It has been some 18 months since my last posts on autism

• Autism Microbiome
• Impacting Autism bacteria
• BPA, Autism and the Microbiome

An update on new studies since then:

• ” we found an increased hazard ratio of autism associated with otitis media[inflammation of the middle ear] (1.83 95% CI 1.71-1.95) and antibiotics usage (1.29 95% CI 1.17-1.43).  ” [2018]
• “In the sibling-stratified Cox model, only broader spectrum antibiotics were associated with increased risk of autism: hazard ratio (HR) = 1.16 ” [2019]
• ” Among 3253 children with ASD, 37.0% had a GI-related diagnosis during the last 2 years of their 5-year health coverage enrollment period, compared to 20.0% of 278,370 children from the general population without an ASD diagnosis. Greater numbers of oral antibiotic fills during the first 3 years of enrollment were found to significantly increase the hazard rate of having a later GI-related diagnosis (adjusted hazard ratio 1.48; 95% confidence interval 1.34, 1.63) in children both with and without ASD. ” [2018]
• Alteration of gut microbiota-associated epitopes in children with autism spectrum disorders[2019].
• The Gut Microbiota and Dysbiosis in Autism Spectrum Disorders [2018].
• The role of microbiota in autism spectrum disorders[2018].
• Gut Microbial Dysbiosis in Indian Children with Autism Spectrum Disorders [2018].
• ” we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions.  ” [2018]
• ” In this review, the latest evidence linking mitochondrial dysfunction and abnormalities in mitochondrial DNA (mtDNA) to the pathogenesis of autism will be presented.  ” [2018] – Ouch, it’s associated with the mother’s DNA, or mutations from it.
  • ” we uncovered elevated common polygenic risk, …and a maternally inherited X-linked deletion ” [2018]
• “in the results found in this review, the highest prevalence of the C. albicans in children with ASD stands out. However, little is still known about the involvement of Candida spp., and other types of fungi, on gastrointestinal symptoms and ASD symptoms, in children with ASD. ” [2019]
  • Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders[2018].
  • “ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45”
• Reduced microbiome alpha diversity in young patients with ADHD. [2018]
• The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism [2018].
  • ” In conclusion, our data on the gut microbial community of the 400-E12 rats in response to prenatal VPA exposure indicate that this model, in addition to demonstrating behavioral and anatomical similarities to autism, also mimics the microbiota features of autism, making it one of the best-suited rodent models for the study of autism. “
  • Alteration of gut microbiota-associated epitopes in children with autism spectrum disorders[2019].
• ” In this review, the latest evidence linking mitochondrial dysfunction and abnormalities in mitochondrial DNA (mtDNA) to the pathogenesis of autism will be presented.  ” [2018] – Ouch, it’s associated with the mother’s DNA, or mutations from it.
  • ” we uncovered elevated common polygenic risk, …and a maternally inherited X-linked deletion ” [2018]
• “in the results found in this review, the highest prevalence of the C. albicans in children with ASD stands out. However, little is still known about the involvement of Candida spp., and other types of fungi, on gastrointestinal symptoms and ASD symptoms, in children with ASD. ” [2019]
  • Anti-Candida albicans IgG Antibodies in Children With Autism Spectrum Disorders[2018].
  • “ASD children had a higher rate of high-positive values compared to typically developed children with an unadjusted odds ratio of 3.45”
• “At the genus level, we found that the relative abundance of Sutterella, Odoribacter and Butyricimonas was much more abundant in the ASD group whereas the abundance of Veillonella and Streptococcus was decreased significantly compared to the control group.  ” [2018]
• The valproic acid rat model of autism presents with gut bacterial dysbiosis similar to that in human autism [2018].
  • ” In conclusion, our data on the gut microbial community of the 400-E12 rats in response to prenatal VPA exposure indicate that this model, in addition to demonstrating behavioral and anatomical similarities to autism, also mimics the microbiota features of autism, making it one of the best-suited rodent models for the study of autism. “

Treatment Implications

• Diet Can Impact Microbiota Composition in Children With Autism Spectrum Disorder.[2018]
• Probiotic treatment reduces the autistic-like excitation/inhibition imbalance in juvenile hamsters induced by orally administered propionic acid and clindamycin [2018].

