum DSM24736

·        Bifidobacterium infantis DSM24737

·        Lactobacillus acidophilus DSM24735

·        Lactobacillus plantarum DSM24730

·        Lactobacillus paracasei DSM24733

·        Lactobacillus delbrueckii ssp. bulgaricus DSM24734

 

The beneficial effect was there, but not huge.

 

No differences between groups were detected on the primary outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated Severity Score (ADOS-CSS). An exploratory secondary analysis on subgroups of children with or without Gastrointestinal Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated with probiotics a significant decline in ADOS scores as compared to that in the placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months. In the GI group treated with probiotics we found greater improvements in some GI symptoms, adaptive functioning, and sensory profiles than in the GI group treated with placebo. These results suggest potentially positive effects of probiotics on core autism symptoms in a subset of ASD children independent of the specific intermediation of the probiotic effect on GI symptoms. Further studies are warranted to replicate and extend these promising findings on a wider

 

Viviomixx/Visbiome is one of the expensive probiotics, but it is one of the serious ones. It looks like some people without GI issues are likely to benefit to some degree.  Is it worth the expense?  You would have to try it.

We have seen case histories of people with autism, and severe GI issues, greatly improving with VSL#3/ Viviomixx/Visbiome.

 

Effects of Probiotic Supplementation on Gastrointestinal, Sensory and Core Symptoms in Autism Spectrum Disorders: A Randomized Controlled Trial

Participants were randomly assigned to probiotics (De Simone Formulation) (n=42) or placebo (n=43) for six months. Sixty-three (74%) children completed the trial. No differences between groups were detected on the primary outcome measure, the Total Autism Diagnostic Observation Schedule - Calibrated Severity Score (ADOS-CSS). An exploratory secondary analysis on subgroups of children with or without Gastrointestinal Symptoms (GI group, n= 30; NGI group, n=55) revealed in the NGI group treated with probiotics a significant decline in ADOS scores as compared to that in the placebo group, with a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months. 

In the GI group treated with probiotics we found greater improvements in some GI symptoms, adaptive functioning, and sensory profiles than in the GI group treated with placebo. These results suggest potentially positive effects of probiotics on core autism symptoms in a subset of ASD children independent of the specific intermediation of the probiotic effect on GI symptoms. Further studies are warranted to replicate and extend these promising findings on a wider population with subsets of ASD patients which share targets of intervention on the microbiota-gut-brain axis.

 

A novel and promising finding of our study is the significant decline in ADOS CSS scores (both Total and Social-Affect scores) in the NGI group treated with probiotics as opposed to those obtained in the placebo group. This result, although deriving from a secondary analysis, is particularly important from a clinical point of view, especially in the light of the abovementioned psychometric properties of the used tool. In fact, a mean reduction of 0.81 in Total ADOS CSS and of 1.14 in Social-Affect ADOS CSS over six months constitutes a clinically significant decrease of ASD symptoms (34). Not all previous trials with probiotics examined their effect taking into consideration the presence/absence of GI symptoms (25). Our result suggests that ASD children with and without GI symptoms could represent two different populations and that probiotics interventions could potentially provide different effects, likely due to distinct microbiota targets. Previous studies have already suggested that differences in microbiome (45, 46) are independent from GI dysfunction, and Luna et al. (45) argued that larger and well-designed studies are still needed to determine whether microbial composition may stratify ASD children beyond the GI symptoms. Within this framework, a positive impact of probiotics on autism severity in children without pre-existing GI symptoms supports the complexity of the microbiota-gut-brain axis warranting further studies on this subgroup of ASD subjects.

 

 

In the subgroup of children with GI symptoms we found a positive effect of probiotics not only on GI symptoms, but also on adaptive functioning, developmental pathways, and multisensory processing, the latter now reported by the DSM-5 (1) among core symptoms of ASD.

