Why do some people have permanent effects and others don’t? Donor quality vs matching. Outcomes 

IsthmusSIBO

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So, after having seen outcomes here and on the HM spreadsheet, I still am unable to see a clear pattern that can explain why some people take FMT better and others don’t.

Some, like @Michael Harrop, believe its a combination from donor quality and colonization resistance from recipients (which could be caused by other proposed factors like inmune system, lack of nutrients, diet etc.).

Yet, when addressing donor quality, some people take FMT better even without needing to do things like enemas or biofilm busting beforehand, regardless of level of illness.

I thought it could be that sicker people are the ones with most colonization resistance, but so far, the HM spreadsheets show that the healthiest also have lots of resistance (with them having the least benefits AND risks).

Yet, someone with microscopic colitis and other things alleged that they retain FMT effects permanently, better than most in the spreadsheet (FL-RS-1997). This wasn’t universal and others with IBD didn’t permanently take their donor, but they also had significant improvements.

So, I wonder if the main next step after donor quality shouldn’t be microbiome clearing, but donor matching?
 
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It matters what microbes are in the recipient's gut and the donor's stool, and their exact problem. Some people's problems are easier to resolve than others, and we're far from being able to determine the exact reason. Donor-recipient matching is a factor, just not as important as donor quality in my opinion.

I compared it here to a jigsaw puzzle: https://archive.fo/2JChJ#selection-2291.10-2291.11

For donor quality, you'd be looking for a donor with the complete puzzle.

For donor matching you'd need to figure out which pieces the recipient is missing, and which the donor has and is able to transfer to the recipient. If you see this wiki section you can see how far we are from being able to do such a thing with microbes: https://humanmicrobiome.info/testing/

To expound on this, donor matching, and other customization/individualization, only comes into play once we've first met requirements/standards for a high quality donor. Donors with an unperturbed, disease-resistant, eubiotic gut microbiome. I've outlined these criteria, and no one yet has met them. Thus, so far it seems that we have only been using low quality donors who all have dysbiotic gut microbiomes themselves, and thus it's completely irrational to expect the current donors to be able to cure the dysbiosis of others.
 
Donor-recipient matching is a factor, just not as important as donor quality in my opinion.
Yeah, I don’t know Michael, but I don’t think it will ever be feasible to find super donors you want anymore with how the world is going. Donor matching though…

By the time research and testing finally catches up with mapping a person’s entire microbiome down to strains and individual microbes count (decades or centuries), there will no longer be any high quality donors left. Donor-recipient matching may be more feasible though.

I am not suggesting donor quality is not important, but that it’s role for an effective treatment is more responsible for safety, while donor matching is better for efficacy. For example, you swear by the fact that donors 1 [a teen highschool athlete taking weed, having cramps and drinking RO water (this last is a good thing)] and 4 (which had variable stool like donor 11) are somehow better donors than donor 11, a full on professional track-and-field athlete with variable stool. But that is only because you believe that for your case.

Yes, all the prior three donors are definitely high quality, but considering how people responded to 11, I am sure someone else with a different situation wouldn’t have benefited from 1 and 4 as much as you. In other words, 1 and 4 weren’t effective because they were superdonors, they just were better for you. Hell, I may even as bold to say that 1 and 4 were that effective because they were your first high quality donors, and your dysbiosis wasn’t as bad (pathogens from bad donors, nutritional deficiencies from food intolerances and possible biofilms are making it more inhospitable for FMTs to be retained, at least in your specific case).

I have read your sources and I just think that donor quality, while important overall, its just not feasible now nor ever en masse.

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One thing to add, which is a personal opinion, is that an universal “hyper” donor, while possibly living in our current population, is probably a n=1. It functionally doesn’t exist and is hypothetical. Not only that, but the microbiome is so sensitive to so many factors, that they are not bound to be hyper donors for long.

Yeah yeah, Anna Karenina hypothesis. But if we REALLY get picky, even donors 1 and 4, a “happy family”, have their own type of dysbiosis.

The many genetic populations bottlenecks from pandemics, natural disasters and wars have made it harder to find that one guy/girl. Not even billionaires (maybe because of hyperfocus on pharmaceutical approaches) with all their money (and the more morally bankrupt with their human trafficking) have clearly found that person, as it will be obvious if someone like Musk or Trump found an FMT hyperdonor by their health improvements.

So, I know it’s not optimistic, but this is just my argument to say that the fabled search for the super donor is as pointless as the search for the Holy Grail… Nobody alive has or will ever have the complete donor quality puzzle.

The people you have found is as good as it will ever get, Michael. Unless a celebrity or a famous Olympian finds this forum, soaks it up, and asks pals to be donors.
 
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I am not suggesting donor quality is not important, but that it’s role for an effective treatment is more responsible for safety, while donor matching is better for efficacy.
I don't agree. I've said elsewhere that non-super-donors all seem to be missing something similar, which is vital for efficacy. Some people are able to mostly resolve their worst symptoms without it, but even many of the people who claim to be "cured" aren't really; they're just "mostly able-bodied".

But that is only because you believe that for your case.
No, I take all evidence into account. Including one recipient who had done FMTs from more people than me at one point, including the Hadza, and he agreed with my hypothesis.

Yes, all the prior three donors are definitely high quality, but considering how people responded to 11, I am sure someone else with a different situation wouldn’t have benefited from 1 and 4 as much as you. In other words, 1 and 4 weren’t effective because they were superdonors, they just were better for you. Hell, I may even as bold to say that 1 and 4 were that effective because they were your first high quality donors, and your dysbiosis wasn’t as bad
No. This is a conclusion arrived at due to missing pieces of info. Most of the info is public, so I won't elaborate.

