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Prof Trevor Marshall
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"Bacteria in the gut of autistic children different from non-autistic children"

http://www.microbeworld.org/index.php?option=com_jlibrary&view=article&id=8088

http://www.microbeworld.org/index.php?option=com_jlibrary&view=article&task=download&id=8088

http://mbio.asm.org/content/3/1/e00261-11


"the study was uniquely powerful because they used tissue samples from the guts of patients"

"We detected either IgG or IgM antibodies against Sutterella wadsworthensis proteins in ~48% (11/23) of AUT-GI children"  "One Control-GI child had very weak IgG immunoreactivity against S. wadsworthensis proteins." {the other controls were negative}

..Trevor..
 

Russ
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Thanks for posting this Dr. Marshall.  I'd be curious to hear what your insights from it are.  Thanks.

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Russ, I am not sure whether the modification to the gut flora is a result of a compromised innate immune system, or whether the gut flora significantly contribute to the intraphagocytic microbiota. I suspect it is a little of each.

What this paper does demonstrate is that Autism and immune dysfunction occur in association. It is my opinion that the Autism Spectral Disorders are all syndromes of the immune-mediated dysfunction we call the 'Th1' syndromes.

..trevor..
 

Russ
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What do you make of the fact that a single species stood out so prominently?

To me, if difference in gut bacteria was just the result of a compromised immunue system, you'd think you'd see many different bacteria showing up in higher levels in the autistic kids, and no one particular species standing out so prominently. 

Here's a different study that did find that species, Sutterella wadsworthensis, to be commonly found in controls/healthy individuals.   The study was investigating a link between this bacteria and inflammatory bowel disease.  It used PCR instead of antibodies.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0027076

 

Last edited on Fri Jan 13th, 2012 14:58 by Russ

Prof Trevor Marshall
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Russ, no single species is causal for specific diseases. What was interesting was this one group, which compared controls and diseased with the same methodology, identified a significant difference.

PCR is a very imprecise tool. Antibodies are worse. We discussed the potential for both errors in our recent book chapter. Every group will likely get different results. That's why it is important not to try and "collect knowledge" from PubMed, but to carefully examine each study methodology and results. Often their conclusions have to be discarded, but, oh well...
 

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This study proposes some of the mechanisms for the interactions:

http://www.annualreviews.org/doi/abs/10.1146/annurev-med-012510-175505

Prof Trevor Marshall
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Their mechanisms are not the key, Nick. The key is to understand that once the microbiota invade the phaogocytes - the monocytes, macrophages, lymphocytes and neutrophils - then the pathogens can interact directly with each other, and with the transcription of the human genome.

They can then directly alter the interactome.

Most scientists don't realize that microbes can live inside cells, even though mycobacteria, rickettsia, EBV and a host of others have been documented over the years. It is this lack of understanding which prevents them from understanding what is really happening. They need to read the Wirostko papers... Or ours...

Liz and I published a (crude) paper way back in 2003 explaining this:

Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics - implications for autoimmune disease. Autoimmunity Reviews,2004; 3(4):295-3001.
Available from URL http://dx.doi.org/10.1016/j.autrev.2003.10.001
PMID: 15246025 or access FullText at author website

..Trevor..

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On the autism thread, I have posted a few times about GI studies and ASD.

Clostridia bacteria were once thought to be the culprit bugs which caused ASD, especially because vancomycin used to kill clostridia caused temporary improvement in symptoms until the vancomycin was stopped. Now the main researcher interested in this, Sidney Finegold, has moved onto to another species, namely, desulfovibrio – see http://cogentbenger.com/autism/interviews/finegold-interview/. Finegold has been looking directly for bugs in stool samples.

Others, less well known, have found other fecal flora abnormalities in stool samples. My son Jason’s fecal flora was grossly abnormal for what researchers (Tim Roberts of the University of Newcastle) thought were streptococcal species of bacteria. Treatment to address this led nowhere as did a course in vancomycin therapy followed up with probiotics.

I am therefore a bit blasé about new studies which purport to find a putative gut brain connection.

