Theoretical Immunology

[Leonard]

I invite you all to open the wikipedia page on the 'leaky gut' http://en.wikipedia.org/wiki/Leaky_gut
Scroll down a bit and you find the following text:

quote Health care practitioners who diagnose "leaky gut syndrome" explain that intestinal inflammation which may originate from intestinal dysbiosis or other sources of irritation, widens the junctions between the cells of the intestinal lining, allowing endotoxins and incompletely digested particles to be partially absorbed. These are targeted by antibodies, forming immune complexes which cause a semi-infectious state and can be carried by the bloodstream to distant sites where they may stimulate the release of cytokines. Low grade fever, transient gut pain, and a sense of inability to absorb nutrients are some reported symptoms in otherwise undiagnosed patients. unquote

You may also have look at ref 26 of the wikipedia page on the leaky gut which provides a beautiful description of what underlies MS
http://www.herbs2000.com/disorders/leak ... ndrome.htm

I think here lies the core of our problem. It is causing the "autoimmunity" that has so long held the medical sector hostage and impeded progress in this field. It is not an autoimmunity that comes out of the clear blue sky, if you wish it is an autoimmunity that is provoked by incompletely digested particles that are correctly earmarked by the body's immune system as 'foreign' and that leak into the blood stream. And it is these complexes when they start circulating in our blood stream that do their damaging work, for us in the cerebro-spinal because the tissue of our BBB was compromised before by ccsvi... Cytokines are released and the rest follows. I amended the concept on page 1 accordingly.

If we would have been in 1913 today, these insights would have allowed the sector to make fast progress. But today we are not in 1913, we are in 2013. We are in a different world where virtually everything is locked up in a grid. And no one seems to have the power and democratic legitimacy needed to take control... The medical sector will look for help from the outside (see for instance the list of issues in table 2 of http://link.springer.com/article/10.100 ... 6-6#page-1 ), policy makers and public health 'instances' will not act because they see it as a medical problem. And the whole system remains stagnant, as it has been for the last decade...

The stagnation seems confirmed by this course of events. This article was published in 2011 http://www.ncbi.nlm.nih.gov/pubmed/21683931 Although it mixes up primary and secundary, causal and caused, and often takes the wrong turn on things (ccsvi is considered secondary where I think -from my personal experience as MS patient- it is the primary issue where it all starts), if you can read between the lines, the article is not without its merits as it brings together and explains many things (at least to me). It was done by neurologists... But if I look now almost 2 years later, the actions taken by these same people are centred on improving endothelial health in the cerebro-spinal e.g. by improving cellular nutrition by medication, in fact by a Prozac derivative. But the approach is conceptually incomplete, narrowly neurologically inspired; the key role of the gut is completely absent. It is like pumping a sinking ship that is taking on water without fixing the hole... And a promising path may eventually be left because the underlying problem was not fixed...

It is becoming clear to me that it is not easy to see what to fight and who to fight here.
I think it is the system..

THIS WHOLE AREA HAS RED TAPE WIRED AROUND VIRTUALLY EVERYTHING.
THE CHALLENGE IS TO CUT THAT RED TAPE AND TO ENABLE THE SYSTEM AGAIN.

[Leonard]

from Lynda's thread on Insulin - Could This Be the Key? http://www.thisisms.com/forum/general-d ... c1878.html

Insulin control of blood glucose is very crude and poor as that was never it's primary role to control maximum glucose levels, whereas we have multiple systems and hormones for managing low blood glucose very precisely, this suggests we were never really designed to consume a high carbohydrate diet daily in every meal.
I think when we are properly tuned our bodies are quite capable of managing seasonal and opportunistic carb binges, but these should be the exception rather than the norm.

Once Insulin & Glucose are under control and the inflamatory threats like Omega 6 PUFA's are removed then Leptin levels also begin to recede, Leptin is likely the first hormone dysregulated, many years before Insulin or high blood glucose appears.

