Who to contact to get an FMT clinical trial with high quality donors? Poor donor quality is likely what's keeping this from being an available cure

[MaximilianKohler]

Just because something is published, does not necessarily make it true. Even peer-reviewed science isn't necessarily 'true' nor should it always be taken as fact.

There can be flaws in methodology, or a lack of follow-up, or a failure to publish negative or null results.

I'm not in disagreement, just a little confused how these factual statements relate to what was quoted.

I'm not yet convinced that the science behind FMT is there. We need large-scale RCTs with objective, consistent and reliable measures of benefit before we can make bold claims of it being a 'panacea' (even 'close to' one)--and I'm naturally sceptical of such claims.

Getting this large-scale RCT done is exactly what this thread is about. So how do we get it?

You seem to be the one making the dogmatic positive statements here. I am simply expressing scepticism.

The problem is that my statements are based on a large amount of supporting evidence, whereas your skepticism seems to be disconnected from the current evidence.

Do I know about this field? Well a few months back the UK Medical Research Council set up an advisory board on research strategy into ME/CFS. They invited three people to guide them on choice of research projects. Those three people were Maureen Hanson, Derya Unutmaz and myself. So at least the MRC seems to think I know a bit about the wider context of this.

Fantastic. Looks like I found the right place.

In this case I would desperately plead with you to review the evidence I provided in the OP. In addition to what I feel is valuable information in the google doc, the wiki has a specific section on CFS in relation to the microbiome and FMT:
https://old.reddit.com/r/HumanMicrobiome/wiki/intro#wiki_cfs.2Fme.3A

And there are also review articles in the "FMT" section which mention FMT for CFS:
Wide benefit from fecal transplants (2015): http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284325/
Fecal Microbiota Transplantation: Current Applications, Effectiveness, and Future Perspectives (2016): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895930/

There are also other wiki sections that don't directly cover CFS, but do cover the mechanisms by which the gut microbiome impacts the entire body:
https://old.reddit.com/r/HumanMicrobiome/wiki/immunesystem
https://old.reddit.com/r/HumanMicrobiome/wiki/intestinalpermeability
https://old.reddit.com/r/HumanMicrobiome/wiki/intro#wiki_mechanisms.3A
https://old.reddit.com/r/HumanMicrobiome/wiki/systemic

And there is additional info not listed in that wiki, such as:
Mitochondria Play an Unexpected Role in Killing Bacteria. The energy-producing organelles also send out parcels with antimicrobial compounds to help destroy pathogen invaders in macrophages. (2018): https://www.the-scientist.com/the-l...-an-unexpected-role-in-killing-bacteria-65246 - since the mitochondria is the main site of energy production, it's plausible that chronic infection could reduce its energy production since it's spending its resources fighting infections.

If you are going to be advising important research councils, you need to be familiar with all of that. Otherwise you are doing us harm.

Since you don't have a signature or anything in your profile about you, may I ask why they went to you for advice? Are you a researcher, doctor, patient advocate, patient?

nobody has any very clear theory as to why it should be relevant. The evidence that it is relevant is zero so far.

I refer to the above information and again state that this claim does not seem based on the current evidence whatsoever.

That at least is my understanding from attending conferences and reading the literature. If you want to claim otherwise I am very eager to hear evidence but it has to be something plausible and reliably obtained.

I'm a little confused why this statement was made considering I provided/referenced a large amount of evidence in the OP.

But maybe we should get back to your main claim - that we need completely healthy donors. Why?That sounds intuitively sensible at first but it cannot be based on any evidence if we have no results from trials to confirm it.

We do have evidence. It's in the wiki and the google doc I provided. Getting a large scale trial to confirm it is again exactly what this thread is about.

Moreover, if you think a bit more it must be very likely that the ideal mix of bacteria for ME, if there is such a thing, is going to occur in rather unusual conditions where for some reason the 'best' bacteria are more prevalent than usual. In fact the logical conclusion would be that the ideal transplant would be an entirely artificial mix made up in the lab based on what had proven to be the best from trials. It is highly implausible that there is such a thing as a 'healthy balanced microbiome'.

Again I do not see this as accurate or logical. And that last statement seems to be conjured up out of nothing. I have cited evidence to the contrary.

These are also highly relevant and help explain why high quality donors are so rare:
https://archive.fo/ukhtQ#selection-803.0-803.1
https://archive.fo/XUhyi

They think (although there is little conclusive proof) that a wide variety of species within gut flora is a good thing and pooling stools (an expression that i find quite unsavoury) from a wide variety of donors is the better course of action rather than using carefully isolated super donors. The premise being ...we don’t really know what’s going on so if we throw the kitchen sink at it (I’m terms of lots of species) it should sort itself out better than trying to force a super donor flora onto an indivdual when we know that flora varies a lot between healthy individuals.

