A New Decade of ME Research: The 11th Invest in ME International ME Conference 2016
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TGF-beta: complex interplay regulator between gut microbiota and immune system

Discussion in 'Other Health News and Research' started by adreno, Aug 9, 2017.

  1. adreno

    adreno PR activist

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    Several studies, including the last big cytokine study from Stanford, has found elevated TGF-beta in PwME. According to this article, TGF-beta is central in the interactions of the gut microbiota and immune system.
    [​IMG]

    http://www.nature.com/cti/journal/v6/n4/full/cti20179a.html
     
  2. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I don't know about gut microbiota but the idea that TGFbeta might be relevant to ME/CFS does make a lot of sense to me. It governs more or less everything. That makes it hard to pin down which pathway it is affecting in ME/CFS specifically but a thought came to mind about how it might explain the time pattern of the disease.

    Some years ago, together with Ajay Bhatia and Selina Blades we did some work on the connective tissue protein fibrillin-1. This protein forms a fibre mesh that is particularly important in tissues that stretch, and is closely linked to elastin. It is everywhere but much more in some places than others. The amazing thing about fibrillin fibre bundles is that they are painted with immune signalling molecules. In some places they are painted with complement inhibitors. In other (or the same) places they are painted with antibody receptors. But perhaps most importantly they link up with a protein called LTBP or latent TGF beta binding protein, which slots into the bundles at regular intervals.

    What this means is that each tissue has its fibre base coated with an amount of latent TGF beta that is appropriate for that tissue. And TGF beta seems to me to be a bit like the speed limit on roads. It is there to ensure that inflammation traffic does not get out of hand. So some tissues will have signposts painted with 30mph, some with 50mph and some with derestricted signs. But there is also the option for circulating TGF beta to dictate a change in the speed limit even for derestricted areas - like when there is a fuel crisis and the maximum on all roads is 50mph.

    The reason for thinking that this might be interesting in ME/CFS is that the painting of tissues with TGFbeta is quite a long term process. I suspect that during periods of serious ill health fibrillin bundles may get painted with immune signals that may hang around for months. It may be that the number of LTBP molecules stitched in can increase. Which means that the 'slow down, go to bed' signals built into the tissues may remain there for a long time. Most of the time one would still expect them to gradually fade away, as in post viral fatigue syndrome. But TGF beta modulates so many things, including both T and B cells, that some sort of vicious cycle might kick in so that the fatigue 'go to bed' signals just keep being rewritten into muscles, joints, and even brain.

    What might be crucial about this is that it would all be largely invisible. Nothing need be found in the blood except maybe a little bit more TGF beta in some studies but not in others. Because the signalling is painted into the fabric of the tissues, not sent around like cytokines are in the blood. Finding TGF beta in tissues would not be easy but it is possible to immunisation for LTBP. Maybe there are some muscle biopsies around that could be stained for LTBP. Quantitation is hard but one might find a qualitative difference in distribution.
     
  3. daisybell

    daisybell Senior Member

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    Is this something being talked about at the researcher meetings?
    It sounds like a really promising avenue......
     
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  4. A.B.

    A.B. Senior Member

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    Anecdotally hypermobility, EDS and CFS tend to appear together in families. Whitney's sister has EDS for example.

    In Marfan syndrome there is high TGF-beta because there is some problem with fibrillin.

    Just two random thoughts.
     
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  5. A.B.

    A.B. Senior Member

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    I may also have hypermobility in the shoulders because I can do the "reverse prayer hands", with fingers going up to the level of the neck. Curiously this is only in the shoulders. The other joints are not like this at all.
     
    Last edited: Aug 9, 2017
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  6. KME

    KME

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    Really interesting. I’m always keen to know if ideas/hypothetical models like this could explain post-exertional malaise, remission and relapse and even different responses to GET?

    What would be the predicted outcome(s) if the speed limits/‘go to bed’ signals were ignored? (I’m thinking GET, but exertion of any kind could do it, cognitive or physical.)



    And how about the cases of people who have long remissions between episodes of “active” ME/CFS? (I’m thinking of people who had it as children or teenagers, recovered, or seemed to, but relapse 10 or 20 years later as adults.) Is there something that could keep the previous speed limit stored in memory? Or a reason why relapses tend to be worse than the original period of illness?
     
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  7. CFS_for_19_years

    CFS_for_19_years Hoarder of biscuits

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    I can do the shoulder stretch you show, but can't touch my fingers with the following shoulder stretch, which is a traditional test for shoulder flexibility:
    https://www.verywell.com/shoulder-flexibility-test-3120278
    upload_2017-8-9_3-27-27.jpeg
     
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  8. Cheesus

    Cheesus Senior Member

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    @Jonathan Edwards

    Very interesting hypothesis. How would you go about treating something like that? Are there any existing medications that can modulate or reset TGFbeta?
     
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  9. adreno

    adreno PR activist

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    I would think one possibility is through the normalization of the gut microbiota.
     
  10. Cheesus

    Cheesus Senior Member

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    This wouldn't surprise me at all (at least for a subset of patients). My ME was triggered by taking antibiotics, and my gut microbiome has some very unusual bacteria accounting for extremely high percentages of the population. I have verified those abnormalities across multiple tests with three different labs, so I am fairly confident in the results.
     
  11. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I am not sure that that would be the right approach. If there is some vicious cycle that keeps painting TGF beta on to tissues because T or B cells have got confused then the right thing would be to unconfused the T or B cells. Trying to shift the TGFbeta would probably be an uphill struggle with no real chance of success.
     
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  12. A.B.