Indeed, there is an overwhelming number and diversity of abnormalities found with ASD subjects compared to controls in relation to a host of markers, of which stool bacteria studies is just one. Abnormalities with respect to serology markers and urinary excretions are even more diverse and extensive among ASD sufferers than differences in findings with respect to gut flora.

John

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john,
In Singapore I addressed this issue. there can be no single pathogen, and there can be no single pathway for the disease causality. The body is too complex to allow that.

http://vimeo.com/32641708

I am sorry if I didn't make it clear, but all I see in this paper is the confirmation that a Th1 weakened immune system allows different flora to flourish in a gut. No more than that. Some of the species will join the microbiota, but the person is already ill when their gut shows this dysbiosis :)

The Interactome will determine the dysfunction which a person suffers from. Or combination of dysfunctions.

I hope that helps,
Trevor

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While the previous reports have examined fecal specimens, Williams and coworkers (20) took a new approach and included intestinal gene expression and identification of the microbiota in the intestinal mucoepithelium. Their study revealed deficiencies in the enzymatic activity of disaccharidases and hexose transporters among the ASD patient group. These deficiencies suggest that impaired digestion and transport of intestinal carbohydrates may contribute to ASD GI symptoms. Consistent with the notion that the intestinal microbiota contributes to the enzymatic activities of the human intestine needed to degrade carbohydrates, there were also changes in the microbiota identified among the ASD group. Metagenomic analyses disclosed a significant dysbiosis with reductions in Bacteroidetes and increases in the ratio of Firmicutes to Bacteroidetes, as well as in Betaproteobacteria.
Williams et al. (13) report detecting Sutterella 16S rRNA gene sequences in ileal mucosal biopsy specimens from 12 of 23 patients diagnosed with autism and GI symptoms but in none of the specimens from 9 control children with GI symptoms. Sutterella wadsworthensis sp. nov. was described 15 years ago from clinical isolates from patients with infections that were below the diaphragm (21). In addition to the molecular taxonomy that Williams et al. describe (13), Sutterella can be identified fairly easily in the laboratory by its resistance to bile and its fatty acid profile (21).

http://mbio.asm.org/content/3/1/e00019-12.long

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Treating autism with antibiotics

http://www.youtube.com/watch?v=yOno_2m_8LY&feature=youtu.be

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Another study that puzzles some but completely aligns with Marshall Pathogenesis.

http://www.mercurynews.com/science/ci_20328655/rare-gene-mutations-found-heighten-risk-autism

Gary
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And a day later, another one that aligns with the Marshall Pathogenesis

http://timesofindia.indiatimes.com/articleshow/12547017.cms

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bugs from day 1 - the fetus is not sterile....

http://www.newscientist.com/article/mg21428603.800-babies-are-born-dirty-with-a-gutful-of-bacteria.html

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First, though, doctors will have to come to terms with the fact that we are born with our own set of bacteria. "Standard medical teaching is that the fetus is sterile," says Kinross. "The notion that gut development is influenced by maternal bugs will come as a shock. It's a completely new way of thinking about human disease.
 

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So how do we change the gut microbe composition we've inherited? 

Seems like the alternative medicine community has known this is an important part of the puzzle for a while but all attempts to alter the microbial community in the gut have proved temporary at best (probiotics, antibiotics, anti-candida treatments, etc.). 

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The bacteria in the GI tract do not directly cause chronic disease. Over months and years they move into the bloodstream and circulate throughout the body, adding to the microbiome. Alternative Medicine actually have the wrong concept :)

Intervening in GI tract composition, and expecting short-term results, is futile.

A single course of Cipro knocks out all GI tract bacteria for months. Dave Relman (Stanford) gave a presentation at the Paris and Seattle microbiome conferences giving data on this.
(can somebody search and see if he has published his data, otherwise I will have to see if I have a video of the presentations)

Russ
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Is this is the study you were referring to?
http://med.stanford.edu/ism/2010/september/relman.html

So I guess you are saying that the microbiota in the gut are less important than the intracellular microbes in the brains, organs, etc., at least as far as the disease process is concerned?  And the diseases can be reversed without having to change the gut ecosystem? 

