The microbiome hypothesis: Lipkin's collaborative, part 1 (Simon McGrath blog)

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New blog at ME/CFS Research Review




A gut reaction is the problem in ME/CFS – that’s the main idea being pursued by Dr Ian W. Lipkin of the Center for Infection and Immunity at Columbia University. He believes that the body’s response to changes in the gut could be what’s driving ME/CFS for at least some patients.

Lipkin’s collaborative group, the Center for Solutions for ME/CFS, will test this theory as part of a $9.6 million, five-year research programme, which Lipkin was good enough to discuss with me via phone and email.

This huge research programme, which is funded by the National Institutes of Health (NIH), is made up of three main projects. This blog looks at the first two, which will use high-tech approaches to see if changes in the gut are causing changes in the body, particularly in the immune system. The third project, which looks at the biological response to exertion in ME/CFS, will be covered in the next blog.

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Read the full blog
 
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percyval577

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Maybe at any opportunities they also could have an eye on the other direction, eg that the immunesystem would drive/keep the gut microbiome for some purpose in some direction. The reason being that the microbiome produced a lot of stuff needed/utilizised by the body.
(I personaly would opt for this - but probably more complicate to investigate - possibility.)
 
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ljimbo423

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With these three approaches – a high-tech dive into the microbiome, linking changes in the microbiome to changes in the immune system at all molecular levels, and a search for what patients’ antibodies respond to –

Lipkin’s investigation of what’s going on in ME/CFS patients is impressive. He hopes that this combination of depth and breadth will help to unlock ME/CFS.

One final point: Lipkin is not alone in thinking that problems with the microbiome might be driving ME/CFS via the immune system. Dr Derya Unutmaz is pursuing the same idea with his own collaborative.

The main difference between the two researchers’ approaches is that while Lipkin has a more molecular focus, Unutmaz is focusing more on the different cells of the immune system, such as T cells and their subtypes.
Thanks Simon, great info!:thumbsup::)

I would just like to add that ME/CFS researcher Chris Armstrong also thinks the gut is driving ME/CFS-

Well we all experience a bacteremia when we exercise. The type of bacteria that enter your bloodstream are usually quite controllable by your immune system but if your gut is further compromised they may release more bacteria into your blood or

more pathogenic species or your immune system may already be depleted. This is the concept for the chronic sepsis or SIRS and this is what I think may be behind PEM.
LINK

So that's 3 leading ME/CFS researches now, that are publicly saying they think the gut is the driving force behind ME/CFS. Three and counting!:)

My feeling is, that as the research continues to unfold, more researchers will be onboard with this hypothesis.

Jim
 

Frenchguy

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The problem in US research (in general, not specific to ME/CFS research) is that they don't works properly on plausible physiological models based on currents data.

NIH invests millions $ in differents centers. Theses researchers collect massive informations , put them in a computer and are sure that the response is here.

I don't think it's the best way to resolve a problem. When we look at actual data on pubmed, we can see a lot of work (ok, many studies performed on oxford and Fukuyama criteria should be excluded).

I like people like R.Phair because he presented an hypothesis based on data, which could explain many symptoms, and works to prove or disprove this hypothesis. He is Professor in biomedical engineering, and for now, it's the only who work on a plausible hypothesis.

If researchers don't ask the right questions, for example, why people have light and sound sensitivity, why they have orthostatic intolerance, which mechanism could explain conceivably PEM, they risk to spending time and money for nothing.

The company BM systems works on physiologicals models establishments for disease known incurable, or difficult to treat (you can see pdfs on their website). It's like machine learning like @mariovitali uses.
http://www.bmsystems.net/ (@Ben H , in case it's interesting for Ron).
They are working with French researchers to establish models. The goal is to perform additional tests to confirm or disprove theses models, and test treatments.

It's possible that the gut can be a factor for some people (i myself have problems...). It's don't think studying the gut will lead to treatment (I don't know a disease in which the gut cause neurological, autonomic, PEM, and "brain pain" symptoms . Like in many disease, i think ME/CFS have entry points, but they have to find the way to cut the vicious circle, it's the more important for us.

