TGF-beta: complex interplay regulator between gut microbiota and immune system

[adreno]

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.

Largely overlooked until the last decade, the interplay between the microbiota and the mammalian host organism is now widely regarded as essential for host homeostasis and health. In this review, we have highlighted the complexity of this interplay within the gut and the central role of TGF-β in regulating these interactions. TGF-β levels in the gut are directly and indirectly modulated by the gut microbiota, which impacts the development and functions of immune cell subsets, which in turn regulates microbiota sequestration within the mammalian lumen.

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

 

[Jonathan Edwards]

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.

 

[daisybell]

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

 

[A.B.]

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.

Transforming growth factor beta (TGF-β) plays an important role in Marfan syndrome. Fibrillin-1 directly binds a latent form of TGF-β, keeping it sequestered and unable to exert its biological activity. The simplest model of Marfan syndrome suggests reduced levels of fibrillin-1 allow TGF-β levels to rise due to inadequate sequestration. Although it is not proven how elevated TGF-β levels are responsible for the specific pathology that is seen with the disease, an inflammatory reaction releasing proteases that slowly degrade the elastic fibers and other components of the extracellular matrix is known to occur. The importance of the TGF-β pathway was confirmed with the discovery of the similar Loeys-Dietz syndrome involving the TGFβR2 gene on chromosome 3, a receptor protein of TGF-β.[23] Marfan syndrome has often been confused with Loeys-Dietz syndrome, because of the considerable clinical overlap between the two pathologies.[24]

Just two random thoughts.

 

[A.B.]

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.

 

[KME]

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.

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?

 

[CFS_for_19_years]

I may also have hypermobility in the shoulders because I can do this.
Curiously this is only in the shoulders. The other joints are not like this at all.

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

 

[Cheesus]

@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?

 

[adreno]

@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?

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

 

[Cheesus]

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

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.

 

[Jonathan Edwards]

@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?

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.

 

[A.B.]

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.

 

[Marco]

@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.

 

[Wonko]

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
View attachment 22978

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.

 

[Daisymay]

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.

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?

 

[A.B.]

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?

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

Subsequent molecular analysis established that the genes in each class encode components of three different signaling pathways: a TGF-β-related pathway, an insulin-related pathway, and a cyclic nucleotide pathway. In this section, I will refer to the TGF-β-related pathway that functions in dauer development as the Dauer TGF-β pathway. See appropriate chapters for more information on dauer development and the insulin and cyclic nucleotide signaling pathways.

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.

 

[Jonathan Edwards]

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?

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.

 

[Daisymay]

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.

Thanks.

What would cause such wrong immune memory?

 

[Snow Leopard]

I am not convinced so far that we have good evidence on a metabolic shift as such, although it would fit.

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...

 

[Jonathan Edwards]

Thanks.

What would cause such wrong immune memory?

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.