@Caveman, we think alike. For me, MS stands for Metabolic Syndrome, a dysregulated metabolism; the multiple sclerosis in our brains are just symptoms on the fringes...

the center of our nervous system and our conscious control is located between our ears, and that is where the multiple sclerosis are found as well. that may help explain why the medical system has grown as it did, neuro-centric. but our biological center is the gut, the gut microbiota makes who we are, it makes our metabolism. the gut is the center of our food intake that we need for our survival, where 'foreign' is processed to 'own', a microbiome that is 100 times larger than the whole human genome. with 2 kg of 'foreign' bacteria etc, the gut is also the center of the immune system that keeps it all in check... biologically seen, the gut is the center, the rest of the body is fringes/periphery..

insulin sensitivity is key. and perhaps, with Caveman, the leptin regulation. this is determined by the gut microbiota, see the presentation under the link below. there are only a few "bloodgroups"/dominant enterotypes. hunger, fasting etc will influence the microbiota; extreme low-calory diet for 6 weeks can even heal you from diabetes. and as we know, feces transplantation is a real option, and is becoming ever more real, because of its very central role in our biology, but also because its implementation protocols seem fairly mature...

I invite you all to have a look at this presentation: http://www.cvgk.nl/legacy/bestanden/cvc ... rp-def.pdf

[CaveMan]

Thanks Leonard

Interesting presentation,
There is a couple of points I question though, the section on Choline and TMAO is a bit dubious, again association/corrolation does not equal causation and there is evidence that suggests the bacteria responsible for the formation of TMAO is prevalent in grain based diets and the prescence of choline that far down in the bowel may be moreso an indication of poor digestive process rather than a causal factor in heart disease.

The first thing to remember with microbiota is these relationships are far more complex than even our supercomputers can not decipher them, so one should tread warilly on making the assumption that we have the answers.
There is a very important point stated that "the microbiota profile is primarily determined by diet" now with the fecal transplants, then one of the key points would be to study diet and longer term follow up to determine if the microbiota profile is maintained.
I would expect that this is not the case, as this is the reason people suffer the imbalances of microbiota in the first place, eg. take a neglected lawn, dig it up and lay new turf, looks beautiful and green for a while, continue to neglect it and it eventually reverts to the same condition as the lawn that was replaced, on the other hand if the new lawn is watered and fertalized it flourishes.

Therefore, IMO it is more important to establish the criteria that define a healthy environment for the appropriate microbiota profile, i.e. what is the most appropriate diet?, change the diet first, then appropriately seed the microbiota if required.

There is a number of mechanisms that indicate communication between our cells and the microbiota, when one needs a sugar fix, this is often refered to as "Your Candida calling", there was also an article I read called "Whose fat is it anyway" which described the relationship between a specific gut bacteria, leptin signalling and obesity, this suggests the bacteria tells us when energy is in abundance and we should put some away and also calls on the fat reserves when intake is low, so does this mean we are just a complex incubator for our microbiome, who's really calling the shots?

There is certainly a place for fecal transplanting, particularly with acute microbiota conditions, but without dietary intervention the promise of longer term results in chronic disease is doubtful.
There is a delicate ecosystem in there and it can be quite robust and allow for significant nutrient variation, but if we upset the nutritional balance too much for too long, then we create a different ecosystem that may require significant intervention to re populate appropriately.

[Leonard]

@Caveman, good points, good questions, don't have answers, of course you can/should not do transplant without following up with a good diet.. (and agreed, that is not so easy done..)

great information and links on your topic on Leptin's role in MS
http://www.thisisms.com/forum/general-d ... 22104.html

The links below provide further evidence that the gut microbiota which may be influenced through diet contribute to the control of the energy homeostasis. Also, that the gut microbiota control enteroendocrine functions such leptin sensitivity, and gut permeability. And, as we may see from this presentation, insulin sensitivity which will double in only 6 weeks time after a feces transplantation, raising it to almost normal levels, see http://www.cvgk.nl/legacy/bestanden/cvc ... rp-def.pdf

http://www.endocrine-abstracts.org/ea/0 ... 29S4.3.htm

http://diabetes.diabetesjournals.org/co ... 2775.short

http://www.ncbi.nlm.nih.gov/pubmed/18516406

http://www.ncbi.nlm.nih.gov/pubmed/21933985

http://www.ncbi.nlm.nih.gov/pubmed/21808634

http://www.ironmagazineforums.com/super ... gut-m.html

At the risk of repeating myself, I can see an approach that consists of one or more the following steps:

1. open the neck veins (ccsvi)
2. transplant the feces (in case of progressive MS and bad gut; early MS is different)
3. enhance the Cerebral Blood Flow by medication e.g. by blocking ET-1, at least temporarily. Cerebral Blood Flow will increase by itself when the tissue sensitivity goes up after feces transplant and inflammation goes down. But a bit of help may accelerate recovery..
4. follow a good pre-diabetics diet (Swank, Wahls, green food)

When following such approach, I think it is not impossible to achieve 'freedom from disease'.