” we found that treatment with L. reuteri selectively rescues social deficits in genetic, environmental, and idiopathic ASD models. Interestingly, the effects of L. reuteri on social behavior are not mediated by restoring the composition of the host’s gut microbiome, which is altered in all of these ASD models. Instead, L. reuteri acts in a vagus nerve-dependent manner and rescues social interaction-induced synaptic plasticity in the ventral tegmental area of ASD mice, but not in oxytocin receptor-deficient mice. Collectively, treatment with L. reuteri emerges as promising non-invasive microbial-based avenue to combat ASD-related social dysfunction. ”

Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.

There is promising evidence to suggest that probiotic therapy may improve gastrointestinal dysfunction, beneficially alter fecal microbiota, and reduce the severity of ASD symptoms in children with ASD. Future research is still warranted in this area because there are methodologic flaws in the available literature and optimal species, strains, dosages, and duration of treatment have not been identified.

Role of Probiotics in Managing Gastrointestinal Dysfunction in Children with Autism Spectrum Disorder: An Update for Practitioners. [2018]

The results showed that children on exclusion diets reported significantly lower scores of abdominal pain and bowel movement, as well as lower abundance of Bifidobacterium spp. and Veillonellaceae family, but higher presence of Faecalibacterium prausnitzii and Bacteroides spp. In addition, significant correlations were found between bacterial populations and faecal amino acids in this group, compared to children following an unrestricted diet. Following B-GOS® intervention, we observed improvements in anti-social behaviour, significant increase of Lachnospiraceae family, and significant changes in faecal and urine metabolites.

A prebiotic intervention study in children with autism spectrum disorders (ASDs). [2018]

Bottom Line

Autism appears to be associated with two major factors: mutations in the DNA, especially in mtDNA. and microbiome. DNA and the microbiome have intense interplay with microbiome shifts likely causing epigenetic changes in DNA in some cases.

Altering the microbiome (although complex to do), promises the greatest hope in moderating the symptoms of Autism and ASD.

I have updated my microbiome analysis site with additional information taken from the various articles cited above for those who have had microbiome done by ubiome.com or others.

For those that have not, there is a Apriori Adjustment page located here.

In a correspondence today a reader wrote:

Conditions That Release Histamine
 1. Tissue injury: Any physical or chemical agent that injures tissue, skin or mucosa are particularly sensitive to injury and will cause the immediate release of histamine from mast cells. 
2. Allergic reactions: exposure of an antigen to a previously sensitized (exposed) subject can immediately trigger allergic reactions. If sensitized by IgE antibodies attached to their surface membranes will degranulate when exposed to the appropriate antigen and release histamine, ATP and other mediators. 
3. Drugs and other foreign compounds: morphine, dextran, antimalarial drugs, dyes, antibiotic bases, alkaloids, amides, quaternary ammonium compounds, enzymes (phospholipase C). Penicillins, Tetracyclines, Basic drugs- amides, amidines, diamidines, Toxins, venoms, Proteolytic enzymes, Bradykinin, Kallidin, & Substance P  [Src]

Missing the bacteria that produce DAO and having the MAO mutation is a major part of [someone] issues.

This triggered some lateral thinking (Edward de Bono fan here). Histamine comes from mast cells. Mast cells contains TWO items:

• histamines
• heparin

What it the histamine problem was not the primary effect but the side effect?

Suppose the body is sending out a chemical message for heparin and the histamine effect is just a side effect.

Heparin is something that I am familiar with, as well as mild coagulation defects. Heparin is not a single chemical but a complex mixture of chemicals. It impacts multiple stages of coagulation.

Suppose that the natural heparin produced by the body has a defect. They do – I know from personal experience. I have the prothrombin G20210a-mutation and have been on heparin. The plead from the body for heparin provides the heparin — but it is not a complete heparin. The body keeps asking for heparin…. causing more and more histamine to be released.

The naive approach to test this hypothesis would be to take heparin!

Any Evidence?