I have read your sources and I just think that donor quality, while important overall, its just not feasible now nor ever en masse.
Then you'll have to wait for AI to completely decode the human gut microbiome and create the missing pieces. 20 years? 40? More?

Not even billionaires (maybe because of hyperfocus on pharmaceutical approaches) with all their money (and the more morally bankrupt with their human trafficking) have clearly found that person
They're not trying. They're as ignorant as most people.

So, I know it’s not optimistic, but this is just my argument to say that the fabled search for the super donor is as pointless as the search for the Holy Grail… Nobody alive has or will ever have the complete donor quality puzzle.
This is silly. I've already found multiple donors good enough for a near-complete cure, and I still have access to all the 1.5 million+ donors who've applied, and I'm still screening and using more.

If I had help instead of being hindered every step of the way, it would be possible to end the chronic disease crisis within a few years. I won't say more than that, for previously stated reasons.
 
This is silly. I've already found multiple donors good enough for a near-complete cure, and I still have access to all the 1.5 million+ donors who've applied, and I'm still screening and using more.
If you have found multiple donors good enough for a near-complete cure, then I'd gather that you're nearly completely cured? If so, why are you still looking for more donors? Are you looking to go from "nearly completely" cured to "completely" cured? Or are you accepting that the donors who you claim are good enough to cure you may not cure everyone, and are still looking for donors who might cure everyone?

No. This is a conclusion arrived at due to missing pieces of info. Most of the info is public, so I won't elaborate.

Ok, so if most info is public, could you arrange the data (graphs, tables, etc.) in such a way so as to justify to someone that you were on the way to eventually finding a super-donor at the point in time at which you stopped sharing data?

What I mean is something like this:

--Take all HM donors tried by at least 5 recipients, from the date that HM started operating to the date at which it was shut down.
--Calculate the average recipient rating (out of 10) across all recipients for each of these donors, and note the year in which this donor passed the interview/stool screening process (or month if you can get that specific).
--From this you are able to calculate/plot, for each year, the average rating of the best donor who joined HM thus far (either in that year or a previous year).
--Together with the approximate number of prospective donors per year, this should allow you to calculate how many prospective donors needed to be screened as a function of the best donor found. In other words, how many donors needed to be screened to find at least one who averaged above 5/10, how many to find one who averaged above 6/10, etc.
--One we agree on how to define a "universal super-donor", say for example someone with an average rating of 9/10 or more, a bit of statistics should allow someone to extrapolate the trend from the previous step to determine the expected number of prospective donors needing to be screened to find such a super-donor. Is this less than the population of the developed world? Does it fit within the 1.5 million-ish donors you've screened already? If not, is there a publicly disclosable change to your method of search since HM closed that could justify doing better than this expectation?

I would have done the above myself, but the earliest copy of the results spreadsheet that I have downloaded and saved is from 2024 when I first ordered from HM. That was after (if I recall, actually quite soon after) the sheet was cleaned up to remove results from donors prior to UT-AW and FL-RS who were no longer active. CozyFire was in there but he only shipped to NZ, which could skew things, and also BuddingBear but we all agree he was a bad donor who in no way surpassed these others. I also don't know if those were interviewed before or after UT-AW and FL-RS.

As far as I know, the only "evidence" you have presented in favor of the fact that you might have been approaching a super-donor (aside from the non-public N=1 results) is the fact that there were higher-ranked donors than the ones people had already used at the time that HM was shut down. But what did you do if anything to validate this ranking?

The recently published study regarding super-donors in the IBS trial (https://forum.humanmicrobiome.info/threads/a-simulation-of-2-548-gut-transplants-identified-two-super-donors-with.1456/) did leave-one-out cross-validation of their metabolic metric. Keep in mind that in order to even be validatable, a ranking needs to either be "objective" (based on a publicly-disclosed formula, such that anyone given, e.g. the interview answers and the Bristol stool numbers of each interviewee's stools could arrive at the same or very close to the same ranking), or else prospective rather than retrospective, i.e. the ranking would need to be "frozen" before the donors are actually tried by the recipients by giving a public copy to someone else for safekeeping and then the results compared to the ranks later.

Without such statistical support, all we have to go on is that ~1 million applicants in, the best donor so far, who seemed to have been the best for quite some time, was definitely NOT a universal super-donor. And from such a fact, IsthmusSIBO's deduction about it being like the holy grail is far from "silly".

Think about it like this--if you are seeking funding for FMT experiments, you need to imagine you're trying to convince someone who isn't biased against your hypotheses about stool type and consistency and such, but also isn't coming into the game being biased toward them.
 
why are you still looking for more donors?
People have been applying all on their own for years. They keep applying, and I keep screening them. There's only more to gain from having access to more good donors.

Regarding the rest of what you said:

1. You're talking about something different.
2. Why should I? What benefit is there for me in doing that?

if you are seeking funding for FMT experiments
imagine you're trying to convince someone
I'm not.
 
I would argue donor matching to be impossible due to the complexities surrounding the whole thing. It would be more practical to focus on quality and consistency.
 
I would argue donor matching to be impossible due to the complexities surrounding the whole thing. It would be more practical to focus on quality and consistency.
I mostly agree with that. Donor quality is already mostly solved. Donor matching will take many years to solve, and it doesn't negate donor quality.
 
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