[CaveMan]

Microbiota definately plays a vital role in our health and it is a topic I've been looking at for a while.

Just as a bit of an exploration, not specifically related to MS, but parallels can be drawn from this example.

Helicobacter Pylori - an upper GI bacteria living in the mucosal lining of the stomach.
It has been associated with Gastric ulcers and stomach cancer and also the incidence of diabetes so we should erradicate it, so some researchers advocate, but wait.
It has also been associated with reduced risk of gastric reflux and oesophageal cancer.
Then there is the interrelationship it has with Leptin & Ghrelin and when it is erradicated there is an increase in BMI, people get fatter.
There is also some suggestion that it protects against Asthma and Allergies.

So what to do, do we erradicate or do we fecal transplant it, is it good or bad???
Well as always the answer is not as simple as one finding from a study, it needs to be looked at in the overall context of health and population.

Basically some 70-100,000 ybp we walked out of Africa with these little bugs in our gut, and in fact their genetics is providing more clues as to the routes we took, but anyway it has likely been with us since before the first Homo Sapien was born.

When we look at epidemiological data we find that it has a high infection rate in the developing world over 90% but low in the developed world somewhere in the order of 25-35% most likely due to the prolific use of antibiotics and obsession with hygene.
So if I was regular researcher I would conclude that there is an strong inverse corrolation between the infection rate with H Pylori and the incidence of MS & other chronic diseases, therefore infection with H Pylori may be an effective measure to guard against these diseases.

But I'm not, so my conclusion is, hmmm interesting, what else is this telling us.
Why is it sometimes harmful and why is it sometimes beneficial, well one of those controlling factors may well be diet, H Pylori, like many bacteria loves glucose (sugar, flour etc.) so could it be that our excessively glucose dependant diets are causing an overgrowth in those with H Pylori and leading to negative consequences. Those that have been looking specifically at Ancestral Diets are now concluding that all carbohydrates are not the same, consuming cellular carbohydrates like fruit & starchy tubers does not seem to result in the same poor health outcomes as consuming acellular carbohydrates like flour & processed sugar. I picked up this review article after following your last link:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402009/
When you compare Kitavans who also rely on a large carb intake in their diet, they do not have obesity or chronic disease and all their health markers are good, including leptin, yet even healthy looking individuals in the west have significant abnormalities in these markers.
There are obviously many other factors at play in terms of lifestyle etc., but there is no denying that the diet we have been presented by our Govt's, Medicine & corporate interests is far from optimal.
I love the whole USDA food pyramid that most people take as a nutritional recommendation, when you disect the acronym, it is United States Department of Agriculture, it is a summary of agricultural production to be sold to achieve the highest net profit, not a nutritional guide.

Here's a bunch of links on H Pylori, that I went through to extract some of this info.
http://high-fat-nutrition.blogspot.com. ... ucose.html
http://stochasticscientist.blogspot.com ... ylori.html
http://www.doctorshealthpress.com/diabe ... o-diabetes
http://www.sciencedaily.com/releases/20 ... 124650.htm
http://www.ncbi.nlm.nih.gov/pubmed/20009392
http://www.eje-online.org/content/158/3/323
http://cancerpreventionresearch.aacrjou ... 5/308.full
https://www.mja.com.au/journal/2005/182 ... on-between

[Leonard]

The Helibacter pylori may certainly influence the gut microbiota, e.g. through the sugar pathway, even to a point where the glucose homeostasis is affected. But I do not believe it is necessarily the only bad bacteria. We need to keep a critical look.

The gut microbiota is rich (with about 6000 different bacteria identified) and many studies have been carried out on gut immunology, including on how it is influenced through exposure in childhood. I remember having seen some papers on the exposure to parasites from South America which linked, allegedly, this exposure to a lower risk for MS. I tried to find them back but I could not. As far as my understanding now goes, out of these 6000 bacteria, there are 6 or 7 bacteria types that cause the dysbiosis, the imbalance. And they are pretty well known, as are the logistics protocols for the feces transplantation to restore a healthy gut balance.