Taken together, these different results on NGI and GI groups of children suggest that the effects of probiotic supplementation in ASD children may be due to distinct mechanisms. The well-known neurobiological heterogeneity of ASD implies that each medication is likely to benefit only a subset within the spectrum of affected children, as suggested by results of pharmacological trials in this population (49, 50). The described positive effect on both GI and NGI children paves the way for the identification of those ASD subjects who can respond to probiotic supplementation beyond the presence of GI symptoms, and even beyond GI inflammatory status. In fact, in the current study, the supplementation with DSF compared with placebo resulted in no significant effects on the levels of plasma and fecal inflammatory biomarkers. In a previous investigation, we have reported that the values of these biomarkers were in the normal range already at baseline (51); thus, we do not confirm the two previous studies (52, 53) reporting some positive effects of probiotics on biomarkers of inflammation, and we could hypothesize that the effect of probiotics on adaptative functioning is not mediated by a reduction in systemic or intestinal inflammation.

 

Efficacy: Secondary Exploratory Analyses on GI and NGI Parallel Arms

One of the original aims of this study was to evaluate the effects of probiotics on ASD core symptoms, GI symptoms, and plasma and fecal inflammatory biomarkers in ASD children with and without GI symptoms. For this purpose the randomization was made independently in the GI and NGI groups, to obtain four parallel arms. At the end of recruitment, the sample size of each arm did not reach the target already determined for the whole sample; the GI group, already less numerous, was also affected by a bigger drop-out rate than the NGI one. Therefore, secondary exploratory analyses among subgroups were performed. The four parallel arms were well balanced for the total number of hours of rehabilitative treatments (GI placebo: 175± 91, GI Probiotic 156 ± 68, NGI placebo 134± 84, NGI probiotic 137 ± 129 p>0.05 for all the comparisons).

In the NGI group we found a significant decrease both in the primary outcome measure, Total ADOS-CSS scores (which decreased from 6.72 to 5.91 in the probiotic group and increased from 6.96 to 7.17 in the placebo group; mean change probiotic vs placebo, - 0.81 vs + 0.21 [95%CI, -0.76 to +0.20]; P = 0.026), and in Social-Affect ADOS-CSS (mean change probiotic vs placebo -1.14 vs -0.04 [95%CI, -1.01 to +0.06]; P = 0.027).

In the GI group, statistically significant effects were found in GI symptoms (Total GSI, Total 6-GSI, stool smell and flatulence mean scores), and in adaptive functioning (Receptive Skills, Domestic Skills and Coping Skills VABS-II subscales) for which probiotic therapy was associated with greater improvements than placebo (Table 3). In addition, in the GI group a significantly higher proportion of children in the probiotic group than in placebo group showed a normalization of Sensory Profile scores in the Multisensory Processing subscale (p= 0.013): the scores improved in 87% vs 28%, respectively, and got worse in 0% vs 42%, respectively (Tables S4, S5).

 

 

 

Several limitations must be noted. Firstly, the large dropout rates, although satisfactory considering the duration of the study, may have affected the trial’s ability to reliably detect significant differences between the two main treatment groups. This seems to have affected particularly the subjects within the GI group, in which almost half of participants dropped out, mostly in the placebo group (as reported in Figure 1). We could speculate that parents of these children had more expectations about the efficacy of the probiotic supplementation on GI symptoms than parents of children within the NGI group. For this reason, they could be disappointed when the treatment (or placebo) was not fully effective on GI symptoms of their children, dropping out of the trial without waiting for its possibile positive effects on core and developmental symptoms. Consequently, children who dropped out were substantially comparable to children who completed the trial in all clinical variables, with the exception of higher levels of GI symptoms. This discrepancy between the two groups could impact the study’s ability to detect other possible significant differences in the whole spectrum of GI symptoms. A second limit is that the use of the ADOS-CSS evaluation as an outcome measure in clinical trials has been recently disputed (43), mostly because it lacks sensitivity to detect changes in short time periods.