I do not agree this is an accurate summary of the cited super-donor review. What you've described is what the Taymount Clinic is trying to do. And this is something I've heavily criticized as being a sign that they have a poor understanding of the gut microbiome and FMT.

There is some preliminary evidence to suggest that among donors who are already effective, combining them gives better results. For example, Mo Farah's (elite long distance runner) plus Messi's poop may be more effective than using either of them alone. But there is not evidence that multiple low quality donors can equate one high quality donor. People who take that stance are showing their own personal ignorance rather than the ignorance of the entire field.

BTW, that review and more have been in the /r/HumanMicrobiome wiki.

What the article skims over is the cause or effect argument ....basically it acknowledges that cause is difficult to prove since we don’t know enough but then goes on to say that the plethora of small inconclusive studies that suggest a cause is sufficient. It reads a bit contradictory in places.

Causation has been overwhelmingly proven at this point, in my opinion. I covered this previously in this thread.

 

[AliceLily]

Maureen and some other groups have been doing speculative work into the possible role of microbiota in ME but nobody has any very clear theory as to why it should be relevant. The evidence that it is relevant is zero so far.

It's so good to have researchers looking into the microbiome and I hope continue to look. I had a major sudden change in microbiome composition (vaginally, sorry everyone, TMI !)and I think this dysregulation made me vulnerable to getting ME and OI years later via a flu.

I don't think the fix is topical though in my circumstance. It was a pessary antibiotic that caused the immediate change and it was permanent. It feels to me a deeper metabolic change but I don't have enough knowledge about these things. How this happens I don't know.

@MaximilianKohler Not able to read all your posts but will try to eventually. Wishing you the best.

 

[Jonathan Edwards]

Dear @MaximilianKohler,

I am afraid that none of your documents are of any scientific use. This forum is designed to discuss the science of ME, which in simple terms means the reasonably reliable evidence for or against various theories about what ME is and how it might be treated.

To be any use in that context evidence needs to allow reasonably reliable predictions. For instance take these two statements.

It rained today, so it will rain next Thursday.
The sun set earlier last week than either the week before or this week, so it must be December.

The first statement we know has no reliable basis. The second we know does.

All the statements I have seen about the microbiome and ME/CFS fall into the first category as far as I can see. They are either one off observations that do not predict anything reliable or they make use of analogies so loose that we have no idea if they are worth taking seriously.

That does not mean that I can predict that the microbiome has nothing to do with ME/CFS. It just means that nobody knows if it does.

Since you don't have a signature or anything in your profile about you, may I ask why they went to you for advice? Are you a researcher, doctor, patient advocate, patient?

I am a professor of medicine at University College London. My main contribution to science was the introduction of rituximab as a treatment of autoimmune diseases such as rheumatoid arthritis and lupus. I am trained in rheumatology, immunology and pathology and have worked on both inflammatory mechanisms such as cytokines and physiological mechanisms like fluid dynamics. I was invited to advise the ME research community on research quality about five years ago and have spent a lot of time gathering information, both from patients and scientists since then. I assume that because I have no vested interest in any particular research programme that charities and funding bodies find me useful as an unbiased advisor. I have in various ways advised the NIH, the MRC, Wellcome, Cochrane, and a number of charities and have been asked to act as expert witness for the UK NICE guidelines committee.

 

[Sly Saint]

Are you a researcher, doctor, patient advocate, patient?

https://me-pedia.org/wiki/Jonathan_Edwards

 

[lansbergen]

That does not mean that I can predict that the microbiome has nothing to do with ME/CFS. It just means that nobody knows if it does.

I think it does but I decided a long time ago that FMT is not the answer.

I think if the underlying cause can be eliminated the microbiome will go back to how it was before falling ill.
As long as the underlying problem is not solved the microbiome will respond to it.

 

[Alvin]

In fact the logical conclusion would be that the ideal transplant would be an entirely artificial mix made up in the lab based on what had proven to be the best from trials.

I've had this exact thought ever since i first heard about microbiota transplants being used anecdotally for Crohns disease a few decades ago.
Our current understanding of the microbiome is at a very basic level, we need to figure it all out then design a proper mix that is either perfected by scientific understanding or if necessary tailored to each patient if it turns out that is necessary. We may also need to wipe out their current population but i don't know if thats needed or ideal, something else that needs to be worked out.