When I was looking around a bit for gut microbiota and childhood exposure, what I did find are postings from the Summer of 2011, now almost 2 years ago. Postings that clearly link MS as a dysregulated metabolism to the gut. And papers that describe the gut dysfunction, the problems with the epithelial cell wall in the gastro intestinal tract, the mucus inner layer and outer layer (MUC1 and MUC2), and how 'neurologic' inflammation is caused.

But now we are almost two years later, the feces transplantation is mature for diabetes and the metabolic syndrome [it is nothing as major as a liver or kidney transplantation, perhaps you should compare it more with a blood transfusion] and we know that it works. Including for MS as you might expect and as Thomas Borody has shown. But what have we seen for MS? I start wondering whether this is still pre-eminently a 'medical' dossier, or whether there are other dimensions that prevail or should prevail.

[CaveMan]

Wasn't suggesting H Pylori as a cause or in any specific context relating to MS,
merely an example of the pitfalls of assuming a singular causal factor in relation to any disease.

How's this for an analogy?
To make fire you need 4 things.
1/ An ignition source.
2/ A suitable Fuel
3/ Adequate Oxygen supply
3/ The right conditions (temperature)

Likewise for MS and other chronic disease, there is a set of conditions and factors required to be present at the same time for the disease cascade to ensue, we see this time and time again in infectious disease epidemics, the entire population is exposed, some die, some get sick and recover, some don't get sick at all and there is a range of severities between these distinct categories.

I agree entirely with you that one of those key factors is gut health and that is broken down to three factors:
1/ Gut integrity and damage
2/ Microbiota profile
3/ Dietary nutrition

Fecal transplants address the 2nd point primarily, but there needs to be a structured program to address the other two issues and when they are addressed then there is progressive changes in the bodies other metabolic mechanisms as it adapts to improved nutrition and hormonal processes are adjusted.
It may well be that some individuals may need to repeat the fecal transplant process a second or third time over the course of a few years, kind of like a microbiota booster, others may do just fine with the improved diet and probiotics.
Most of my research is related to chronic disease in general and gut, microbiota & diet seems to feature very prominantly in everything from Thyroid, Rheumatism, CFS, Fibromalgia through to the neuralogical conditions and the use of a ketogenic diet, all the clues seem to point to eating the wrong food.
There is certainly a factor of genetic predisposition, we can't do anything about that, but that only governs the type of condition we are predisposed to, everyone's got some weak points. What needs to be determined are the environmental conditions and triggers, if these can be reduced or eliminated then there will be no disease cascade and a good chance of reversal.

I think about the diet thing like the story of the "Frog in a Pot" on the stove, the temp is gradually rising, but the change is so subtle the frog doesn't react till it just seizes up and is cooked. Likewise our diet seems no different from last years, so we tend to dismiss it's effects and instead focus on more recent changes in our lives, like stress, infection, drug reactions etc., but when you compare our diets now to 50 years ago or more you realise they are completely foreign, everything has changed, we are slowly cooking from the inside and like the frog we just don't realise it.

[Leonard]

some trying to get a stranglehold on feces and feces transplant?

http://www.regenexx.com/2013/05/your-poop-is-a-drug/

I guess -and I hope- that sooner or later this whole matter will become political.
Where I trust that our political masters will take the right decisions.

[Leonard]

What a beautiful article! This is a must read.

http://www.nytimes.com/2013/05/19/magaz ... ted=1&_r=1

quote

But is inflammation yet another symptom of metabolic syndrome, or is it perhaps the cause of it? And if it is the cause, what is its origin?

One theory is that the problem begins in the gut, with a disorder of the microbiota, specifically of the all-important epithelium that lines our digestive tract. This internal skin — the surface area of which is large enough to cover a tennis court — mediates our relationship to the world outside our bodies; more than 50 tons of food pass through it in a lifetime. The microbiota play a critical role in maintaining the health of the epithelium: some bacteria, like the bifidobacteria and Lactobacillus plantarum (common in fermented vegetables), seem to directly enhance its function. These and other gut bacteria also contribute to its welfare by feeding it. Unlike most tissues, which take their nourishment from the bloodstream, epithelial cells in the colon obtain much of theirs from the short-chain fatty acids that gut bacteria produce as a byproduct of their fermentation of plant fiber in the large intestine.