    A.B. Senior Member

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    By the way the "serious ill health" portion of the hypothesis would be inconsistent with my case, where I had some odd prodromal symptoms for a few years and then suddenly got what I initially considered to be the first signs that I was about to come down with a flu or a cold. There was no fever or runny nose, just physical sensations similar to an infection. So I thought that I was about to get an infection. I didn't and I think what I felt was just immune & ANS activation. It happened for no obvious reason. It was't that bad at first but never really went away and got worse over time. Then again I'm in the moderately ill category and it might have been different had there been a serious real infection.
     
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  13. Marco

    Marco Grrrrrrr!

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    @Jonathan Edwards

    Interesting angle. I can easily see how this would fit with physical exertion - less so for mental/emotional exertion which as you know can also result in PEM. OK using your speed limit analogy, if TGFb resets the limit in brain from 50 to 30mph then it's easy to envisage the brain appearing to be overloaded and everything slows or freezes (just like old CPUs/operating systems did when multitasking) and there is some evidence of slowed mental processing in ME/CFS.

    On the other hand, from what I can see, TGFb in the brain has an anti-inflammatory/inhibiting effect on microglia whereas there is limited evidence for microglial activation in ME/CFS.

    OK I'm being overly literal/simplistic but I'd be interested if you have any thoughts on how TGFb might impact on the cognitive side of things.
     
    Last edited: Aug 9, 2017
  14. Wonko

    Wonko Senior Member

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    It's only about 10 years ago I lost the ability to do this (I'm now 51), I never understood the references in books/films about stabbing someone in the back so they couldn't pull the knife out, there was nowhere on my back I wouldn't have been able to, so assumed it was just dramatic licence. I wouldn't have said this "ability" would make someone hypermobile, I've known people who were "double jointed" and I definitely wasn't. Most dislocations sodding hurt, the only ones that didn't were my thumbs, whereas people who were "double jointed" didn't appear to feel any pain at all when they dislocated things, for a laugh, to show off.
     
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  15. Daisymay

    Daisymay Senior Member

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    So do you mean there would be some factor perpetuating the vicious cycle ( eg environmental, infectious, genetic) which would need to be found and eliminated to solve the TGF beta situation?

    Or do you think the vicious cycle can be caused by some sort of wrong signalling or something which persists after one of these sorts of onslaughts?

    Your analogy of the speed limits, are you meaning TGF beta could be the cause of the reduced "speed" of metabolic functioning as in Naviaux's dauer state findings?
     
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  16. A.B.

    A.B. Senior Member

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    The TGF-beta pathway is one of three involved in the Dauer state in worms.

    http://www.wormbook.org/chapters/www_tgfbsignal/tgfbsignal.html#d0e451

    What this means exactly for ME/CFS and for this hypothesis, I have no idea.
     
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  17. Jonathan Edwards

    Jonathan Edwards Senior Member

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    I tend to think in terms of the vicious cycle depending on an internal loop based on immune memory or something similar. I rather doubt external factors are involved.

    I am not convinced so far that we have good evidence on a metabolic shift as such, although it would fit. I think the speed limit signs may just create symptoms by fooling the brain. The body need not actually take notice - a bit like those flashing 30mph signs that people tend to ignore but get annoyed by.
     
  18. Daisymay

    Daisymay Senior Member

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    Thanks.

    What would cause such wrong immune memory?
     
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  19. Snow Leopard

    Snow Leopard Hibernating

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    It is easy to get carried away with confirmation bias as biochemistry is multipurposed and "a theory that explains everything, explains nothing" (the trap of non-specificity).

    There is certainly potential for peripheral changes, not merely "fooling the brain", given the links between TGF-Beta and the metabolic findings of Fluge & Mella:

    "Reverse crosstalk of TGFβ and PPARβ/δ signaling identified by transcriptional profiling."
    https://www.ncbi.nlm.nih.gov/pubmed/20846954

    "Transforming growth factor-beta1 is a molecular target for the peroxisome proliferator-activated receptor delta."
    https://www.ncbi.nlm.nih.gov/pubmed/18007025

    "PPARdelta promotes wound healing by up-regulating TGF-beta1-dependent or -independent expression of extracellular matrix proteins."
    https://www.ncbi.nlm.nih.gov/pubmed/19538467

    The decreased NK Cell activity findings could be explained by elevated TGF-Beta:
    "TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway."
    https://www.ncbi.nlm.nih.gov/pubmed/26884601

    "Reverse crosstalk of TGFb and PPARb/d signaling identified by transcriptional profiling"
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3017614/

    "Transforming Growth Factor Beta, Bioenergetics and Mitochondria in Renal Disease"
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444292/
    (discusses relationships between energy sensing pathways and TGF-Beta cross regulation)


    "TGF-β – an excellent servant but a bad master" (about development of neoplasms)
    https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-10-183

    "TGF-β: A New Role for an Old AktTOR"
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789270/

    "PI3K/mTORC2 regulates TGF-β/Activin signalling by modulating Smad2/3 activity via linker phosphorylation"
    https://www.nature.com/articles/ncomms8212


    Everyone's favourite hypotheses confirmed. ;)
    I don't pretend to understand the feedback loops which would result from all the findings discussed above...
     
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  20. Jonathan Edwards

    Jonathan Edwards Senior Member

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    The sort of thing that causes all the standard autoimmune diseases - a self-feeding signal between memory immune cells that converts a normal switch off signal into a switch on signal. There are several known options for B cells. T cells are a bit more tricky but psoriasis is probably some sort of loop of this sort.
     

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