As French, I haven't to say that because Europe don't invest 1€ in research (i hope things are changing in France).
If we look many diseases, researchers are working since decades on trying to find the causal factor, but they don't. They now treat mechanisms which allow disease's control.
 

ljimbo423

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I like people like R.Phair because he presented an hypothesis based on data, which could explain many symptoms, and works to prove or disprove this hypothesis.
I don't think mitochondrial dysfunction and the gut being the driving force in ME/CFS have to be separate issues. I think the immune system activation and the oxidative stress from the gut, can cause the mitochondrial dysfunction seen in ME/CFS.

I think that's what Chris Armstrong, Derya Unutmaz and Lipkin
are saying too. That it's the gut causing the mitochondrial issues.

I don't think research into the gut as the driving force behind ME/CFS, in any way discounts how important mitochondrial dysfunction is.

This is a quote from Simon's blog explaining Ian Lipkins ongoing research-

The final level is metabolomics, looking at metabolites, such as glucose and some amino acids. Metabolites are key molecules in the chemistry of life: for example, they make up the energy cycle in the mitochondria – where Professor Ron Davis and others have identified abnormalities in ME/CFS patients.
So Lipkin is also looking into mitochondrial dysfunction, even though he thinks the gut is driving ME/CFS.

If researchers don't ask the right questions, for example, why people have light and sound sensitivity, why they have orthostatic intolerance, which mechanism could explain conceivably PEM, they risk to spending time and money for nothing.
If immune system activation from the gut is causing low grade brain inflammation, which very plausible from the research I've done. The low grade brain inflammation, mitochondrial dysfunction and immune system activation, could explain most or all of the things you mention above.

That's why the 5 teams from the ME/CFS collaborative and the 5 teams from Solve ME/CFS initiative (SMCI) are all focused on the gut, the immune system, the brain and metabolomics- (mitochondria).

These four areas, if dysfunctional, could explain all of the symptoms of ME/CFS, in my view.

The 5 SMCI teams are from all over the world.:) Sweden, Spain, USA, United Kingdom, Germany and Israel.


  1. Biomarkers for initiation (infection) and metabolic derangement in ME/CFS (Team 1, Sweden)
  2. Epigenetic regulation in specific immune cell types (Team 2, USA and Spain)
  3. Intestinal virome alterations and abnormalities in ME/CFS (Team 3, United Kingdom)
  4. Immunometabolism of T cells and monocytes in ME/CFS (Team 4, Germany)
  5. Antibody reactivities against autoantigens & the microbiome in ME/CFS (Team 5, Israel)
LINK


Jim
 

percyval577

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If researchers don't ask the right questions, for example, why people have light and sound sensitivity, why they have orthostatic intolerance, which mechanism could explain conceivably PEM, they risk to spending time and money for nothing.
:thumbsup::thumbsup::thumbsup:
Neverthless, they might find something even without good searching questions.
 

mariovitali

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Everyone is looking at the Gut without looking at the Liver.

This is going to be "fun"....

EDIT : I am sorry to say this in such a way but i begin to feel at loss here.
 
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percyval577

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Si. It´s stumbeling around. On the other hand science needs luck sometimes, you never know where you will arrive.
btw: [Mn + any infection]:time -> iNOS (<)-> NO <-> ACh <- [fat, sugar]:time. You might hook what this is?
 

Frenchguy

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Si. It´s stumbeling around. On the other hand science needs luck sometimes, you never know where you will arrive.
btw: [Mn + any infection]:time -> iNOS (<)-> NO <-> ACh <- [fat, sugar]:time. You might hook what this is?
You can search, if you don't know what to look for, you will not find. It's my view.

I'm not doctor, researcher or biochemist. I worked in industry as engineer before get sick.
When we worked on a complex and costly project, we generate differents hypothesis before working.
 

percyval577

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Oui, you need ideas. Without ideas no evaluation of facts. More on the long run, without facts no ideas.
The recent paper has found a correlation between severness of our disease and amount of microgenomics in the blood (or so, my mecfs brain, you know probably), including specific correlations.

"In ME/CFS without IBS, decreased tyrosine correlated with decreased P. distasonis. Increased TG 54:6 A was correlated with D. formicigenerans and TG 54:8 was correlated with decreased B. caccaeand D. formicigenerans. Parabacteroides and Bacteroides species have the ability to convert complex polysaccharides into energy sources24. D. formicigenerans ..."

It´s a trace and a great finding,
maybe not already a good idea to propose: "gut ->strange disease". I find it rather unlikely.

A more interesting idea is: gut<-usage of the gut, or as things like to be complex: gut<->usage of the gut.
But now what for a usage? How many years do they have? Maybe something will develope if they manage to have fantasy.