But if the epithelial barrier isn’t properly nourished, it can become more permeable, allowing it to be breached. Bacteria, endotoxins — which are the toxic byproducts of certain bacteria — and proteins can slip into the blood stream, thereby causing the body’s immune system to mount a response. This resulting low-grade inflammation, which affects the entire body, may lead over time to metabolic syndrome and a number of the chronic diseases that have been linked to it.

Evidence in support of this theory is beginning to accumulate, ...

[Leonard]

Terry Wahls writes in her book Minding My Mitochondria that "The health of our mitochondria affects the health of nearly every cell in the body. … Mitochondrial failure drives the development of diabetes, heart disease, lung disease, heartburn from stomach acidity, Alzheimer's, Parkinson's, many psychiatric disorders, and Multiple Sclerosis." …

I think this is true, very true. I think that mitochondrial stress and eventually failure underlies the progression for a majority of MS cases. Where an over-active immune system as is now being addressed by bone marrow transplantation (e.g. in Toronto, see another thread on this forum) is responsible only for a minority of MS cases. In addition, there are obviously the infectious agents, mainly responsible during the RR phase (see e.g. 1st posting page 1 on New Concept for MS).

The mitochondrial energy failure can be addressed by feces transplantation. In fact, and that point is also mentioned in the above article from the NYT but it is not further developed, the insulin sensitivity and the leptin sensitivity of all cells in the body can be greatly increased by feces transplantation. As the Amsterdam experiment shows ( http://www.cvgk.nl/legacy/bestanden/cvc ... rp-def.pdf ), even doubled in 6 weeks time. At the same time the permeability of the gut barrier will be reduced. As the NYT article elaborates and as can be found in the links below, the fat metabolism in the gut holds the key. (I guess Swank's low fat diet comes into the picture here as well).

If you do a Google search on mitochondrial energy failure insulin sensitivity leptin sensitivity you find many articles on how the gut microbiota influences the sensitivity of the cells.

http://www.plosbiology.org/article/info ... io.1001212
Our results emphasize the role of microbiota in the complex network of molecular and cellular interactions that link genotype to phenotype and have potential implications for common human disorders involving obesity, diabetes, and even other immunological disorders.

http://care.diabetesjournals.org/conten ... /2277.long
connect an altered microbiota composition to the development of obesity, insulin resistance, and diabetes in the host through several mechanisms: increased energy harvest from the diet, altered fatty acid metabolism and composition in adipose tissue and liver,..

http://bfg.oxfordjournals.org/content/e ... 4.abstract
The contribution of the gut microbiota to the development of several diseases (e.g. obesity, type 2 diabetes, steatosis, cardiovascular diseases and inflammatory bowel diseases)..

http://www.ncbi.nlm.nih.gov/pubmed/21933985
We conclude that specific gut microbiota modulation improves glucose homeostasis, leptin sensitivity, and target enteroendocrine cell activity in obese and diabetic mice. By profiling the gut microbiota, we identified a catalog of putative bacterial targets that may affect host metabolism in obesity and diabetes.

[NHE]

What a beautiful article! This is a must read.

http://www.nytimes.com/2013/05/19/magaz ... ted=1&_r=1

Another good article on helpful bacteria...

Germs Are Us
Bacteria make us sick. Do they also keep us alive?
by Michael Specter: October 22, 2012

http://www.newyorker.com/reporting/2012 ... rentPage=1

[Leonard]

Peter Stys is right; there is an underlying degeneration that is the cause of the inflammatory reaction.
http://www.thisisms.com/forum/general-d ... 22388.html

this article "Multiple sclerosis genetics is dead" is going in the same direction, casts doubt on the concept of a complex genetic disease:
http://www.msard-journal.com/article...155-1/abstract

many of the arguments made in the article do not lie. 25 years of MS research into the waste bin. yet untold worse is the 25 year delay in effective treatment of MS.

but this failure should not lead to yet again 25 years of research into the neurodegenerative. I think that the problem is not specific neurodegenerative but a wider problem with the (energy supply of the) mitochondria. the neurodegenerative is but one element of it. the broken BBB by ccsvi contributes specifically to MS...