The involvement of coagulation factors, such as tissue factor and fibrinogen, in the pathogenesis of asthma has been reported. The finding of platelet activation in asthma also indicates a link between bronchial inflammation and hemostasis. The pathogenesis of mast celldegranulation and CSU was also shown to be associated with the activation of hemostatic factors such as fibrinogen and FXIIa.

Hemostasis in Allergy. [2018]

Chronic spontaneous urticaria (CSU) [HIVES] is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch. Recently, the activation of the blood coagulation cascade has been suggested to be involved in CSU, but the trigger of the coagulation cascade remains unclear.

Chronic spontaneous urticaria and the extrinsic coagulation system. [2018]

Mast cell heparin released upon activation provides negatively charged surfaces for factor XII (FXII) binding and auto-activation. Activated FXII, the initiating serine protease in both the contact and the intrinsic coagulation system, activates factor XI and prekallikrein, respectively. FXII-mediated bradykinin (BK) formation has been proven in the human plasma of anaphylactic patients as well as in experimental models of anaphylaxis.

The Mast Cell, Contact, and Coagulation System Connection in Anaphylaxis. [2017]

Has it been tried?

• ” The inhibitory action of medium molecular weight heparinyl phenylalanine (MHF) on the type I allergic reaction was due to a reduction or delay in histamine release from mast cells. MHF may be a potent anti-allergic agent. ” [2019]
• ” Chondroitin sulfate and Heparin may inhibit secretion of histamine from rat connective tissue MC, but their effect on human MC remains unknown.  ” [2018]

Bottom Line

This is just a hypothesis. I could not find any paper on testing for inherited coagulation defects of patients with histamine issues. The hypothesis is a feedback loop caused by ‘corrupt heparin’ being produced and the body asking for complete heparin. The over production of histamine is a side effect of this loop.

While working on an email response to a reader’s question about mold/mycotoxins, I found this 2018 article: Mycotoxin: Its Impact on Gut Health and Microbiota.

Evidence of disturbance on gut microbiota modulation induced by mycotoxin only had been studied on animal and the results have been summarized (Table ​(Table1).1). The changes in gut microbiota can be observed up to species level in some of the studies using advance molecular approaches. However, the compositions of gut microbiota are greatly influenced by various factors during the experiment. Confounding factors affecting microbial composition and function may include diet (Cani and Everard, 2016), the exposure of environmental chemical and antibiotics (Claus et al., 2017), genetic background (Goodrich et al., 2016b), as well as the mental health condition (stress) of the host (Karl et al., 2017). These factors can explain that the microbiota in same species may not be able to reduce the level of mycotoxins. Besides, the changes in gut microbiota due to the presence of mycotoxin may contribute by some uncontrolled variables. 

Mycotoxin: Its Impact on Gut Health and Microbiota.

The highlighted text above is echo in natural observations. For example avocado cannot be handle by some bird species, chocolate and xylitol to dogs [src]. I suspect the same for humans — depending on the microbiome / DNA, sensitivity to mold is high in some and safely decomposed in others.

This may be due to explicit strains or epigenetic side-effects:

Interestingly, a study showed the ability to metabolize DON can be obtained via gut microbiota transfer in swine. However, the transfer of gut microbiota revealed no changes in the DNA-profiles of the gut bacterial composition (Eriksen et al., 2002).

Bacteria Able to Transform some toxins

From the above article, we have:

• Anaerofilum, Bacillus Clostridiales, and Collinsella (Yu H. et al., 2010).
• a significant increase of Bacteroides/Prevotella group and decreased concentration levels of Escherichia coli were observed after feeding the rats  with Deoxynivalenol  (DON)
• The first study on the effect of Zearalenone (ZEA) on gut microbiota has been carried out by Piotrowska et al. (2014). …  the data showed the concentration of Clostridium perfringens, Enterobacteriaceae, and E. coli was significantly reduced 
• showed that Lactobacillus reuteri present during the start-up period, was permanently disappeared at the end of the Ochratoxin A treatment period accompanied by some minor changes in the bifidobacteria population… the relative abundance of Lactobacillaceae was increased whereas the Bacteroidaceae was decreased. 
• The exposure of gilts to ZEA and DON was found to pose an adverse impact on mesophilic aerobic bacteria. In particular, the amounts of C. perfringens, E. coli, and other bacteria in the family Enterobacteriaceae were reduced significantly after the 6th week of the experiment (P < 0.05)… , a study confirmed AF and fumonisin mixture increased Shiga Toxin-producing E. coli (STEC) level in fecal   