 

[MaximilianKohler]

Dear @MaximilianKohler,
I am afraid that none of your documents are of any scientific use.

There are many researchers and doctors who will not agree that case reports and citizen science have no value/use. Especially when they are accompanied by a large amount of supporting citations/evidence.

There are not multiple documents. There is A document. The rest of the links are scientific studies.

To be any use in that context evidence needs to allow reasonably reliable predictions. For instance take these two statements.

It rained today, so it will rain next Thursday.
The sun set earlier last week than either the week before or this week, so it must be December.

The first statement we know has no reliable basis. The second we know does.

I do not know enough about sun set cycles to comment on this.

See what I just did there? That is what a reasonable, intelligent person does when they are confronted with something they are ignorant on.

I decided a long time ago that FMT is not the answer.

I think if the underlying cause can be eliminated the microbiome will go back to how it was before falling ill.
As long as the underlying problem is not solved the microbiome will respond to it.

This is entirely contradictory to the current body of evidence.

I've had this exact thought ever since i first heard about microbiota transplants being used anecdotally for Crohns disease a few decades ago.
Our current understanding of the microbiome is at a very basic level, we need to figure it all out then design a proper mix that is either perfected by scientific understanding or if necessary tailored to each patient if it turns out that is necessary. We may also need to wipe out their current population but i don't know if thats needed or ideal, something else that needs to be worked out.

This comment fails to appreciate current limitations, which are extreme: https://old.reddit.com/r/HumanMicrobiome/wiki/index#wiki_testing.3A

It will likely take a decade or more to identify the specific microbes that make FMT effective, and learn how to isolate and grow them. In the meantime we could have been using FMT to cure thousands/millions of people.

Ideally discussion about the relevance of FMT/microbiome would be kept to a separate thread.

The last sentence in that quote is already covered in the wiki. But additionally, this method to renew the mucus membrane of the gut may be helpful either on its own or prior to FMT:

https://www.theguardian.com/society...-treatment-could-end-daily-insulin-injections

http://diabetes.diabetesjournals.org/content/67/Supplement_1/1137-P

 

[adambeyoncelowe]

With all due respect, your 'evidence' comprises swathes of links and text. It's not very accessible on a forum where many of us have brain fog (and I've just started getting terrible ocular migraines where it's like looking through a kaleidoscope). Rather than sending lots of links, it is standard practice here to quote directly from your primary sources, so that we can see exactly what the argument is, and then link to the full paper. It's harder to interpret your opinion alone and this isn't a place where most of us can do days of research on just one topic.

Case reports and citizen science can indeed be very useful, but you haven't provided sufficient evidence that there's an ideal super donor out there and I don't think you would be able to, as we know far too little about the science behind the microbiome at this stage. Even a person who presents as healthy may later develop a severe illness which might affect their gut bacteria many years before it's detectable.

I agree with others that the best chance may be an artificially constructed sample. There are just too many variables taking samples from a live host. Of course, the opposite may turn out to be true (that there's some elusive special ingredient in live human poo that we just can't synthesise in a lab), but again, that's kind of hard to prove at the moment (and it makes the idea of providing a repeatable, reliable treatment very difficult indeed). Poo isn't like a drug. If every sample is slightly different, there's an inherent lack of quality control, and thus proving safety becomes much, much harder.

Finally, I think your general tone isn't very conducive to civil discussion on here. You've called people ignorant, told us we need to spend days researching your links, told us how we should respond, etc, etc. It's on you to present a cohesive, persuasive thesis. We can't make that for you.

 

[MaximilianKohler]

I took a few days break to allow for people to review the relevant information.

In science we do not make up our minds. We review the currently available information to try and deduce what the strongest supported position is. When contrary evidence comes along it is vital to be able to switch our position to what the new evidence supports.

With all due respect, your 'evidence' comprises swathes of links and text. It's not very accessible on a forum where many of us have brain fog (and I've just started getting terrible ocular migraines where it's like looking through a kaleidoscope).

I completely understand that! I have these same issues myself.

All I'm asking is that people not make authoritative statements regarding things they haven't thoroughly reviewed. That is how misinformation is spread, and misinformation is extremely harmful.

One example is a science based nutrition forum. I mostly only observe there because I do not have the time or brain power to review all the evidence myself.

Rather than sending lots of links, it is standard practice here to quote directly from your primary sources, so that we can see exactly what the argument is, and then link to the full paper. It's harder to interpret your opinion alone and this isn't a place where most of us can do days of research on just one topic.