 

 

In conclusion, a six-month probiotic supplementation did not result in statistically significant changes in autism symptoms in the whole sample of ASD preschoolers. Nevertheless, for the first time at our knowledge, we have observed in children without GI symptoms treated with probiotics significant modification of core ASD symptoms measured by the ADOS-CSS scores (specifically Social-Affect domain) that are unrelated to the specific intermediation of the probiotic effect on GI symptoms. As far as children with GI symptoms, the six-month supplementation with DSF showed significant effects, when compared to placebo, in improving not only GI symptoms but also multisensory processing and adaptive functioning.

All these findings could pave the way for further studies on larger subgroups of ASD with the aim of improving precision medicine in ASD.

 

  

Conclusion

I am a big fan of affordable drug therapy.

There are some extremely clever one-off therapies that cost more than $1 million.  That seems OK, you give it to a baby who then may go on to have a normal life, but someone has to pay.

 

A $2.1 Million Drug for a Deadly Childhood Disease Is Approved by FDA

A potential cure for a lethal childhood disorder -- the first of its kind in the U.S. -- is hitting the market at a cost of $2.1 million, paving the way for more therapies that bring dramatic benefits for patients, along with challenges for health-care systems.

The U.S. Food and Drug Administration on Friday approved Novartis AG’s Zolgensma, a gene therapy targeting children under two years old who have a severe illness called spinal muscular atrophy. The Swiss drugmaker said it’s offering novel payment options, including spreading out the costs over time, refunds for patients whose treatment fails and discounts for insurers that provide swift coverage. 

What looks really unacceptable is repurposing a cheap existing approved drug and then charging a King’s ransom for it.

It is very expensive, and hugely risky, to develop a new drug, much less so to repurpose an old one.

Repurposing a cheap drug does cost money and somebody has to pay for this, and also the risk of it not being successful.

All the autism start-ups think they are entering a $2 billion a year market, but they neglect the fact that people with severe autism will likely need polytherapy.  They think people will pay $50,000 a year for a drug, but what if you really need 3 or 4 of these clever drugs?

Take Knut’s idea to repurpose Ponstan.  This NSAID is sold OTC in many countries for a few dollars.  Is it realistic to charge $50,000 for a slightly modified autism version?  In the case of Ponstan, this would be a preventative therapy for just a few years.

Metyrosine was probably another three dollar drug, before it stopped being used.  Now a one month supply costs $30,000.

 

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

  

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

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

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

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

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

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

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

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

 

First a quick recap

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

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

 Lactobacillus reuteri 17938 (Lactobacillus reuteri Protectis)

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

Lactobacillus reuteri ATCC PTA 6475

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

Viviomixx and VSL#3

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

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

Some other interesting, commercially available, bacteria

I came across several interesting products. 

Lactobacillus reuteri NCIMB 30242

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

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

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

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

Lactobacillus reuteri NCIMB 30242 research

L. reuteri NCIMB 30242: A Probiotic with Benefits

 Objectives

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

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

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

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

  

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

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

CONCLUSIONS:

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

  

Building healthy bones takes guts

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

  

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

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

Lactobacillus Reuteri NCIMB 30350

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

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

 They told me:-

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

They plan to make their own autism clinical trial.

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

Lactobacillus Johnsonii NCIMB 30351

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

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

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

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

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

  

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

Lactobacillus johnsonii research

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

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

Research Shows How Household Dogs Protect Against Asthma, Infection

UCLA research suggests that gut bacteria could help prevent cancer

  

The Intestinal Microbiota Modulates the Anticancer Immune Effects of Cyclophosphamide

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

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

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

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

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

  

 Lactobacillus rhamnosus GG

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

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

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

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

Medical research and use

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

Peanut allergy

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

Diarrhea

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

Respiratory tract infections

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

Atopic dermatitis, eczema

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

Urogenital tract

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

Intestinal tract permeability

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

Gastrointestinal carriage of VRE

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

Anxiety

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

This paper was mentioned previously in this blog

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

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

Weight loss

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

Risks

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

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

Abstract

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

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

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

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

Bifidobacterium Infantis 35624 

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

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

Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut

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

The research highlighted by Proctor & Gamble is here:-

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

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

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

Conclusion

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

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

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

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

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

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

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

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

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

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

My current list of potentially interesting probiotics is:-

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

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

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

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