Probiotics

Prohep [Lactobacillus rhamnosus GG, heat-inactivated VSL#3, and viable E. coli Nissle 1917 (1:1:1)] successfully relieved the microbial imbalance and hepatic inflammation, which further decreased liver tumor growth (Li et al., 2016).  A human study by El-Nezami et al. (2006) demonstrated a statistically significant decrease (up to 55% at 5th week; P < 0.05) of urinary AFB-N7-guanine level in the probiotic (L. rhamnosus LC705 and Propionibacterium freudenreichii subsp. shermanii) mixture group compared to the placebo group. Similar finding was found by Mohd Redzwan et al. (2016) where serum AFB1-lys level were significantly lower (P < 0·05) in the Lactobacillus casei Shirota supplemented individuals. Besides, hepatic transcriptome in AFB1-induced HCC was positively altered by probiotics (Monson et al., 2015).

Bottom Line

From the above excellent review, I would infer the following treatment options:

• For mold exposure, a FMT from a person subject to the same mold exposure that did not react. Why: They likely have bacteria that is able to decompose the toxins. The logic is akin to using serum from a survivor of an infection.
• The following probiotics (I have ranked order them by my personal preference)
  1. Mutaflor – E.Coli Nissle 1917: Why: This is a robust probiotic that inhibits Shiga Toxin-producing E. coli (STEC)
  2. Lactobacillus casei Shirota (see this post on Yakult)
  3. Propionibacterium freudenreichii  (see this post)
  4. Lactobacillus rhamnosus GG (see this post “A MCS Probiotic?“)

The full text of the article is here, with links to earlier studies in the margin.

Quick review of the numbers for my various components.

Blog continues to grow in Readership

Facebook Page over last 28 days

Microbiome Site

Bottom Line

77K (21%) to http://microbiomeprescription.com/

282K (79%) to this Blog site

A reader asked me about this probiotic. It is unusual because it contains some species not seen in other probiotics.

Review of the atypical species

This looks like an impressive list of atypical species.

• Lactococcus Cremoris – “It is not a natural inhabitant of the human gastrointestinal tract, but does survive passage through it, and has been used to deliver bioactive peptides to the gut. ” [src]
• Lactobacillus Kefir – Wikipedia – used in making kefir
• Lactobacillus parakefiri – Wikipedia – used in making kefir
• Lactobacillus lactis biovar diacetylactis – starter for cheese [src]
• Associated with Sausage Making
  • Leuconostoc lactis – Wikipedia –
  • Leuconostoc mesenteroides – Wikipedia –
  • Leuconostoc cremoris – Wikipedia –
  • Leuconostoc dextranicum – Wikipedia –
• Following are YEASTS
  • Kluyveromyces marxanus – Wikipedia – has been associated with candidemia
  • Brettanomyces anomalus – Wikipedia – Brewing – no human impact information could be located.
  • Debaryomyces hansenii – Wikipedia – no human impact information could be located.
  • Saccharomyces unisporus – nill
  • Saccharomyces turicensis – nil
  • Saccharomyces cerevisiae – Wikipedia – Bread, Brewing – no human impact information could be located.
  • Saccharomyces exiguus – Wikipedia– Bread – no human impact information could be located.
  • Torulaspora delbrueckii – Wikipedia – Wine – no human impact information could be located.

Ding — Tossing the kitchen sink in to make a product

My impression after finding that most of these are used in brewing, wine making, sausage making — etc. Is that someone decided to toss a stack of commercial products used in food production to make a nice sounding product.

My challenge to the manufacturer (or their representatives) is to provide pubmed citations for each and every species cited above showing they have medical benefit. It they are unable, then the hypothesis that this is not a health-orientated engineered product but a marketing-to-the-masses marketing product, appears probable.