Without fantasy no ideas. Without ideas theory. Without theory no useful facts.
 
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percyval577

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Everyone is looking at the Gut without looking at the Liver.
...
EDIT : I am sorry to say this in such a way but i begin to feel at loss her.
No, I have looked at the liver, and I have come to the conclusion that the arginase would be indirectly the first cause of our disease: Messages #17 and #29 ff. Accordingly I improve (very slowly though).
Please read, especially if your difficult to understand program has come to a comparable conclusion.
Manganese and arginine are key. Nitric oxide is central. Part of an equilibrium might be acetylcholine.
 
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Learner1

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I think the immune system activation and the oxidative stress from the gut, can cause the mitochondrial dysfunction seen in ME/CFS.
Immune system activation yes, but I doubt the gut is the main cause of mitochondrial dysfunction in all of us.

I've identified different contributors to my mitochondrial dysfunction, some of which are genetic as well as others, none which involve the gut.
 

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ljimbo423

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Immune system activation yes, but I doubt the gut is the main cause of mitochondrial dysfunction in all of us.
I agree that there are many things that can cause or contribute to mitochondrial dysfunction.

Such as mold allergies, drugs, genetics, epigenetics, high levels of heavy metals, high levels of pesticides or other toxins, etc.

I feel like these things, if they cause ME/CFS, will be considered as "atypical ME/CFS" as research continues. My feeling is that a dysfunctional gut will be found to be "typical ME/CFS" or the primary cause of ME/CFS.

I think that's where the research has and is leading and that's why there are a few leading ME/CFS researchers already, that are saying publicly that they are in agreement with the gut as the main driver of ME/CFS.
 

Hip

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but if your gut is further compromised they may release more bacteria into your blood or more pathogenic species or your immune system may already be depleted. This is the concept for the chronic sepsis or SIRS and this is what I think may be behind PEM.
I think we might be able to rule out the idea that PEM is caused by bacteria leaking into the bloodstream by the following simple observation: ME/CFS patients who take corticosteroids can eliminate any PEM effects from exercise.

Now corticosteroids are known to reduce the antiviral Th1 immune response, but increase the antibacterial Th2 immune response. This means that if the immune response to bacteria were the cause of PEM, then corticosteroids would likely make PEM worse, because they increase the antibacterial Th2 immune response.

But we know corticosteroids ameliorate PEM, so that fact is evidence against the idea that PEM is caused by bacteria in the bloodstream.
 
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ljimbo423

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But we know corticosteroids ameliorate PEM
Yes they do in some people short term. A very, very few will have major long term benefits. Most people that take them for weeks, months or years, of which there are many here, get some minor to moderate improvements.

Some are made much worse by corticosteroids. I am one person they make worse and there are others as well.


Now corticosteroids are known to reduce the antiviral Th1 immune response, but increase the antibacterial Th2 immune response. This means that if the immune response to bacteria were the cause of PEM, then corticosteroids would likely make PEM worse, because they increase the antibacterial Th2 immune response.
Steroids also lower the TH2 response of the immune system not just the TH1 arm. Asthma is often TH2 dominant and steroids bring relief to many people with asthma.

Lipopolysaccharides increase the innate immune system or TH1-

Abstract
Bacterial lipopolysaccharides (LPS) are the major outer surface membrane components present in almost all Gram-negative bacteria and act as extremely strong stimulators of innate or natural immunity in diverse eukaryotic species ranging from insects to humans.
LINK

LPSs are a powerful trigger for the innate immune system response. Upon binding to the Toll-like receptor 4 and its coreceptors, LPSs trigger a cascade of responses ultimately resulting in the release of proinflammatory molecules that interfere with modulation of glucose and insulin metabolism, promote development and rupture of the atherosclerotic plaque, and favor progression of fatty liver disease to steatohepatitis. This review gives a comprehensive breakdown of the interaction among gut microbiota, LPSs, and the innate immune system in the development of obesity and promotion of an individual’s cardiovascular risk.
LINK

I think the immune system dysfunction/exhaustion etc. in ME/CFS is very complicated.

I think Chris Armstrong's, Derya Unutmaz's and Ian Lipkins hypothosis, that the gut is the primary driver in ME/CFS is right on the money. My feeling is they probably have more of the "inside" scoop than you or I do.:)