Prof Trevor Marshall
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Russ, that citation looks like one of the papers :)

The GI tract ecosystem affects whether the Th1 system is exhausted dealing with microbes in the gut (which gives system-wide palliation). It also affects the cytokine storm levels, so it is very significant.

But altering the gut microbiota, once one is sick, has not been able to reverse any disease process in man :)

Antibiotics profoundly change the gut flora :)

 

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Dr Trevor Marshall wrote: But altering the gut microbiota, once one is sick, has not been able to reverse any disease process in man :)

But I wonder about the opposite.  For diseases like autism, where the gut microbiotia is suspected to play a major role, is it possible to reverse the disease process without altering the gut microbiota?

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Anytime one takes an antibiotic, one is altering the microbiota :)

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Indeed antibiotics alter the gut flora directly. However I see less people on the MP using antibiotics these days.

Can I assume long term use of olmesartan alone also changes the gut flora?

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I would hope that the human immune system knows which species are most harmful, and focuses on them. At this point, whether my hopes are well-founded is still largely unknown :X
 

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Dr Trevor Marshall wrote: First, though, doctors will have to come to terms with the fact that we are born with our own set of bacteria. "Standard medical teaching is that the fetus is sterile," says Kinross. "The notion that gut development is influenced by maternal bugs will come as a shock. It's a completely new way of thinking about human disease

That would be consistent with this recent study:

All MCs were more prevalent among case mothers compared with controls. Collectively, these conditions were associated with a higher likelihood of ASD and DD relative to controls (odds ratio: 1.61 [95% confidence interval: 1.10–2.37; odds ratio: 2.35 [95% confidence interval: 1.43–3.88], respectively).


http://pediatrics.aappublications.org/content/early/2012/04/04/peds.2011-2583.abstract

NickBowler
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there seems to be some evidence for making a difference through changing gut microbiota:

http://www.nutraingredients.com/Research/Gut-bacteria-could-hold-key-in-obesity-fight

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Nick,
One of the issues argued at length last year and this year at the Microbiome conferences has been why Peter Turnbaugh's (ca. 2007) mouse-based microbiota-transplant discoveries don't work in human beings.

Obesity in man is different from obesity in mice and rats. Been known since about 2010...

..Trevor..
 
ps: I have begun to discount everything I read in "Nutrition" journals :)
 

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I am not obese by any means...but I will tell you this...and it may be my own thing. When I did began to lose body fat and get down into a range I had not been in since way before the expression of morbidities, I began to experience everything all over again.

Besides all of this talk about the gut,it makes me wonder if some of the pathogens hide deep into fat,muscle or nervous tissue to evade some aspects of the immune system.

Once I began to get 'fat' again, all of the symptoms strangely disappeared.

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Yes, the microbiota love adipose tissue (fat). There was a presentation mentioning that at the recent Paris conference...
 

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And do they proliferate from there? Is this why many major disease factors are increased with obesity? If you eat more and gain more fat does it make it harder for he immune system to target microbiota living in the fat tissue? Will the immune system eventually get to them anyway?

Last edited on Thu Apr 26th, 2012 19:58 by seanlane

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The microbes traffic through blood, inside phagocytic cells, to all regions of the body.
 

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Sorry....off the subject but..fat as an organ?


Far from hormonally inert, adipose tissue has in recent years been recognized as a major endocrine organ[1], as it produces hormones such as leptin, resistin, and the cytokine TNFα


https://www.ncbi.nlm.nih.gov/pubmed/15181022

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Dr Trevor Marshall wrote: Yes, the microbiota love adipose tissue (fat). There was a presentation mentioning that at the recent Paris conference... 

Dr. Marshall, this sounds fascinating.  I would love to hear more about this presentation.  Did they find this with DNA techniques?  Could we maybe get a discussion of this in another thread?