I think the focus of research on the progressive part is correct, and if that is resolved and addressed, and cells are again well fed and strong, the immune complexes from the gut stop, then those secondary RR attacks will also disappear...

we come back to the new concept for MS and an important role for the intestines as described in the very first posting on the first page of this topic...

[lyndacarol]

Until now, I have not been convinced of this "gluten sensitivity." But after hearing Dr. Arthur Agatston on The Dr. Oz Show talk about the intestinal inflammation, resulting malabsorption of nutrients, and ultimate involvement of the immune system, I think this wheat element (whether gluten or gliadin) is critical to MS. Insulin causes inflammation also. And wheat (whole wheat in particular) cause a spike in insulin. Between these two – insulin and wheat/gluten, inflammation is reached and impedes nutrient absorption (resulting in the deficiencies jimmylegs has found) and leads to the immune problem of MS. I think his book would be good to read: The South Beach Diet Gluten Solution by Dr. Arthur Agatston

Here is the four-minute video from The Dr. Oz Show: http://www.doctoroz.com/videos/secrets- ... -diet-pt-4


Animation of Gluten in the body (triggers inflammation cascade)

"Gluten sensitivity is most underrecognized, underdiagnosed condition of our time."

The Gluten Trifecta
1. Intestinal Inflammation
Triggers bloating, diarrhea, migraines, reflux
(@1:40 When gluten is not digested, it causes local inflammation; where the inflammation is, it blocks absorption of the specific nutrient normally taken in at that location)
2. Absorption of Nutrients
Can lead to anemia, hormonal imbalance, mood disorders
3. Autoimmune Response
Immune system mistakes the undigested gluten for invaders

This would seem to fit with Leonard's statement that "Peter Stys is right; there is an underlying degeneration that is the cause of the inflammatory reaction." And with the importance of gluten that others have found.
I welcome your comments.

[vesta]

I am in no doubt that a gluten intolerance is "toxic". When I first de-toxified and healed in the 80's, I entirely recovered from MS - nerve damage and all (it took a year). Then I moved to France and went off the diet in 1992. It took about a year to fall apart, and because I didn't have an acupuncturist to stop the blood reflex, the nerve damage persisted. Early 2012 I resumed my diet and began to feel better. I'm convinced removing glutens is the most beneficial aspect of my diet (as well as raw vegetable juice) since in other ways not much has changed. It's weird to recuperate function for no apparent reason. I believe everyone should go off glutens even if they haven't been tested for food intolerance (which isn't the same as allergy). I think besides the inflammation and nutrient absorption issue, if the body finds glutens to be toxic - stressful - this can contribute to the body tension blood reflux. My Kinesiologist felt that up to 80% of the population had a gluten intolerance.

MS Cure Enigmas.net

[Leonard]

This article postulates that bacteria in the sinus flora may be a factor in MS. In particular staphylococcal immune complexes are suspect.
http://www.sciencedirect.com/science/ar ... 4813000059

I think this could well be correct. I can not remember the earliest incidences of my own MS history because they are too long ago, and I did not know anything about MS at that time. But I do remember a very heavy pressure on my head and in particular on the sinus during my last serious flare; and if I remember well it occurred over several subsequent years, always in the Spring/early Summer. I explained it for myself as a hay fever, as if I was developing an allergy… But this happened at 45/46/47 where I did not have any such reactions before. I remember I found it all a bit weird at the time, but now it finds an explanation here…

If I remember well, I even asked the neurologist who diagnosed me at 47. He responded that MS has no relationship to the sinus. Just as he said that massive chocolate consumption (see earlier posting) has no relationship to MS. With the knowledge of today, how wrong can you be...
[I remember he even went away to ask the older neurologists in the local hospital. I don't blame them. In family psychology, it is referred to as the fate of generations, this time of the neurological family...]

I looked also a bit on the staphylococcal infection on Wikipedia. Besides the toxicity argument of the article, I found that these bacteria can also cause micro-blood clots. And in fact that could cause further energy problems for the mitochondria, in particular if the BBB is breached and the endothelium is already weak. I do believe that the sinus infection is a factor in MS although it is not clear to me whether the sinus infection is causal or whether the infection is part of a bigger syndrome caused by weakened endothelial conditions in a bigger part of the head...

I have included the sinusitis in the new concept for MS on the first page..