Thank you for letting me know. I'm new here and not familiar with standard practice. I'm willing to pull some quotes but the amount of quotes to be pulled will be quite large if they are to give a proper representation of the current evidence. Also, it would be off-topic for this thread, and I didn't think beforehand that I would first need to create a discussion around the relevance of FMT/microbiome to CFS! Now I see that this is likely a vital step I missed.

I can create a separate thread (where it would be on-topic) to discuss the relevance of FMT to CFS, and link it here.

Case reports and citizen science can indeed be very useful, but you haven't provided sufficient evidence that there's an ideal super donor out there and I don't think you would be able to, as we know far too little about the science behind the microbiome at this stage.

I would question whether you have reviewed all the evidence prior to making this statement. Particularly since you also just talked about the fatigue limitations to doing so.

Also, who is "we"? As in "we know far too little". I agree that most people are not up to date with the microbiome literature and thus "know far too little". But to suggest that every single person "knows far too little" is too broad a statement. You should only be making such a statement if you've been following the literature daily for years and are thus up to date with it. It seems that the majority of microbiome researchers do not even do this. Thus there is an extremely small amount of people qualified to make such a statement.

Even a person who presents as healthy may later develop a severe illness which might affect their gut bacteria many years before it's detectable.

That really depends on what criteria you are using to determine "healthy". One of my biggest complaints is that the current criteria being used are woefully inadequate, and I have suggested much more in depth criteria.

 

[roller*]

Actinobacterium Eggerthella enzyme strain CGR2

A. Eggerthella strain cgr2 from the gut deactivates Quabain.
Eggerthella cgr2 may have benefits for ppl with high quabain, even though the bacterium is considered pathogenic ?

Ouabain is a cardiac glycoside and in lower doses, can be used medically to treat hypotension and some arrhythmias. It acts by inhibiting the Na/K-ATPase, also known as the sodium-potassium ion pump.
https://en.wikipedia.org/wiki/Ouabain

• endogenous ouabain (EO ) and related substances can be produced in the human body
• high ammonia increase ouabain like substances
• exercise increases ouabain
• hormonal stimuli like ACTH, angiotensin II and epinephrine also trigger ouabain

if ouabain binds to glycoside binding globulin (in the blood, in the kidneys, heart) then sodium in blood cells increases (problem in pwMecfs). (if i misunderstood glycoside binding, please anyone correct)

eggerthella cgr2 was found to deactivate digoxin (a heart med, substitute for ouabain).
digoxin has no effect in ppl with eggerthella (estimated 40%) in the gut.

 

[Alvin]

It will likely take a decade or more to identify the specific microbes that make FMT effective, and learn how to isolate and grow them. In the meantime we could have been using FMT to cure thousands/millions of people.

Interestingly there is a Star Trek TNG episode that deals with exactly this appropriately called Ethics.
Real research takes time and resources and talent. But if you wish to take huge risks go ahead but you could end up far worse off permanently

What we should be doing is getting resources and talent working on the problem right away so that the time needed is reduced.

 

[MaximilianKohler]

But if you wish to take huge risks go ahead but you could end up far worse off permanently

The current evidence says FMT from high quality donors is safe. So classifying it as a "huge risk" is not evidence-based.

 

[Alvin]

The current evidence says FMT from high quality donors is safe. So classifying it as a "huge risk" is not evidence-based.

Your own link says

Current limitations and unknowns are extreme. There are a plethora of microbes which are either unknown and/or not tested for currently.

This recent study for example, showing one bacterial strain inducing liver damage (2018): http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198262 - That kind of thing is absolutely not tested for with either conventional or 16s commercial testing.

 

[MaximilianKohler]

True. That is in regards to testing. We can and should determine donor quality through other means, such as a detailed questionnaire. True that adverse events are under reported, but so far the evidence says that FMT is safe if the donor is healthy. The issue comes in with finding someone in perfect health.

 

[adambeyoncelowe]

And we all know the problems of 'detailed questionnaires'.

 

[MaximilianKohler]

And we all know the problems of 'detailed questionnaires'.

Sure. A questionnaire is absolutely not fool proof and shouldn't be used as a sole determination of donor quality or safety.

 

[Sly Saint]

finding someone in perfect health

maybe you should try finding some 7th Day adventists?
https://theplaidzebra.com/why-seventh-day-adventists-live-longer-than-any-other-group-in-america/

 

[Alvin]

The issue comes in with finding someone in perfect health.

Good luck