Cynthia

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Not sure this is the right category for this. Saw this posted today......

http://www.sciencedaily.com/releases/2012/04/120429234641.htm

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My recollection is that adipose tissue also produces estrogen.
Best regards,
Mike

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This is a link to yet another study about abnormal microbiota in the guts of ASD children -

http://mbio.asm.org/content/3/1/e00261-11.full.pdf

All manner of baddies have now been proposed to infect the guts of ASD children with this study proposing yet another species.

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 This study goes a little further, by linking a metabolite in the gut with one in the brain, but only for the sick folk:

http://goo.gl/jHLtF

Of course, I am sure there are dozens, or hundreds, of other significant metabolites, but at least this is one step further along the path...
 

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Very intriguing study Dr Marshall.  I wonder if the gut also may show the early signs of ALS another neurological disease that severely affects motor neurons.  I have noticed more constipation the last couple of years before my ALS diagnosis ... and the article mentions this is seen in Parkinson's patients also.  This whole idea of gut microbes affecting the CNS implies a systemic effect on the whole body when infected with the microbiota. 

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Just caught the very end of this show, heard the word "microbiota" and had to look it up.

http://www.cbc.ca/natureofthings/episode/autism-enigma.html

A fresh perspective on autism research with the developing "Bacterial Theory" of autism. The fastest-growing developmental disorder in the industrialized world, autism has increased an astounding 600 per cent over the last 20 years. Science cannot say why. Some say it's triggered by environmental factors and point to another intriguing statistic: 70 per cent of kids with autism also have severe gastrointestinal symptoms. Could autism actually begin in the gut? The Autism Enigma looks at the progress of an international group of scientists who are studying the gut's amazingly diverse and powerful microbial ecosystem for clues to the baffling disorder.

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Hello,

my son had real problems, he had what I would call a brainfog that made his functioning in school almost unbearable. After a horrible path along several docters, one who would cut in his stomage, one with medicines that gave in a poisoning, we found one who gave him an laxative, which should do nothing but cure his digetion which was disturbed. Now the mirical happend, the brainfog slowly disapeared, and after a year or two we had a bright active inteligend boy back. It has certainly a relation!
If this is bacteria that live in the gut, or something else I do not know ( as marshal follower I should say it is bacteria) but the laxative still works, and as soon as we stop it the problem comes back.

I am trying to get him on the MP but he is not yet ready for it.

Erik (Roelof)

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Very interesting, roelof. Your son's experience correlates with my own as a teenager and young adult with brain fog and constipation (brain fog started out seeming to correlate with constipation, later developed into brain fog all the time, regardless of digestive system function).

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Interesting. I recently started drinking raw (i.e., unpasteurized) milk from a local farmer and one of the first things I noticed was that my digestion improved. Heartburn is reduced and stools are soft and more regular. Sorry for bringing up poo, but it seems to me that the raw milk is changing my gut flora pretty significantly. I haven't noticed a direct correlation to brain fog but I will pay attention.

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laura1814 wrote: Interesting. I recently started drinking raw (i.e., unpasteurized) milk from a local farmer and one of the first things I noticed was that my digestion improved. Heartburn is reduced and stools are soft and more regular. Sorry for bringing up poo, but it seems to me that the raw milk is changing my gut flora pretty significantly. I haven't noticed a direct correlation to brain fog but I will pay attention.
That's interesting.  Do you know what types of bacteria raw milk is supposed to contain?  I wonder if it is the same as the popular probiotics (acidophilus, lactobacillus, etc.).  What do the proponents of raw milk say is the reason for it's health benefits?

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If I remember correctly raw milk has enzymes in it that make it more digesstable. Pasturization destroys the enzymes.

Pam

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Pamela H-F wrote: If I remember correctly raw milk has enzymes in it that make it more digesstable. Pasturization destroys the enzymes
Pam, it is actually infinitely more complex than that. The microbial content is actually the key factor, not enzymes. Don't get caught up in believing the simplified explanations you read on most Internet websites :) :)

A recent study started to open up the complexity - by showing that some species of bacteria in milk can actually become activated by pasteurization, not killed:

http://www.news.cornell.edu/stories/July12/FoodSpoil.html

Additionally, even though raw milk might be more pleasant for you at this stage of your recovery, that can change as your body slowly kills microbes, and your gut flora changes. The milk microbiota also changes from cow-herd to cow-herd, even if the bottler is the same. So you need to be continually looking for shifts in dietary tolerance as you recover.

