Donor quality and stool type hypothesis for FMT (Fecal Microbiota Transplant)

Michael Harrop

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I've discussed and listed this sporadically in various places, including the wiki, so I'm compiling it all here.

Also relevant is my FMT roadmap proposal (2019).

Intro:​

Most clinical trials, and other sources of stool/stool donors, have been operating on the notion that they can find "generally healthy" people, screen them for a handful of well-known pathogens, and nothing more needs to be considered. To me, that is obviously ridiculous and ignores a plethora of vital donor-quality considerations, including stool type.

During my extensive personal experiences with numerous FMT donors, I identified stool type as a vital donor-quality characteristic. And I wrote to hundreds of researchers to inform them and urge them to consider it for their studies.

Info like this helps explain why donor quality is so important and so rare:
While antibiotic resistance gets all the attention, the damage being done to our host-native microbiomes is arguably as big a threat as climate change, as the damage compounds over generations, and once it's gone you can't get it back. (Apr 2019)

Usual talking points are things like "We reject 90% and put them through extensive testing". Cool. That's completely inadequate. Anyone pushing that line is either ignorant themselves or is depending on you being ignorant. Current testing can in no way determine safety or efficacy. "We only accept 3%". Still inadequate. 0.4%, still inadequate. "After donation we'll discard the stools that are not type 3 or 4". Inadequate - and not just because of the 4.

Regarding testing, most providers seem to be over-relying on testing in an erroneous attempt to make up for general donor-quality deficiencies. One example of [many more] testing limitations is that a patient who used Openbiome and experienced adverse effects (and saw new pathogens via before-and-after GI MAP test) discovered that Openbiome is unable to use PCR to check donor stool due to the glycerol content they add to the stool.

Anna Karenina hypothesis and stool type:​

A Grand Unified Theory of Unhealthy Microbiomes. The Anna Karenina hypothesis says that every unbalanced microbiome is unbalanced in its own way. “All happy families are alike; each unhappy family is unhappy in its own way.” https://www.theatlantic.com/science/archive/2017/08/a-grand-unified-theory-of-unhealthy-microbiomes/537945/

This hypothesis matches my extensive experiences with numerous FMT donors. Low-quality donors have very heterogeneous stools, and the stools of the best donors were identical. And since that article was published, I've seen more evidence (some listed below) to support my stool-type & donor-quality hypothesis.

Paper on it:
Stress and stability: applying the Anna Karenina principle to animal microbiomes https://www.nature.com/articles/nmicrobiol2017121

Soft stool = lack of microbes?​

I was asked "What are you basing your assessment of soft stool = lack of microbes off of?"

Answer:
Antibiotics cause it, unmetabolized bile acids cause it (which is typically due to missing microbes required for bile acid metabolism), if a pathogen is causing it that's often due to missing-microbes not suppressing that pathogen, both "perfect" donors I used (and every highly successful DIY report I've seen that mentions stool type) had identical firm stools, and various studies support it:

Firmness or longer transit time was associated with greater diversity (2016): https://www.gutmicrobiotaforhealth.com/new-insights-colonic-transit-time-relate-health/ - https://www.nature.com/articles/nmicrobiol201693.

Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates (2015): https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717365/ "Species richness declines with looser stools"

"correlation between stool consistency and microbial loads – with loose stool containing less bacteria than their firm counterparts in healthy controls" (Feb 2019) https://www.tandfonline.com/doi/full/10.1080/17843286.2019.1583782

Distal colonic transit is linked to gut microbiota diversity and microbial fermentation in humans with slow colonic transit (Feb 2020) https://journals.physiology.org/doi/full/10.1152/ajpgi.00283.2019

More frequent bowel movements = lower diversity (2020) https://www.nature.com/articles/s41467-020-18871-1/figures/3

One conflicting data point is that someone who went to the Hadza (they have some of the highest diversity in the world) to do FMT from them said their stool is softer than type 4 and not the color I think is optimal. They said they still agree with my hypothesis and suggested that the Hadza stool color & softness are due to the pathogens they carry.

Donor matching vs donor quality:​

I think most of the evidence backs donor quality rather than donor matching. I shared some relevant links below, and there's more in the wiki.

Donor matching, and other customization/individualization, should mostly only come into play once we've first met the 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.

For a simplified (very likely oversimplified) view, think of it as a jigsaw puzzle. 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 review the testing section of the wiki, you can see how far we are from being able to do such a thing with microbes.

Relevant links/discussion:​

This link is one of the main explanatory ones: Another email I've been sending to researchers regarding donor quality (Nov 2018).

Another letter to the NIH (and FDA). Cancer patients as FMT donors. If you care about the future of FMT please consider also writing to them. (Mar 2019).
 
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Studies testing or supporting my stool-type hypothesis:​


Microbial determinants of effective donors in faecal microbiota transplantation for UC (Jul 2022) Donor microbiota stability and species evenness were identified as novel metrics that were associated with therapeutic efficacy in UC, beyond individual microbial species or metabolites https://gut.bmj.com/content/early/2022/07/25/gutjnl-2022-327742

Objective Faecal microbiota transplantation (FMT) has variable efficacy in treating UC. Recently, oral lyophilised FMT was found to induce remission in patients with UC, with one donor having 100% efficacy compared with a second donor (36% efficacy). We characterised differences in the gut microbiota of these two donors with the aim of improving FMT donor selection.

Design Faecal samples from the two donors were collected over a period of 44 (donor 1) or 70 (donor 2) weeks. The microbiome and metabolome were profiled using shotgun metagenomics and untargeted metabolomics
 
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