..Trevor..

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Front cover of the economist magazine:

http://www.economist.com/node/21560523

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"Though less reliably so than the genes in egg and sperm, microbiomes, too, can be inherited. Many bugs are picked up directly from the mother at birth. Others arrive shortly afterwards from the immediate environment. It is possible, therefore, that apparently genetic diseases whose causative genes cannot be located really are heritable, but that the genes which cause them are bacterial"

Nice. We are not totally alone in the wilderness. Somebody else realizes the importance of the microbiome :) Now we can just hope that the author(s) of this article stumble across our papers and videos :) :)

 

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This quote points to them asking the right questions:

Again, the details are obscure, but in each case some component of the microbiome seems to be confusing the immune system, to the detriment of body cells elsewhere.

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Dr. Marshall,

Will the ARF contact the authors of this story in The Economist?

Sherry

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Sherry, I am much too busy working on other paperwork right now. Feel free to write to them and let them know about what we have been doing. The Saint Petersburg presentation brings together many of their points, I think, as do our last paper and book chapter.

It is probably tough for The Economist to accept that any answers could come from left field, I suspect. They are looking for answers from the usual group of 'prominent researchers'. :)
 

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I wrote "The Economist".  One never knows if it has any effect or not; but we've come a long way since I started reading http://www.sarcinfo.com in January 2005.

Think positively.

Sherry

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Here in Australia, a documentary on autism and gut bugs has just been aired – see http://www.abc.net.au/4corners/stories/2012/08/23/3574441.htm. This North American (Canadian I think) program was posted on this thread or perhaps the Autism thread some time back.

This program packed a punch for me.

In particular, the experience of one of the children (now 19) regressing badly after multiple abxs were given for an ear infection and the sudden onset of ASD and gut problems. As I posted on the Autism thread in the early days, Jason as an infant had not very many courses of abxs for an ear infection but enough to develop antibiotic-induced diarrhoea and then, so it seemed, catatonic autism.

We tried the vancomycin therapy followed by probiotics (through a Melbourne gastroenterologist well before the MP) but we did not get the positive results that caused me to go after this therapy in the first place. I also briefly considered stool infusions to correct gut flora as this had been done on an ASD child in Sydney by a gastroenterologist there and this had helped with behaviour.

I have of course raised some of this on the MP site and Trevor kindly responded. I think his view is that the abxs for the ear infection that may have damaged Jason’s gut flora as an infant was just a straw that broke the camel’s back. I think he feels Jason was well primed for a fall as he had likely acquired a toxic microbiota pre-birth and thereafter (vaccines, L-forms encouraged from penicillin administration and vitamin D-fortified formula) before the abxs just prior to his regression were given which tipped him over the edge.

If Trevor is monitoring this, I would appreciate any correction to this interpretation if it is needed.

The researchers looking into gut bugs and ASD seem to be suggesting that it is damned difficult to destroy gut pathogens (such as spore forming clostridia) but their effects can be limited by ingesting probiotics or starving them of nutrients by dietary changes (eg less carbohydrate and meat that it is not the product of antibiotic-laced stock feed). Also, stool infusions seem to be contemplated as a means of replacing pathogenic flora with a healthy flora that will not produce metabolites that affect the brain or switch on the wrong genes. This is a pretty crude summary I know.

One factor of interest to me is that propionic acid – a product of gut bacteria and ingested as a food preservative (E280) – was found in excess in the urine of ASD kids. This acid was injected into mice which made them temporarily autistic until its effect dissipated and the mice reverted to being normally sociable. This suggests I go looking to ensure Jason does not ingest e280 or have his urine tested for this acid (if possible in Australia).

I imagine trying to correct gut bugs (or their effects), in the ways suggested in the program, would be of limited value unless this could somehow assist to correct VDR function and the restoration of this is what is fundamentally needed to recover from ASD. I imagine the MP and the MP alone is the most likely way to restore the VDR and immune function anywhere and everywhere in the body and thereby heal affected organs, both brain and gut in the case of ASD.

I would be interested if Trevor would care to comment on whether these gut therapies could complement the MP.

John

Last edited on Mon Aug 27th, 2012 23:21 by healingjason

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he had likely acquired a toxic microbiota pre-birth and thereafter (vaccines, L-forms encouraged from penicillin administration and vitamin D-fortified formula) before the abxs just prior to his regression were given which tipped him over the edge
Not "before birth." The microbiota before birth may well have been non-toxic, but the contribution of childhood infections and vaccine microbes may have allowed it to become so at a very young age. Children accrete microbes very rapidly in the first few months of life, through food, water and contact.

Use of the incorrect antibiotics (like penicillin) may well have helped the "bad bugs" overpower the "less bad bugs."

Our members have tried many variations of probiotics, over the years, and although they may have led to short term palliation, that therapy did not affect their long-term recovery.

Similarly, stool "transplants" provide short-term benefits. By the time somebody is chronically ill the microbes have long ago migrated out of the GI tract.

I am sure that E280 is one of just thousands of metabolites dysregulated by the microbes. Remember the CFS and Lyme Proteome study?

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0017287

Here is what they found:



Those are awfully big numbers, by comparison with one (E280), the one which has already been studied. It will take a lot of work to even begin to study the plethora of metabolites which are causal for each disease symptom



healingjason
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Dr Trevor Marshall wrote:

Not "before birth." The microbiota before birth may well have been non-toxic, but the contribution of childhood infections and vaccine microbes may have allowed it to become so at a very young age. Children accrete microbes very rapidly in the first few months of life, through food, water and contact.

Trevor

I was wondering if you have moved away somewhat from a previous view where you commented on the Autism thread that a pathogenic microbiota was present at birth as follows -

 Posted: Fri Nov 7th, 2008 16:22

An interesting new study which shows that Autism is present from birth (We have suspected all along that a lot of the metagenomic microbiota is passed down the maternal line).

"Strange play in infancy may point to autism"

http://www.reuters.com/article/healthNews/idUSTRE4A58ZL20081106
 
Do you now feel post-birth exposure to pathogens is more important for the development of autism than a maternal inheritance?

Perhaps it is the case that some ASDs develop very early on - reflecting an extreme pathogenicity of the infant's microbiota - while the effects of a bad (though less toxic) microbiota show up in other ASDs later on? As to a later onset, severe cases of regressive ASD (like my Jason) seem to happen at age 2-3 years while higher functioning Asberger sufferers and the like take after 4 years to be diagnosed or are not diagnosed until adulthood, if at all.

Further to the idea that the severity of infection correlates with the severity of the ASD, I think a number of studies have found infection markers working this way. Prof Tim Roberts who tested my Jason as an infant for a urinary Hydroxyproline metabolite (believing it was reflecting a chronic infection) found this metabolite was higher in more severe ASD cases (including Jason) than for Asbergers or ADHD sufferers.

John

Last edited on Tue Aug 28th, 2012 17:25 by healingjason

Prof Trevor Marshall
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Do you now feel post-birth exposure to pathogens is more important for the development of autism than a maternal inheritance

Both are important, otherwise identical twins would both have identical ASD / ADHD :)
 

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http://www.nature.com/ni/journal/v13/n10/full/ni.2403.html


'Housing Ltbr−/− mice with their obese siblings rescued weight gain in Ltbr−/− mice, demonstrating the communicability of the obese phenotype.'

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http://www.nutraingredients-usa.com/Research/Immune-support-in-the-omics-age-Moving-away-from-old-ideas-of-nutrition-and-immunity/

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Possibly die to differences in carbohydrate consumption (specifically HCFS here):

http://www.clinicalepigeneticsjournal.com/content/4/1/6

Prof Trevor Marshall
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"Clinical Epigenetics Journal"?

all I see there is a whole lot of gobbeldy-gook. Nobody there seems to understand DNA Methylation. This journal is unreliable, from a Biology point of view.



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